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Sample records for cisplatin-induced ototoxicity effect

  1. The protective effects of whortleberry extract against cisplatin-induced ototoxicity in rats.

    Science.gov (United States)

    Özdemir, Doğukan; Özgür, Abdulkadir; Kalkan, Yıldıray; Terzi, Suat; Tümkaya, Levent; Yılmaz, Adnan; Çeliker, Metin; Dursun, Engin

    2017-11-10

    Cisplatin is one of the main chemotherapeutic agents used for the treatment of many types of cancer. However, ototoxicity, one of the most serious side effects of cisplatin, restricts its usage. We aimed to investigate the protective effects of whortleberry extract against cisplatin-induced ototoxicity by evaluating hearing and histopathological cochlear damage and by measuring the biochemical parameters affected byoxidative stress. Forty-eight male rats were included in the study after performing Distortion Product Otoacoustic Emission test to confirm that their hearing levels were normal. The rats were randomly divided into six groups: the control group, the sham group, and, which received only whortleberry extract, only cisplatin, cisplatin+100mg whortleberry extract, cisplatin+200mg whortleberry extract, respectively. Audiologic investigation was performed by performing the Distortion Product Otoacoustic Emission test at the beginning and at the eighth day of the study. Cardiac blood samples were collected for biochemical analysis, and the rats were sacrificed to obtain cochlear histopathological specimens on the eighth day. The results revealed that whortleberry protects hearing against cisplatin-induced ototoxicity independent of the dose. However, high doses of whortleberry extract are needed to prevent histopathological degeneration and oxidative stress. The results obtained in this study show that whortleberry extract has a protective effect against cisplatin-induced ototoxicity. Copyright © 2017 Associação Brasileira de Otorrinolaringologia e Cirurgia Cérvico-Facial. Published by Elsevier Editora Ltda. All rights reserved.

  2. Association Between SLC16A5 Genetic Variation and Cisplatin-Induced Ototoxic Effects in Adult Patients With Testicular Cancer.

    Science.gov (United States)

    Drögemöller, Britt I; Monzon, Jose G; Bhavsar, Amit P; Borrie, Adrienne E; Brooks, Beth; Wright, Galen E B; Liu, Geoffrey; Renouf, Daniel J; Kollmannsberger, Christian K; Bedard, Philippe L; Aminkeng, Folefac; Amstutz, Ursula; Hildebrand, Claudette A; Gunaretnam, Erandika P; Critchley, Carol; Chen, Zhuo; Brunham, Liam R; Hayden, Michael R; Ross, Colin J D; Gelmon, Karen A; Carleton, Bruce C

    2017-11-01

    Cisplatin-induced ototoxic effects are an important complication that affects testicular cancer survivors as a consequence of treatment. The identification of genetic variants associated with this adverse drug reaction will further our mechanistic understanding of its development and potentially lead to strategies to prevent ototoxic effects. To identify the genetic variants associated with cisplatin-induced ototoxic effects in adult testicular cancer patients. This retrospective study was performed by the Canadian Pharmacogenomics Network for Drug Safety using patients recruited from 5 adult oncology treatment centers across Canada. Male patients who were 17 years or older, diagnosed with germ cell testicular cancer, and previously treated with cisplatin-based chemotherapy were recruited from July 2009 to April 2013 using active surveillance methodology. Cisplatin-induced ototoxic effects were independently diagnosed by 2 audiologists. Patients were genotyped for 7907 variants using a custom pharmacogenomic array. Logistic regression was used to identify genetic variants that were significantly associated with ototoxic effects. The validity of these findings was confirmed through independent replication and cell-based functional assays. Cisplatin-based chemotherapy. Cisplatin-induced ototoxic effects. After exclusions, 188 patients (median [interquartile range] age, 31 [24-39] years) were enrolled in this study to form the discovery and replication cohorts. Association and fine-mapping analyses identified a protein-coding variant, rs4788863 in SLC16A5, that was associated with protection against cisplatin-induced ototoxic effects in 2 independent cohorts (combined cohort: odds ratio, 0.06; 95% CI, 0.02-0.22; P = 2.17 × 10-7). Functional validation of this transporter gene revealed that in vitro SLC16A5-silencing altered cellular responses to cisplatin treatment, supporting a role for SLC16A5 in the development of cisplatin-induced ototoxic effects. These

  3. In vitro and in vivo effects of lutein against cisplatin-induced ototoxicity.

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    Roldán-Fidalgo, A; Martín Saldaña, S; Trinidad, A; Olmedilla-Alonso, B; Rodríguez-Valiente, A; García-Berrocal, J R; Ramírez-Camacho, R

    2016-04-01

    Cisplatin is a commonly prescribed drug that produces ototoxicity as a side effect. Lutein is a carotenoid with antioxidant and anti-inflammatory properties previously tested for eye, heart and skin diseases but not evaluated to date in ear diseases. To evaluate the protective effects of lutein on HEI-OC1 auditory cell line and in a Wistar rat model of cisplatin ototoxicity. In vitro study: Culture HEI-OC1 cells were exposed to lutein (2.5-100 μM) and to 25 μM cisplatin for 24h. In vivo study: Twenty eight female Wistar rats were randomized into three groups. Group A (n=8) received intratympanic lutein (0.03 mL) (1mg/mL) in the right ear and saline solution in the left one to determine the toxicity of lutein. Group B (n=8) received also intraperitoneal cisplatin (10mg/kg) to test the efficacy of lutein against cisplatin ototoxicity. Group C (n=12) received intratympanic lutein (0.03 mL) (1mg/mL) to quantify lutein in cochlear fluids (30 min, 1h and 5 days after treatment). Hearing function was evaluated by means of Auditory Steady-State Responses before the procedure and 5 days after (groups A and B). Morphological changes were studied by confocal laser scanning microscopy. In vitro study: Lutein significantly reduced the cisplatin-induced cytotoxicity in the HEI-OC1 cells when they were pre-treated with lutein concentrations of 60 and 80 μM. In vivo study: Intratympanic lutein (1mg/mL) application showed no ototoxic effects. However it did not achieve protective effect against cisplatin-induced ototoxicity in Wistar rats. Although lutein has shown beneficial effects in other pathologies, the present study only obtained protection against cisplatin ototoxicity in culture cells, but not in the in vivo model. The large molecule size, the low dose administered, and restriction to diffusion in the inner ear could account for this negative result. Copyright © 2016 Elsevier GmbH. All rights reserved.

  4. Protective effect of Pycnogenol on cisplatin-induced ototoxicity in rats.

    Science.gov (United States)

    Eryilmaz, Aylin; Eliyatkin, Nuket; Demirci, Buket; Basal, Yesim; Kurt Omurlu, Imran; Gunel, Ceren; Aktas, Safiye; Toka, Ali; Basak, Sema

    2016-11-01

    Pycnogenol®, which is French maritime pine bark extract, is a potent antioxidant. It is used in medical conditions caused by oxidative stress. Cisplatin (cis-diamminedichloroplatinum II) is an antineoplastic agent. However, its serious side effects such as ototoxicity limit its usage. Antioxidants can be used to prevent ototoxicity. We investigated the effect of Pycnogenol® on cisplatin-induced ototoxicity. Rats were randomly assigned to four groups of five. Distortion product-evoked otoacoustic emissions (DPOAE) test was performed for each rat. The experimental groups were as follows: Control Group, Pycnogenol® Group: 10 mg/kg Pycnogenol® intraperitoneally for 7 days, Cisplatin Group: intraperitoneally 15 mg/kg single injection of cisplatin on the fifth day, Cisplatin + Pycnogenol® Group: intraperitoneally 10 mg/kg Pycnogenol® treatment for 7 days, additionally on the fifth day, 15 mg/kg single injection of cisplatin was given. On the eighth day, DPOAE was re-performed and rats were sacrificed. Apoptosis was evaluated histopathologically. Mean percentage of apoptotic cells was 1.5, 3, 30 and 11% in organ of Corti and 2, 2, 40, 15% in spiral ganglion neurons in Control Group, Pycnogenol® Group, Cisplatin Group and Cisplatin + Pycnogenol® Group, respectively. Cisplatin Group and Cisplatin + Pycnogenol® Group were significantly different when compared to Control Group histopathologically both in organ of Corti and spiral ganglion neuron (p Pycnogenol® Group was significantly different when compared to Cisplatin Group at 3, 6 and 8 kHz (p Pycnogenol protected against cisplatin ototoxicity. Also, pycnogenol is not ototoxic.

  5. Effects of ozone (O3) therapy on cisplatin-induced ototoxicity in rats.

    Science.gov (United States)

    Koçak, Hasan Emre; Taşkın, Ümit; Aydın, Salih; Oktay, Mehmet Faruk; Altınay, Serdar; Çelik, Duygu Sultan; Yücebaş, Kadir; Altaş, Bengül

    2016-12-01

    The aim of this study is to investigate the effect of rectal ozone and intratympanic ozone therapy on cisplatin-induced ototoxicity in rats. Eighteen female Wistar albino rats were included in our study. External auditory canal and tympanic membrane examinations were normal in all rats. The rats were randomly divided into three groups. Initially, all the rats were tested with distortion product otoacoustic emissions (DPOAE), and emissions were measured normally. All rats were injected with 5-mg/kg/day cisplatin for 3 days intraperitoneally. Ototoxicy had developed in all rats, as confirmed with DPOAE after 1 week. Rectal and intratympanic ozone therapy group was Group 1. No treatment was administered for the rats in Group 2 as the control group. The rats in Group 3 were treated with rectal ozone. All the rats were tested with DPOAE under general anesthesia, and all were sacrificed for pathological examination 1 week after ozone administration. Their cochleas were removed. The outer hair cell damage and stria vascularis damage were examined. In the statistical analysis conducted, a statistically significant difference between Group 1 and Group 2 was observed in all frequencies according to the DPOAE test. In addition, between Group 2 and Group 3, a statistically significant difference was observed in the DPOAE test. However, a statistically significant difference was not observed between Group 1 and Group 3 according to the DPOAE test. According to histopathological scoring, the outer hair cell damage score was statistically significantly high in Group 2 compared with Group 1. In addition, the outer hair cell damage score was also statistically significantly high in Group 2 compared with Group 3. Outer hair cell damage scores were low in Group 1 and Group 3, but there was no statistically significant difference between these groups. There was no statistically significant difference between the groups in terms of stria vascularis damage score examinations

  6. Monitoring cisplatin-induced ototoxicity.

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    Ana SÁNCHEZ-MARTÍNEZ

    2017-11-01

    Full Text Available Introduction and objective: The ototoxic damage goes unnoticed to disabling levels, being justified to apply control for its early detection procedures, make it possible to a therapeutic change and if necessary, a speech and auditory rehabilitation. The objective of this study will consist to present Protocol we did at the Hospital Clínico Universitario de Valladolid for the follow-up of the patients treated with cisplatin. Method: Ototoxicity monitoring means serially collect hearing thresholds. It is identified on a visit if hearing has worsened in some ear. The comparison allows to detect the change and indicate if it is significant or not in relation to some criteria. We will also evaluate the occurrence of vestibular damage. As auditory monitoring procedures, we will use high frequency audiometry and acoustic oto-emissions. Results: After giving informed consent and a brief medical history we started with baseline assessment of hearing, prior to treatment, continuing with periodic reviews before each cycle. If any change is detected it is reported to the physician and the patient. To grade the ototoxicity, we apply the Brock and Chang criteria. We maintain post-treatment control. Discussion and conclusion: The incidence of ototoxicity of cisplatin is unknown in our country and it is not possible to predict which patients will experience. The increase in the survival rate for cancer involves improving comorbidity, which in the case of its early ototoxicity supposed to find the best solutions to restore the quality of life of patient’s detection.

  7. Future opportunities in preventing cisplatin induced ototoxicity

    NARCIS (Netherlands)

    van den Berg, J. H.; Beijnen, J. H.; Balm, A. J. M.; Schellens, J. H. M.

    2006-01-01

    Cisplatin is one of the most commonly used cytotoxic agents. Ototoxicity is an important and dose-limiting side-effect of cisplatin therapy. It is believed that cisplatin suppresses the formation of endogenous anti-oxidants that normally prevent the inner ear against reactive oxygen species (ROS).

  8. The protective role of tetramethylpyrazine against cisplatin-induced ototoxicity.

    Science.gov (United States)

    Bayram, Ali; Kaya, Altan; Akay, Ebru; Hıra, İbrahim; Özcan, İbrahim

    2017-03-01

    The aim of the present study was to investigate the protective effect of tetramethylpyrazine (TMP) on cisplatin-induced ototoxicity in rats. Forty healthy, female, 24-week-old, Sprague-Dawley rats (n = 40) were randomly assigned to four groups as follows: group one (n = 10) received intraperitoneal (i.p.) physiological saline at daily doses of 3 mg/kg for seven days; group two (n = 10) received a single dose of i.p. 15 mg/kg cisplatin; group three (n = 10) received i.p. 140 mg/kg TMP daily for seven days plus a single dose of i.p. 15 mg/kg cisplatin on the fourth day; group four (n = 10) received i.p. 140 mg/kg TMP daily for seven days. Auditory brainstem response (ABR) and distortion product otoacoustic emission (DPOAE) measurements were obtained from the animals (40 rats, 80 ears) under general anesthesia before and after drug administration. The temporal bulla of animals were bilaterally removed for immunohistopathological examination. In group two, DPOAE and ABR values were significantly deteriorated after drug administration, whereas there was no statistically significant difference between the pre- and posttreatment DPOAE and ABR values for all frequencies for groups one, three and four. The mean scores for external ciliated cells (ECCs), stria vascularis (SV) and spiral ganglion (SG) injuries in hematoxylin and eosin (H&E) staining, and also caspase-3 immunoreactivity were significantly higher in group two than in the other groups. In the present study, the protective effect of TMP on cisplatin ototoxicity was demonstrated through studies of electrophysiology and immunohistopathology. Co-administration of TMP may have potential protective effects against cisplatin-induced ototoxicity. Copyright © 2017 Elsevier B.V. All rights reserved.

  9. Comparison of the Effectiveness of Monitoring Cisplatin-Induced Ototoxicity with Extended High-Frequency Pure-Tone Audiometry or Distortion-Product Otoacoustic Emission

    Science.gov (United States)

    Yu, Kwang Kyu; Choi, Chi Ho; An, Yong-Hwi; Kwak, Min Young; Gong, Soo Jung; Yoon, Sang Won

    2014-01-01

    Background and Objectives To compare the effectiveness of monitoring cisplatin-induced ototoxicity in adult patients using extended high-frequency pure-tone audiometry (EHF-PTA) or distortion-product otoacoustic emission (DP-OAE) and to evaluate the concurrence of ototoxicity and nephrotoxicity in cisplatin-treated patients. Subjects and Methods EHF-PTA was measured at frequencies of 0.25, 0.5, 1, 2, 3, 4, 6, 8, 9, 11.2, 12.5, 14, 16, 18, and 20 kHz and DP-OAE at frequencies of 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, and 8 kHz in cisplatin-treated patients (n=10). Baseline evaluations were made immediately before chemotherapy and additional tests were performed before each of six cycles of cisplatin treatment. Laboratory tests to monitor nephrotoxicity were included before every cycle of chemotherapy. Results Four of 10 patients showed threshold changes on EHF-PTA. Five of 10 patients showed reductions in DP-OAE, but one was a false-positive result. The results of EHF-PTA and DP-OAE were consistent in two patients. Only one patient displayed nephrotoxicity on laboratory tests after the third cycle. Conclusions In our study, the incidence rate of cisplatin-induced ototoxicity was 40% with EHF-PTA or DP-OAE. Although both EHF-PTA and DP-OAE showed the same sensitivity in detecting ototoxicity, they did not produce the same results in all patients. These two hearing tests could be used to complement one another. Clinicians should use both tests simultaneously in every cycle of chemotherapy to ensure the detection of ototoxicity. PMID:25279227

  10. Targeting nitrative stress for attenuating cisplatin-induced downregulation of cochlear LIM domain only 4 and ototoxicity

    Directory of Open Access Journals (Sweden)

    Samson Jamesdaniel

    2016-12-01

    Full Text Available Cisplatin-induced ototoxicity remains a primary dose-limiting adverse effect of this highly effective anticancer drug. The clinical utility of cisplatin could be enhanced if the signaling pathways that regulate the toxic side-effects are delineated. In previous studies, we reported cisplatin-induced nitration of cochlear proteins and provided the first evidence for nitration and downregulation of cochlear LIM domain only 4 (LMO4 in cisplatin ototoxicity. Here, we extend these findings to define the critical role of nitrative stress in cisplatin-induced downregulation of LMO4 and its consequent ototoxic effects in UBOC1 cell cultures derived from sensory epithelial cells of the inner ear and in CBA/J mice. Cisplatin treatment increased the levels of nitrotyrosine and active caspase 3 in UBOC1 cells, which was detected by immunocytochemical and flow cytometry analysis, respectively. The cisplatin-induced nitrative stress and apoptosis were attenuated by co-treatment with SRI110, a peroxynitrite decomposition catalyst (PNDC, which also attenuated the cisplatin-induced downregulation of LMO4 in a dose-dependent manner. Furthermore, transient overexpression of LMO4 in UBOC1 cells prevented cisplatin-induced cytotoxicity while repression of LMO4 exacerbated cisplatin-induced cell death, indicating a direct link between LMO4 protein levels and cisplatin ototoxicity. Finally, auditory brainstem responses (ABR recorded from CBA/J mice indicated that co-treatment with SRI110 mitigated cisplatin-induced hearing loss. Together, these results suggest that cisplatin-induced nitrative stress leads to a decrease in the levels of LMO4, downregulation of LMO4 is a critical determinant in cisplatin-induced ototoxicity, and targeting peroxynitrite could be a promising strategy for mitigating cisplatin-induced hearing loss.

  11. Mechanisms of Cisplatin-Induced Ototoxicity and Otoprotection

    Directory of Open Access Journals (Sweden)

    Sandeep Sheth

    2017-10-01

    Full Text Available Evidence of significant hearing loss during the early days of use of cisplatin as a chemotherapeutic agent in cancer patients has stimulated research into the causes and treatment of this side effect. It has generally been accepted that hearing loss is produced by excessive generation of reactive oxygen species (ROS in cell of the cochlea, which led to the development of various antioxidants as otoprotective agents. Later studies show that ROS could stimulate cochlear inflammation, suggesting the use of anti-inflammatory agents for treatment of hearing loss. In this respect, G-protein coupled receptors, such as adenosine A1 receptor and cannabinoid 2 receptors, have shown efficacy in the treatment of hearing loss in experimental animals by increasing ROS scavenging, suppressing ROS generation, or by decreasing inflammation. Inflammation could be triggered by activation of transient receptor potential vanilloid 1 (TRPV1 channels in the cochlea and possibly other TRP channels. Targeting TRPV1 for knockdown has also been shown to be a useful strategy for ensuring otoprotection. Cisplatin entry into cochlear hair cells is mediated by various transporters, inhibitors of which have been shown to be effective for treating hearing loss. Finally, cisplatin-induced DNA damage and activation of the apoptotic process could be targeted for cisplatin-induced hearing loss. This review focuses on recent development in our understanding of the mechanisms underlying cisplatin-induced hearing loss and provides examples of how drug therapies have been formulated based on these mechanisms.

  12. The impact of erdosteine on cisplatin-induced ototoxicity: a proteomics approach.

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    Waissbluth, Sofia; Garnier, Delphine; Akinpelu, Olubunmi V; Salehi, Pezhman; Daniel, Sam J

    2017-03-01

    Cisplatin is a commonly used chemotherapeutic agent and causes serious side effects, including progressive and irreversible hearing loss. No treatment is currently available for cisplatin-induced ototoxicity. We have previously demonstrated that erdosteine, a potent antioxidant, partially protected the cochlea against cisplatin toxicity in vivo. The aims of this study were to (1) evaluate the protein profiles of the cochlea following cisplatin administration and (2) evaluate the impact of erdosteine on the protein profile using a proteomics-based approach. Thirty Sprague-Dawley rats were injected intraperitoneally with saline (n = 10), cisplatin (n = 10) or with cisplatin and erdosteine (n = 10). The cisplatin dosage was 14 mg/kg and for erdosteine, 500 mg/kg. Following euthanasia, protein lysates were obtained from fresh-frozen cochleae and were processed for mass spectrometry and western blotting. We detected 445 proteins that exhibited a twofold change or greater in the cisplatin group as compared to the control group. Of these, 18 proteins showed a fourfold or greater change in expression associated with cisplatin administration, including ras-related protein Rab-2A, Rab-6A, cd81, ribosomal protein S5, and myelin basic protein, which were downregulated, while Ba1-647 and fibrinogen (alpha chain), amongst others, were upregulated. Co-administration of erdosteine revealed a reversal of these changes in the expression of ras-related protein Rab-2A, ribosomal protein S5, myelin basic protein, and fibrinogen (alpha chain); erdosteine also upregulated glutathione reductase. In this study, we identified various proteins that may play a role in cisplatin-induced ototoxicity. We also observed the changes resulting from co-treatment with an antioxidant.

  13. Peanut sprout extract attenuates cisplatin-induced ototoxicity by induction of the Akt/Nrf2-mediated redox pathway.

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    Youn, Cha Kyung; Jo, Eu-Ri; Sim, Ju-Hwan; Cho, Sung Il

    2017-01-01

    Cisplatin is commonly used to treat solid tumors. However, permanent hearing loss is a major side effect of cisplatin chemotherapy and often results in dose reduction of the cisplatin chemotherapy. Peanut sprouts show cytoprotective properties owing to their antioxidant activities. This study was designed to investigate the effect of peanut sprout extract (PSE) on cisplatin-induced ototoxicity in an auditory cell line, HEI-OC1 cells. Cells were exposed to cisplatin for 24 h, with or without pre-treatment with PSE, cell viability was examined using the MTT assay. Apoptotic cells were identified by double staining with Hoechst 33258 and propidium iodide. Western blot analysis was performed to examine apoptotic proteins including C-PARP and C-caspase, anti-apoptotic protein Bcl-2, and Nrf2 redox system activation. Mitochondrial reactive oxygen species (ROS) were investigated to examine whether PSE could scavenge cisplatin-induced ROS. Real-time PCR analyses were performed to investigate the mRNA levels of antioxidant enzymes including NQO1, HO-1, GPx2, Gclc, and catalase. The cisplatin-treated group showed reduced cell viability, increased apoptotic properties and markers, and increased ROS levels. PSE pre-treatment before cisplatin exposure significantly increased cell viability and reduced apoptotic properties and ROS production. These effects resulted from the up-regulation of antioxidant genes, including NQO1, HO-1, GPx2, Gclc, and catalase through Akt phosphorylation and Nrf2 activation. Our results demonstrate that PSE protects from cisplatin-induced cytotoxicity by activating the antioxidant effects via the Akt/Nrf-2 pathway in this auditory cell line, and indicate that PSE may provide novel treatment to prevent cisplatin-induced ototoxicity. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  14. The role of peroxiredoxin I in cisplatin-induced ototoxicity.

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    Le, Quang; Tabuchi, Keiji; Warabi, Eiji; Hara, Akira

    2017-04-01

    Peroxiredoxin (Prx) is a new family of antioxidative proteins. Prx I is ubiquitously expressed in various tissues and is important in the defense of tissues from increases in reactive oxygen species (ROS). The present study was designed to examine the expression of Prx subtypes in the mouse cochlea and to show the possible involvement of Prx I in protecting the cochlea against cisplatin ototoxicity. Postnatal-day-3-to-5 wildtype mice and Prx I-deficient mice were used. Prx expression in the cochlea was assessed by real-time PCR assay. Prx I protein expression was examined by immunofluorescence staining. Cochlear explants were exposed to 2, 5, and 10-μM cisplatin for 48h, and the cochlear hair cell losses of the wildtype and Prx I-deficient mice were compared. In addition, the histologic features of the cochlear lateral wall were examined after cisplatin incubation. mRNAs of all Prx subtypes were expressed in the mouse cochlea. Prx I was one of the abundant subtypes and was upregulated after 48-h exposure to 5-μM cisplatin. Immunofluorescence staining showed the ubiquitous expression of Prx I in the cochlea. No difference in cochlear hair cell loss induced by cisplatin was found between the wildtype mice and the Prx I-deficient mice. However, spiral ligament fibrocytes of Prx I-deficient mice were significantly sensitive to cisplatin at 20-μM or lower. Prx I is important for protection of at least the spiral ligament fibrocytes of the cochlear lateral wall in cisplatin ototoxicity. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  15. Mitochondria-Targeted Antioxidant Mitoquinone Reduces Cisplatin-Induced Ototoxicity in Guinea Pigs.

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    Tate, Alan D; Antonelli, Patrick J; Hannabass, Kyle R; Dirain, Carolyn O

    2017-03-01

    Objective To determine if mitoquinone (MitoQ) attenuates cisplatin-induced hearing loss in guinea pigs. Study Design Prospective and controlled animal study. Setting Academic, tertiary medical center. Subjects and Methods Guinea pigs were injected subcutaneously with either 5 mg/kg MitoQ (n = 9) or normal saline (control, n = 9) for 7 days and 1 hour before receiving a single dose of 10 mg/kg cisplatin. Auditory brainstem response thresholds were measured before MitoQ or saline administration and 3 to 4 days after cisplatin administration. Results Auditory brainstem response threshold shifts after cisplatin treatment were smaller by 28 to 47 dB in guinea pigs injected with MitoQ compared with those in the control group at all tested frequencies (4, 8, 16, and 24 kHz, P = .0002 to .04). Scanning electron microscopy of cochlear hair cells showed less outer hair cell loss and damage in the MitoQ group. Conclusion MitoQ reduced cisplatin-induced hearing loss in guinea pigs. MitoQ appears worthy of further investigation as a means of preventing cisplatin ototoxicity in humans.

  16. Chemopreventive effect of tadalafil in cisplatin-induced ...

    African Journals Online (AJOL)

    Summary: Nephrotoxicity remains a common untoward effect of cisplatin therapy with limited effective chemopreventive options available till date. This study aims to evaluate the possible chemopreventive effect and mechanism(s) of action of 2 mgkg-1 and 5 mgkg-1 of Tadalafil in cisplatin-induced nephrotoxic rats. In this ...

  17. Ototoxic Effects of Irradiation

    OpenAIRE

    Upadhya, I.; Jariwala, N.; Datar, J.

    2011-01-01

    In this study ototoxic effect of ionizing radiation was studied in 70 ears with minimum follow up of 6 months post radiotherapy. Patients of nasopharyngeal carcinoma and with conductive deafness pre radiotherapy were excluded from the study to eliminate mechanical obstruction that may play role in Eustachian tube dysfunction. We found that Eustachian tube dysfunction and conductive deafness were reversible where as Sensorineural hearing loss was an irreversible effect of radiotherapy. Dose of...

  18. COAST (Cisplatin ototoxicity attenuated by aspirin trial): A phase II double-blind, randomised controlled trial to establish if aspirin reduces cisplatin induced hearing-loss.

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    Crabb, Simon J; Martin, Karen; Abab, Julia; Ratcliffe, Ian; Thornton, Roger; Lineton, Ben; Ellis, Mary; Moody, Ronald; Stanton, Louise; Galanopoulou, Angeliki; Maishman, Tom; Geldart, Thomas; Bayne, Mike; Davies, Joe; Lamb, Carolynn; Popat, Sanjay; Joffe, Johnathan K; Nutting, Chris; Chester, John; Hartley, Andrew; Thomas, Gareth; Ottensmeier, Christian; Huddart, Robert; King, Emma

    2017-12-01

    Cisplatin is one of the most ototoxic chemotherapy drugs, resulting in a permanent and irreversible hearing loss in up to 50% of patients. Cisplatin and gentamicin are thought to damage hearing through a common mechanism, involving reactive oxygen species in the inner ear. Aspirin has been shown to minimise gentamicin-induced ototoxicity. We, therefore, tested the hypothesis that aspirin could also reduce ototoxicity from cisplatin-based chemotherapy. A total of 94 patients receiving cisplatin-based chemotherapy for multiple cancer types were recruited into a phase II, double-blind, placebo-controlled trial and randomised in a ratio of 1:1 to receive aspirin 975 mg tid and omeprazole 20 mg od, or matched placebos from the day before, to 2 days after, their cisplatin dose(s), for each treatment cycle. Patients underwent pure tone audiometry before and at 7 and 90 days after their final cisplatin dose. The primary end-point was combined hearing loss (cHL), the summed hearing loss at 6 kHz and 8 kHz, in both ears. Although aspirin was well tolerated, it did not protect hearing in patients receiving cisplatin (p-value = 0.233, 20% one-sided level of significance). In the aspirin arm, patients demonstrated mean cHL of 49 dB (standard deviation [SD] 61.41) following cisplatin compared with placebo patients who demonstrated mean cHL of 36 dB (SD 50.85). Women had greater average hearing loss than men, and patients treated for head and neck malignancy experienced the greatest cHL. Aspirin did not protect from cisplatin-related ototoxicity. Cisplatin and gentamicin may therefore have distinct ototoxic mechanisms, or cisplatin-induced ototoxicity may be refractory to the aspirin regimen used here. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

  19. The effect of caffeine on cisplatin-induced apoptosis of lung cancer cells

    National Research Council Canada - National Science Library

    Wang, Gan; Bhoopalan, Vanitha; Wang, David; Wang, Le; Xu, Xiaoxin

    2015-01-01

    .... The effect of caffeine on cisplatin-based cancer treatment is not well known. Caspase-3 activation and cell growth inhibition assays were used to determine the effect of caffeine on cisplatin-induced apoptosis and cell growth in lung cancer cells...

  20. Effect of Eisenia foetida Extract against Cisplatin-Induced Kidney Injury in Rats.

    Science.gov (United States)

    Jamshidzadeh, Akram; Heidari, Reza; Golzar, Tahereh; Derakhshanfar, Amin

    2016-01-01

    Kidney injury is a deleterious side effect accompanied by therapeutic uses of cisplatin as an antineoplastic agent. However, no therapeutic option is available against this complication. This study was designed to evaluate the protective role of a glycoprotein extract obtained from Eisenia foetida against cisplatin-induced nephrotoxicity. Rats were treated with cisplatin (7.5 mg/kg, intraperitoneally, i.p.) and Eisenia foetida extract (300 and 500 mg/kg, i.p. and/or oral). Serum creatinine (Cr) and blood urea nitrogen (BUN) were significantly elevated in cisplatin-treated rats. A significant amount of lipid peroxidation was detected in drug-treated animals. Furthermore, kidney histopathological findings revealed acute tubular necrosis and hyaline cast formation caused by cisplatin. Eisenia foetida extract administration (300 and 500 mg/kg, i.p.) significantly reduced serum BUN and creatinine and lipid peroxidation in kidney tissue. Moreover, cisplatin-induced histopathological lesions were alleviated by Eisenia foetida extract. This investigation concluded that Eisenia foetida extract ameliorated cisplatin-induced nephrotoxicity. This protection might be mediated by preventing cisplatin-induced oxidative stress.

  1. Beneficial Effects of Myo-Inositol Oxygenase Deficiency in Cisplatin-Induced AKI.

    Science.gov (United States)

    Dutta, Rajesh K; Kondeti, Vinay K; Sharma, Isha; Chandel, Navdeep S; Quaggin, Susan E; Kanwar, Yashpal S

    2017-05-01

    Overexpression of the proximal tubular enzyme myo-inositol oxygenase (MIOX) induces oxidant stress in vitro However, the relevance of MIOX to tubular pathobiology remains enigmatic. To investigate the role of MIOX in cisplatin-induced tubular AKI, we generated conditional MIOX-overexpressing transgenic (MIOX-TG) mice and MIOX-knockout (MIOX-/-) mice with tubule-specific MIOX overexpression or knockout, respectively. Compared with cisplatin-treated wild-type (WT) mice, cisplatin-treated MIOX-TG mice had even greater increases in urea, creatinine, and KIM-1 levels and more tubular injury and apoptosis, but these effects were attenuated in cisplatin-treated MIOX-/- mice. Similarly, MIOX-TG mice had the highest and MIOX-/- mice had the lowest renal levels of Bax, cleaved caspase-3, and NADPH oxidase-4 expression and reactive oxygen species (ROS) generation after cisplatin treatment. In vitro, cisplatin dose-dependently increased ROS generation in LLC-PK1 cells. Furthermore, MIOX overexpression in these cells accentuated cisplatin-induced ROS generation and perturbations in the ratio of GSH to oxidized GSH, whereas MIOX-siRNA or N-acetyl cysteine treatment attenuated these effects. Additionally, the cisplatin-induced enhancement of p53 activation, NF-κB binding to DNA, and NF-κB nuclear translocation in WT mice was exacerbated in MIOX-TG mice but absent in MIOX-/- mice. In vitro, MIOX-siRNA or NAC treatment reduced the dose-dependent increase in p53 expression induced by cisplatin. We also observed a remarkable influx of inflammatory cells and upregulation of cytokines in kidneys of cisplatin-treated MIOX-TG mice. Finally, analysis of genomic DNA in WT mice revealed cisplatin-induced hypomethylation of the MIOX promoter. These data suggest that MIOX overexpression exacerbates, whereas MIOX gene disruption protects against, cisplatin-induced AKI. Copyright © 2017 by the American Society of Nephrology.

  2. Protective effects of 6-hydroxy-1-methylindole-3-acetonitrile on cisplatin-induced oxidative nephrotoxicity via Nrf2 inactivation.

    Science.gov (United States)

    Moon, Ji Hee; Shin, Ji-Sun; Kim, Jong-Bin; Baek, Nam-In; Cho, Young-Wuk; Lee, Yong Sup; Kay, Hee Yeon; Kim, Soo-dong; Lee, Kyung-Tae

    2013-12-01

    We previously demonstrated the ethanol extract of the roots of Brassica rapa protects against cisplatin-induced nephrotoxicity by attenuating oxidative stress. Here, we investigated the nephroprotective effects of 6-hydroxy-1-methylindole-3-acetonitrile (6-HMA), which was isolated from the roots of B. rapa, on cisplatin-induced toxicity in renal epithelial LLC-PK1 cells and in rats with acute renal injury. Pretreatment of LLC-PK1 cells with 6-HMA ameliorated cisplatin-induced cytotoxicity caused by oxidative stress, as was demonstrated by reductions in the levels of reactive oxygen species (ROS) and malondialdehyde (MDA) and increased levels of glutathione (GSH). In addition, 6-HMA inhibited cisplatin-induced heme oxygenase-1 (HO-1) expression, possibly due to the suppression of the nuclear translocation and binding activity of NF-E2-related factor 2 (Nrf2). Furthermore, 6-HMA administered rats showed lower levels of blood urea nitrogen (BUN), creatinine, and urinary lactate dehydrogenase (LDH) than cisplatin alone-treated rats in cisplatin-induced renal injury model. Moreover, 6-HMA inhibited the cisplatin-induced formation of MDA and GSH depletion and increased the activities of superoxide dismutase (SOD), catalase (CAT), and glutathione reductase (GR). Taken together, these findings indicate 6-HMA is a major active constituent from the roots of B. rapa to have a protective effect against cisplatin-induced nephrotoxicity by attenuating oxidative stress. Copyright © 2013 Elsevier Ltd. All rights reserved.

  3. Nephroprotective effect of electrolyzed reduced water against cisplatin-induced kidney toxicity and oxidative damage in mice

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    Tse-Chou Cheng

    2018-02-01

    Conclusion: ERW exhibits potent nephroprotective effects on cisplatin-induced kidney damage in mice, likely due to both the increase in antioxidant-defense system activity and the inhibition of lipid peroxidation.

  4. Protective effects of pine bark extract against cisplatin-induced hepatotoxicity and oxidative stress in rats

    Science.gov (United States)

    Ko, Je-Won; Lee, In-Chul; Park, Sung-Hyuk; Moon, Changjong; Kang, Seong-Soo; Kim, Sung-Ho

    2014-01-01

    We investigated the protective effects of pine bark extract (pycnogenol®, PYC) against cisplatin-induced hepatotoxicity and oxidative stress in rats. Twenty-four male rats were divided into the following four groups: (1) vehicle control, (2) cisplatin (7.5 mg/kg), (3) cisplatin & PYC 10 (10 mg/kg/day), and (4) cisplatin & PYC 20 (20 mg/kg/day). A single intraperitoneal injection of cisplatin induced hepatotoxicity, as evidenced by an increase in serum aminotransferase and histopathological alterations, including degeneration/necrosis of hepatocytes, vacuolation, and sinusoidal dilation. In addition, an increase in the malondialdehyde (MDA) concentration and a decrease in the reduced glutathione (GSH) content and catalase (CAT), superoxide dismutase (SOD), and glutathione S-transferase (GST) activities were observed in the cisplatin-treated rat hepatic tissues. In contrast, PYC treatment effectively prevented cisplatin-induced hepatotoxicity, including the elevation of aminotransferase and histopathological lesions, in a dosedependent manner. Moreover, PYC treatment also induced antioxidant activity by decreasing MDA level and increasing GSH content and SOD and GST activities in liver tissues. These results indicate that PYC has a protective effect against acute hepatotoxicity induced by cisplatin in rats, and that the protective effects of PYC may be due to inhibiting lipid peroxidation and increasing antioxidant activity. PMID:25628728

  5. The Protective Effects of Sika Deer Antler Protein on Cisplatin-Induced Nephrotoxicity

    Directory of Open Access Journals (Sweden)

    Huihai Yang

    2017-08-01

    Full Text Available Background/Aims: This study measured the effect of Sika deer (Cervus nippon Temminck antler protein (SDAPR, glycoproteins (SDAG, and polysaccharides (SDAPO on cisplatin-induced cytotoxicity in HEK 293 cells, and investigated the effect of SDAPR against cisplatin-induced nephrotoxicity in mice. Methods: Cell viability was measured by MTT assay. ICR mice were randomly divided into five groups: control, cisplatin with vehicle, and cisplatin with SDAPR at three concentrations: 5, 10, or 20 mg/kg, p.o., 10 d. Cisplatin was injected on 7th day (25 mg/kg, i.p.. Renal function, oxidative stress, levels of inflammatory factors, and expression of apoptosis-related proteins were measured in vivo. Renal tissues were stained with TUNEL and H&E to observe renal cell apoptosis and pathological changes. Results: Pretreatment with SDAPR (125-2000 µg/mL significantly improved cell viability, with an EC50 of approximately 1000 µg/mL. SDAPR also ameliorated cisplatin-induced histopatholo- gic changes, and decreased blood urea nitrogen (BUN and creatinine (Cr (P < 0.05. Western blotting analysis showed SDAPR clearly decreased expression levels of cleaved-caspase-3 and Bax, and increased the expression level of Bcl-2 (P < 0.01. Additionally, SDAPR markedly regulated oxidative stress markers and inflammatory cytokines (P<0.05. TUNEL staining showed decreased apoptosis after SDAPR treatment (P < 0.01. Conclusions: These results indicate that SDAPR can be an effective dietary supplement, to relieve cisplatin-induced nephrotoxicity by improved antioxidase activity, suppressed inflammation, and inhibited apoptosis in vivo.

  6. The protective effects of Ribes diacanthum Pall on cisplatin-induced nephrotoxicity in mice.

    Science.gov (United States)

    Tilyek, Akhtolkhyn; Chai, Chengzhi; Hou, Xiaoli; Zhou, Baoping; Zhang, Chunlei; Cao, Zhengyu; Yu, Boyang

    2016-02-03

    Ribes diacanthum Pall. (Saxifragaceae), a Mongolian folk medicinal plant, was used to treat urinary system diseases. The present work aims to investigate the protective effects of Ribes diacanthum Pall (RDP) against cisplatin-induced nephrotoxicity. The renal injury was modeled by intraperitoneal injection of cisplatin for 5 consecutive days (5 mg/kg). Nephroprotection of RDP was investigated by oral administration of RDP aqueous extract at a daily dose of 40 mg/kg for 14 consecutive days, starting 7 days prior to cisplatin administration. We demonstrated that pretreatment with RDP aqueous extract protected the mice from death induced by cisplatin administration. RDP treatment also significantly reduced blood urea nitrogen (BUN) and serum creatinine (Cr) levels observed in cisplatin-administrated mice. Histopathological analysis demonstrated that RDP administration protected cisplatin-induced renal tubular cell apoptosis. Further western blotting analysis revealed that RDP significantly reversed cisplatin-increased expression levels of cleaved-Caspase-3, Bax and cisplatin-decreased expression level of Bcl-2 in renal tissue. Finally, RDP markedly enhanced enzyme activities of reduced superoxide dismutase (SOD), Heme oxygenase 1 (HO-1) and catalase (CAT), suppressed lipid peroxidation as well as reactive oxygen species (ROS) production. We concluded that RDP displayed nephroprotective effects against cisplatin-induced renal tubular cell apoptosis, possibly associated with both enhanced antioxidase activity and suppressed ROS generation. Given the major nephrotoxicity of cisplatin cancer chemotherapy, RDP might be a potential candidate for neoadjuvant chemotherapy. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  7. Physalis alkekengi and Alhagi maurorum ameliorate the side effect of cisplatin-induced nephrotoxicity.

    Science.gov (United States)

    Changizi-Ashtiyani, S; Alizadeh, M; Najafi, H; Babaei, S; Khazaei, M; Jafari, M; Hossaini, N; Avan, A; Bastani, B

    2016-07-01

    Cisplatin is frequently being used for the treatment of different tumors, although the application of this agent is associated with nephrotoxicity. Here, we explored the antioxidant and anti-inflammatory activities of Physalis alkekengi and Alhagi maurorum; 400 mg kg(-1) per day P. alkekengi and 100 mg kg(-1) per day A. maurorum were administered in rats, orally for 10 days after a single dose of 7 mg kg(-1) intraperitoneal cisplatin. The concentrations of creatinine, urea-nitrogen, and relative and absolute excretion of sodium/potassium were evaluated before/after therapy. Levels of malondialdehyde (MDA) and ferric-reducing antioxidant power (FRAP) were measured to assess the oxidative stress induced by cisplatin. Moreover, tissues sections were used for histological analyses and evaluation of the degree of tissue damage. Cisplatin increased serum levels of creatinine and urea-nitrogen, relative/absolute excretion of sodium/potassium, and MDA, whereas decreased FRAP level. Interestingly, P. alkekengi or A. maurorum were able to reduce the level of the renal function markers as well as the levels of sodium/potassium. This effect was more pronounced by P. alkekengi. Moreover, cisplatin induced pathological damage in kidney, whereas treatment with these agents improved this condition. Our findings demonstrate the potential therapeutic impact of P. alkekengi and A. maurorum for improving cisplatin-induced nephrotoxicity, supporting further investigations on the novel potential clinical application of these agents for patients being treated with cisplatin to ameliorate cisplatin-induced nephrotoxicity.

  8. Protective effect of metalloporphyrins against cisplatin-induced kidney injury in mice.

    Directory of Open Access Journals (Sweden)

    Hao Pan

    Full Text Available Oxidative and nitrative stress is a well-known phenomenon in cisplatin-induced nephrotoxicity. The purpose of this work is to study the role of two metalloporphyrins (FeTMPyP and MnTBAP, water soluble complexes, in cisplatin-induced renal damage and their ability to scavenge peroxynitrite. In cisplatin-induced nephropathy study in mice, renal nitrative stress was evident by the increase in protein nitration. Cisplatin-induced nephrotoxicity was also evident by the histological damage from the loss of the proximal tubular brush border, blebbing of apical membranes, tubular epithelial cell detachment from the basement membrane, or intra-luminal aggregation of cells and proteins and by the increase in blood urea nitrogen and serum creatinine. Cisplatin-induced apoptosis and cell death as shown by Caspase 3 assessments, TUNEL staining and DNA fragmentation Cisplatin-induced nitrative stress, apoptosis and nephrotoxicity were attenuated by both metalloporphyrins. Heme oxygenase (HO-1 also plays a critical role in metalloporphyrin-mediated protection of cisplatin-induced nephrotoxicity. It is evident that nitrative stress plays a critical role in cisplatin-induced nephrotoxicity in mice. Our data suggest that peroxynitrite is involved, at least in part, in cisplatin-induced nephrotoxicity and protein nitration and cisplatin-induced nephrotoxicity can be prevented with the use of metalloporphyrins.

  9. The effect of essential oil of Achillea wilhelmsii flowers on cisplatin-induced hepatotoxicity

    OpenAIRE

    Sahar Ghanbari; Leila Amjad; Kahin Shahanipur

    2017-01-01

    Background: The essential oil of Achillea wilhelmsii has‎ anti-inflammatory and antioxidant properties. Cisplatin is one of the most important anticancer drugs that are widely used to treat various types of cancers. This study aimed at examining the effects of the essential oil of A. wilhelmsii flowers on cisplatin-induced hepatotoxicity in rats. Materials and Methods: In this study, 36 male Wistar rats weighing 200-250 g were divided into 6 groups: 1) control, 2) cisplatin (0.4 mg/kg), ...

  10. Effect of aqueous extract of Rheum ribes on cisplatin-induced nephrotoxicity in rat.

    Science.gov (United States)

    Hadjzadeh, Mousa-Al-Reza; Rajaei, Ziba; Keshavarzi, Zakieh; Shirazi, Mohsen Ghasem; Toosi, Vahedeh

    2013-10-01

    The purpose of the present study was to examine whether Rheum ribes extract prevents cisplatin-induced nephrotoxicity. THE ANIMALS WERE DIVIDED INTO THREE GROUPS: Group A considered as control group, group B were treated with cisplatin (3 mg/kg B.W. for 3 alternative days), and group C further to cisplatin received the aqueous extract of Rheum ribes (150 mg/rat). Blood urea nitrogen (BUN) level increased in group B on days 14 and 42 compared to day 0 (P ribes extract decreased the serum BUN level on day 14 compared to group B (P ribes had no effect on blood creatinine level. Serum cholesterol level was increased in group B on days 14 and 42 compared to day 0 (P ribes decreased the blood cholesterol level on day 42 in comparison to group B (P ribes increased the serum glucose level on days 14 and 42 compared to day 0 (P ribes had no effect on the kidney architecture. Cisplatin-induced nephrotoxicity was confirmed in our study. Although Rheum ribes had some effects on biochemical parameters; its effect on renal histology in injured kidney was insignificant.

  11. The Preventive Effect of Oxytocin to Cisplatin-Induced Neurotoxicity: An Experimental Rat Model

    Directory of Open Access Journals (Sweden)

    Tulay Akman

    2015-01-01

    Full Text Available Peripheral neurotoxicity is a frequent dose-limiting side effect of the chemotherapeutic agent cisplatin. This study was conducted to investigate the preventive effect of oxytocin (OT on cisplatin-induced neurotoxicity in rats. Forty-four adult female rats were included in the study. Thirty-six rats were administered intraperitoneally (i.p. single dose cisplatin 10 mg/kg and divided in to 3 groups. The first group (n=12 received saline i.p., whereas the second group (n=12 and the third group (n=12 were injected with 80 µg/kg and 160 µg/kg OT, respectively, for 10 days. The remaining 8 rats served as the control group. Electromyography (EMG studies were recorded and blood samples were collected for the measurement of plasma lipid peroxidation (malondialdehyde; MDA, tumor necrosis factor (TNF-α, and glutathione (GSH levels. EMG findings revealed that compound muscle action potential amplitude was significantly decreased and distal latency was prolonged in the nontreated cisplatin-injected rats compared with the control group (P<0.005. Also, nontreated cisplatin-injected rats showed significantly higher TNF-α and MDA levels and lower GSH level than control group. The administration of OT significantly ameliorated the EMG alterations, suppressed oxidative stress and inflammatory parameters, and increased antioxidative capacity. We suggest that oxytocin may have beneficial effects against cisplatin-induced neurotoxicity.

  12. Protective effect of bixin on cisplatin-induced genotoxicity in PC12 cells.

    Science.gov (United States)

    Dos Santos, Graciela Cristina; Mendonça, Leonardo Meneghin; Antonucci, Gilmara Ausech; Dos Santos, Antonio Cardozo; Antunes, Lusânia Maria Greggi; Bianchi, Maria de Lourdes Pires

    2012-02-01

    Bixin is the main carotenoid found in annatto seeds (Bixa orellana L.) and is responsible for their reddish-orange color. The antioxidant properties of this compound are associated with its ability to scavenge free radicals, which may reduce damage and protect tissues against toxicity caused by anticancer drugs such as cisplatin. In this study, the genotoxicity and antigenotoxicity of bixin on cisplatin-induced toxicity in PC12 cells was assessed. Cytotoxicity was evaluated using the MTT assay, mutagenicity, genotoxicity, and protective effect of bixin were evaluated using the micronucleus test and comet assay. PC12 cells were treated with bixin (0.05, 0.08, and 0.10μg/mL), cisplatin (0.1μg/mL) or a combination of both bixin and cisplatin. Bixin was neither cytotoxic nor genotoxic compared to the controls. In the combined treatment bixin significantly reduced the percentage of DNA in tail and the frequency of micronuclei induced by cisplatin. This result suggests that bixin can function as a protective agent, reducing cisplatin-induced DNA damage in PC12 cells, and it is possible that this protection could also extend to neuronal cells. Further studies are being conducted to better understand the mechanisms involved in the activity of this protective agent prior to using it therapeutically. Copyright © 2011 Elsevier Ltd. All rights reserved.

  13. Premedication with intravenous magnesium has a protective effect against cisplatin-induced nephrotoxicity.

    Science.gov (United States)

    Saito, Yoshitaka; Kobayashi, Masaki; Yamada, Takehiro; Kasashi, Kumiko; Honma, Rio; Takeuchi, Satoshi; Shimizu, Yasushi; Kinoshita, Ichiro; Dosaka-Akita, Hirotoshi; Iseki, Ken

    2017-02-01

    Magnesium supplementation is an effective protective method against cisplatin-induced nephrotoxicity (CIN); however, there are few reports regarding the mechanism of its nephroprotective effect. The aim of this study was to determine whether premedication with intravenous magnesium prevents CIN and to determine the relationship between its nephroprotective effect and serum magnesium level. Fifty-eight patients with head and neck cancer who received cisplatin, docetaxel, and 5-fluorouracil (DCF) were retrospectively investigated. Grade 2 or more serum creatinine elevation was defined as CIN. The incidence of CIN was compared between a magnesium sulfate (20 mEq, 2.46 g) premedication group and a non-magnesium group during the first cycle and in all cycles. CIN did not occur in any patients receiving magnesium premedication but did occur in 5 of 29 patients during the first cycle and in 6 patients during all subsequent cycles in patients who did not receive magnesium premedication. Furthermore, the variation of creatinine clearance was significantly worse in the non-magnesium group than in the magnesium premedication group from baseline. There was no difference in adverse effects or response rate between the two groups. Univariate analysis suggested that magnesium premedication significantly reduced the risk of CIN. On the other hand, serum magnesium depletion was seen in both groups to equal degrees despite supplementation. Intravenous magnesium premedication has a protective effect on cisplatin-induced nephrotoxicity without the influence on the serum magnesium level. Magnesium premedication is a simple nephroprotective method that does not influence other adverse effects or rate of response to chemotherapy.

  14. Chemopreventive Effect of Tadalafil in Cisplatin-Induced Nephrotoxicity in Rats.

    Science.gov (United States)

    Adeneye, A A; Benebo, A S

    2016-08-30

    Nephrotoxicity remains a common untoward effect of cisplatin therapy with limited effective chemopreventive options available till date. This study aims to evaluate the possible chemopreventive effect and mechanism(s) of action of 2 mgkg-1 and 5 mgkg-1 of Tadalafil in cisplatin-induced nephrotoxic rats. In this study, twenty-five male Wistar rats were randomly divided into five groups (n = 5 rats per group) and daily pretreated with oral doses of distilled water (10 mLkg-1), ascorbic acid (100 mgkg-1), Tadalafil (2 mgkg-1 and 5 mgkg-1) for 7 days before cisplatin (5 mgkg-1, intraperitoneal) was administered. 72 hours post-cisplatin injections, rats were sacrificed humanely and blood samples for serum electrolytes, urea and creatinine and renal tissues for reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px) and malonialdehyde dehydrogenase (MAD) assays and histopathology were collected. Results showed that cisplatin injection caused significant decreases in the serum sodium (Na+), potassium (K+), bicarbonate (HCO3-), calcium (Ca2+), phosphate (PO42-) and concomitant significant increases in the serum urea and creatinine levels. In addition, there were significant decreases in the renal tissue GSH, SOD, CAT and increased MAD and GSH-Px levels which were corroborated by histopathological features of tubulonephritis. However, these histo-biochemical alterations were significantly attenuated by ascorbic acid and Tadalafil pretreatments. Overall, results of this study showed the chemopreventive potential of Tadalafil against cisplatin-induced nephrotoxicity which was possibly mediated via antioxidant and anti-lipoperoxidation mechanisms.

  15. Protective effect of bilberry (Vaccinium myrtillus L.) on cisplatin induced ovarian damage in rat.

    Science.gov (United States)

    Pandir, Dilek; Kara, Ozlem; Kara, Mustafa

    2014-08-01

    Cisplatin is one of the most effective chemotherapeutic agents but injury may occur at higher doses. The aim of this study was to investigate the effect of bilberry on cisplatin induced toxic effects in rat ovary. Twenty-one female Wistar-Albino rats were utilized to form three groups: In group 1 (control group), each rat received intraperitoneal injection of 1 mL of 0.9 % NaCl saline solution during 10-days. In group 2 (cisplatin group), a single dose of 7.5 mg/kg b.w. cisplatin was given. In group 3 (cisplatin + bilberry group), a single dose of 7.5 mg/kg cisplatin and bilberry at 200 mg/kg b.w. were given for 10 days. Ovaries were surgically removed in all groups and prepared for biochemical and light microscopic investigations at the examination times. Malondialdehyde (MDA) levels and activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione-S-transferase (GST) of tissue samples were measured. Histopathological damages in cisplatin administrated rats were seen such as severe edema, vascular congestion, hemorrhage and follicular degeneration in the ovary tissue. Moderate pathological alterations were observed in rats treated with bilberry plus cisplatin. Cisplatin administration significantly increased MDA production and decreased SOD, CAT, GPx and GST activities in the ovarian tissue when compared to the control group (p < 0.05). Cisplatin + bilberry administration increased antioxidant enzymes activities and reduced MDA levels. Bilberry administration seems to reduce the cisplatin induced ovarian toxicity thus it alleviates free radical damage. But it dose not protect completely rat ovary tissues.

  16. The ototoxic effects of ethyl benzene in rats

    NARCIS (Netherlands)

    Cappaert, N.L.M.; Klis, S.F.L.; Muijser, H.; Groot, J.C.M.J. de; Kulig, B.M.; Smoorenburg, G.F.

    1999-01-01

    Exposure to organic solvents has been shown to be ototoxic in animals and there is evidence that these solvents can induce hearing loss in humans. In this study, the effects of inhalation of the possibly ototoxic solvent ethyl benzene on the cochlear function and morphology were evaluated using

  17. Nephroprotective Effects of Anthocyanin from the Fruits of Panax ginseng (GFA) on Cisplatin-Induced Acute Kidney Injury in Mice.

    Science.gov (United States)

    Qi, Zhen-Lan; Wang, Zi; Li, Wei; Hou, Jin-Gang; Liu, Ying; Li, Xin-Dian; Li, Hui-Ping; Wang, Ying-Ping

    2017-09-01

    Cisplatin is an effective anticancer chemotherapeutic agent, but the use of cisplatin in the clinic is severely limited by side effects. Nephrotoxicity is a major factor that contributes to the side effects of cisplatin chemotherapy. The aim of this research was to survey the nephroprotective effects of anthocyanin from the fruits of Panax ginseng (GFA) in a murine model of cisplatin-induced acute kidney injury. We observed that pretreatment with GFA attenuated cisplatin-induced elevations in blood urea nitrogen and creatinine levels and histopathological injury induced by cisplatin. The formation of kidney malondialdehyde, heme oxygenase-1, cytochrome P450 E1 and 4-hydroxynonenal with a concomitant reduction in reduced glutathione was also inhibited by GFA, while the activities of kidney superoxide dismutase and catalase were all increased. GFA also inhibited the increase in serum tumour necrosis factor-α and interleukin-1β induced by cisplatin. In addition, the levels of induced nitric oxide synthase and cyclooxygenase-2 were suppressed by GFA. Furthermore, GFA supplementation inhibited the activation of apoptotic pathways by increasing B cell lymphoma 2 and decreasing Bcl2-associated X protein expression. In conclusion, the findings from the present investigation demonstrate that GFA pre-administration can significantly prevent cisplatin-induced nephrotoxicity, which may be related to its antioxidant, anti-apoptotic and antiinflammatory effects. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

  18. Neuro-protective effect of rutin against Cisplatin-induced neurotoxic rat model.

    Science.gov (United States)

    Almutairi, Mashal M; Alanazi, Wael A; Alshammari, Musaad A; Alotaibi, Moureq Rashed; Alhoshani, Ali R; Al-Rejaie, Salim Salah; Hafez, Mohamed M; Al-Shabanah, Othman A

    2017-09-29

    Cisplatin is widely used chemotherapeutic agent for cancer treatment with limited uses due to its neurotoxic side effect. The aim of this study was to determine the potential preventive effects of rutin on the brain of cisplatin- neurotoxic rat model. Forty rats were divided into four groups. Group-1 (control group) was intra-peritoneal (IP) injected with 2.5 ml/kg saline. Group-2 (rutin group) was orally administrated 30 mg/kg rutin dissolved in water for 14 days. Group-3 (cisplatin group) was IP received 5 mg/kg cisplatin single dose. Group-4 (rutin and cisplatin group) was orally administrated 30 mg/kg rutin dissolved in water for 14 days with a single dose of 5 mg/kg cisplatin IP on day ten. Brain tissues from frontal cortex was used to extract RNA, the gene expression levels of paraoxonase-1 (PON-1), PON-2, PON-3, peroxisome proliferator-activated receptor delta (PPAR-δ), and glutathione peroxidase (GPx) was investigated by Real-time PCR. Cisplatin significantly decreased the expression levels of PON-1, PON-3, PPAR-δ and GPX whereas significantly increased PON-2 expression levels. Co-administration of Rutin prevented the cisplatin-induced toxicity by restoring the alteration in the studied genes to normal values as in the control group. This study showed that Rutin has neuroprotective effect and reduces cisplatin- neurotoxicity with possible mechanism via the antioxidant pathway.

  19. [Preventive and therapeutic effects of xiaobanxia fuling decoction on cisplatin-induced pica rats].

    Science.gov (United States)

    Zang, Chun-bao; Ma, Hu; Bai, Yu-ju

    2011-10-01

    To investigate the preventive and therapeutic effects of Xiaobanxia Fuling Decoction (XBFD) on cisplatin-induced pica rats and to study its mechanism. Forty-two male Sprague-Dawley rats were randomly divided into the following 7 groups, i.e., the blank control group, the model group, the high-, middle-, and low-dose XBFD groups (at the daily dose of 30, 15, and 7. 5 g/kg, respectively), the aprepitant (at the daily dose of 13 mg/kg), and pure Chinese medicine group (at the daily dose of XBFD 15 g/kg), 6 in each group. On the 3rd day of this study, 3 mg/kg cisplatin was intraperitoneally injected to rats except the blank control group and the model group to establish the pica rat model. The consumptions of kaolin, food, and the general situation of rats were observed. The protein and mRNA expressions of neurokinin 1 receptor (NK1R) in both the medulla oblongata and the gastric antrum were measured by immunohistochemical assay and Real-time fluorescent quantitative PCR respectively on the sixth day of this study. On the third, fourth, and fifth day of this study, the consumption of kaolin of rats significantly increased when compared with the blank control group (Ppica in rats. Its effect might be correlated with decreasing expressions of NK, R in the medulla oblongata and the gastric antrum.

  20. Effect of free creatine therapy on cisplatin-induced renal damage.

    Science.gov (United States)

    Genc, Gurkan; Okuyucu, Ali; Meydan, Bilge Can; Yavuz, Oguzhan; Nisbet, Ozlem; Hokelek, Murat; Bedir, Abdulkerim; Ozkaya, Ozan

    2014-08-01

    Abstract Cisplatin is one of the commonly used anticancer drugs and nephrotoxicity limits its use. The aim of this study is to investigate the possible protective effect of creatine supplementation on cisplatin-induced nephrotoxicity. Sixty male Sprague-Dawley rats were divided into three groups: Group I: Cisplatin (n=20) (7 mg/kg cisplatin intraperitoneal (i.p.) single dose), group II: Cisplatin+creatine monohydrate (n=20) (7 mg/kg cisplatin i.p. single dose and 300 mg/kg creatine p.o. daily for 30 days starting on first day of cisplatin injection), group III: Control group (n=20) (Serum physiologic, 2.5 mL/kg i.p.). Sacrifications were performed at first week and 30th day. Blood urea nitrogen (BUN) and serum creatinine levels, histopathological evaluation, mitochondrial deoxyribonucleic acid (mtDNA) common deletion rates, and body weights of rats were evaluated. A significant decrease in body weight, higher values of kidney function tests, histopathological scores, and mtDNA deletion ratios were observed in group I compared to control group at days 7 and 30 (pcreatine significantly reversed kidney functions and pathological findings, this improvement was not sufficient to reach normal control group's results at days 7 and 30. In conclusion, the present study demonstrates that creatine administration is a promising adjuvant protective drug for reducing nephrotoxic effect of cisplatin.

  1. Effects of Korean ginseng root extract on cisplatin-induced emesis in a rat-pica model.

    Science.gov (United States)

    Raghavendran, Hanumantha Rao Balaji; Rekha, Sathyanath; Shin, Jang-Woo; Kim, Hyeong-Geug; Wang, Jing-Hua; Park, Hye-Jung; Choi, Min-Kyung; Cho, Jung-Hyo; Son, Chang-Gue

    2011-01-01

    In the present study, we investigate the effect of Korean ginseng root extract (KG) on cisplatin-induced pica in a rat model. Rats were treated with KG before (25, 50, and 100 mg/kg) or after (12.5, 25, and 50 mg/kg) a single intraperitoneal injection of cisplatin (7 and 6 mg/kg, respectively). We examined intake of kaolin and normal food as an indicator of the emetic stimulus every 24 h for 120 h. Changes in body weight, haematology and histopathology were additionally assessed. Pre-treatment with KG (25 and 50 mg/kg) significantly attenuated cisplatin-induced kaolin intake (24, 48, and 72 h) and markedly improved intake of normal food by rats at 48, 72, 96, and 120 h. Cisplatin-induced kaolin intake was markedly decreased upon post-treatment of rats with KG (12.5, 25, and 50 mg/kg) at 24 h. Notably, post-treatment with the lowest KG dose resulted in a significant anti-pica effect and improved food intake until 72 h. The magnitude of body weight reduction was significantly diminished in rats pre-treated/post-treated with 25, 50, and 12.5 mg/kg KG. The anti-pica effects of KG were further confirmed with haematological and histopathological findings. Our findings collectively indicate that KG improves the resistance of rats against emesis. Copyright © 2010 Elsevier Ltd. All rights reserved.

  2. The Protective Effect of Naringenin-Oxime on Cisplatin-Induced Toxicity in Rats

    Directory of Open Access Journals (Sweden)

    Ismail Koyuncu

    2017-01-01

    Full Text Available The aim of this study is to examine the protective effect of naringenin-oxime (NOX on cisplatin-induced major organ toxicity and DNA damage in rats. Thirty-five male Wistar albino rats were equally split into five groups as follows: control (i.p., 0.1 ml of saline, Cis administration (i.p., 7 mg/kg b.w., NOX treatment (i.p., 20 mg/kg b.w., daily for ten days, Cis + NOX20, and Cis + NOX40 combination (i.p., 20 and 40 mg/kg b.w., daily for ten days. Serum and peripheral blood mononuclear leukocytes (PBMC were obtained from blood. Malondialdehyde, glutathione, total antioxidant and oxidant status, and catalase were measured in serum, liver, and kidney, and oxidative stress index was calculated. In parallel, paraoxonase and arylesterase activities were tested in liver and serum. We used 8-OHdOG as a marker for DNA damage in serum via ELISA and in PMBC via comet assay. Treatment with Cis elevated the levels of serum biochemical parameters, oxidative stress, and DNA damage. Pretreatments of NOX restored biochemical and oxidative stress parameters in serum, renal, and liver tissues (p<0.01 and reduced 8-OHdG level, a finding further supported by comet assay in PBMC. Observations of the present study support the fact that treatment with NOX prevents Cis-induced hepatotoxicity, nephrotoxicity, and genotoxicity by restoring antioxidant system.

  3. Effects of Delta-9-Tetrahydrocannabinol and Cannabidiol on Cisplatin-Induced Neuropathy in Mice.

    Science.gov (United States)

    Harris, Hannah M; Sufka, Kenneth J; Gul, Waseem; ElSohly, Mahmoud A

    2016-08-01

    Sativex, a cannabinoid extract with a 1 : 1 ratio of tetrahydocannabinol and cannabidiol, has been shown to alleviate neuropathic pain associated with chemotherapy. This research examined whether tetrahydocannabinol or cannabidiol alone could attenuate or prevent cisplatin-induced tactile allodynia. In experiment 1, mice (C57BL/6) received eight administrations of 2.3 mg/kg cisplatin or saline solution IP every other day to induce tactile allodynia. Mice were then administered vehicle, 100 mg/kg gabapentin, 2 mg/kg tetrahydocannabinol, or 2 mg/kg cannabidiol IP and tested 60 min later on an electronic Von Frey. In experiment 2, prevention studies, cannabidiol (0.0, 0.5, 1.0, and 2.0 mg/kg) or tetrahydocannabinol (0.0, 0.5, 1.0, and 2.0 mg/kg) was given IP 30 min prior to cisplatin administration (2.3 or 1.0 mg/kg) utilizing a six-dose alternate day protocol. In both studies, tactile responses to the hind paws were quantified in g of force using an electronic Von Frey prior to and after the cisplatin administration protocol. Cisplatin produced a reduction in g of force indicative of neuropathy that was attenuated by gabapentin, tetrahydocannabinol, and cannabidiol but not prevented by either cannabinoid. These data demonstrate that each of the major constituents of Sativex alone can achieve analgesic effects against cisplatin neuropathy. Georg Thieme Verlag KG Stuttgart · New York.

  4. Protective effects of the Morus alba L. leaf extracts on cisplatin-induced nephrotoxicity in rat

    Science.gov (United States)

    Nematbakhsh, M; Hajhashemi, V; Ghannadi, A; Talebi, A; Nikahd, M

    2013-01-01

    Cisplatin (CP) as an important anti-tumor drug causes nephrotoxicity mainly by oxidative stress and renin-angiotensin system (RAS). Since flavonoids have high antioxidant activity and probable role in the inhibition of RAS, this study was designed to investigate the protective effect of hydroalcoholic extract and flavonoid fraction of Morus alba leaves on cisplatin-induced nephrotoxicity in rat. Extracts of Morus alba leaves were prepared and analyzed Phytochemically. Male rats (160-200 g) were used in this study (n=7-9). Normal group received 0.2 ml normal saline intraperitoneally (i.p.) once daily for ten days. Control animals received CP on the third day and saline in the remaining days. Other groups received either hydroalcoholic extract (200, 400 and 600 mg/kg, i.p.) or flavonoid fraction (50, 100 and 200 mg/kg, i.p.) for two days before CP administration and thereafter until tenth day. Serum concentrations of blood urea nitrogen (BUN), creatinine (Cr) and nitric oxide were measured using standard methods. Also left kidneys were prepared for pathological study. The serum levels of BUN and Cr increased in animals received CP. Hydroalcoholic extract was ineffective in reversing these alterations but flavonoid fraction (50 and 100 mg/kg) significantly inhibited CP-induced increases of BUN and Cr. None of the treatments could affect serum concentration of nitric oxide. Flavonoid fraction could also prevent CP-induced pathological damage of the kidney. It seems that concurrent use of flavonoid fraction of Morus alba with CP can protect kidneys from CP-induced nephrotoxicity. PMID:24019816

  5. Protective effect of bixin on cisplatin-induced genotoxicity in PC12 cells

    OpenAIRE

    dos Santos, Graciela Cristina; Mendonça, Leonardo Meneghin; Antonucci, Gilmara Ausech; dos Santos, Antonio Cardozo; Antunes, Lusânia Maria Greggi; Bianchi, Maria de Lourdes Pires

    2012-01-01

    Bixin is the main carotenoid found in annatto seeds (Bixa orellana L.) and is responsible for their reddish-orange color. The antioxidant properties of this compound are associated with its ability to scavenge free radicals, which may reduce damage and protect tissues against toxicity caused by anticancer drugs such as cisplatin. In this study, the genotoxicity and antigenotoxicity of bixin on cisplatin-induced toxicity in PC12 cells was assessed. Cytotoxicity was evaluated using the mu assay...

  6. Reactive oxygen species-mediated apoptosis contributes to chemosensitization effect of saikosaponins on cisplatin-induced cytotoxicity in cancer cells

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    He Fan

    2010-12-01

    Full Text Available Abstract Background Saikosaponin-a and -d, two naturally occurring compounds derived from Bupleurum radix, have been shown to exert anti-cancer activity in several cancer cell lines. However, the effect of combination of saikosaponins with chemotherapeutic drugs has never been addressed. Thus, we investigated whether these two saikosaponins have chemosensitization effect on cisplatin-induced cancer cell cytotoxicity. Methods Two cervical cancer cell lines, HeLa and Siha, an ovarian cancer cell line, SKOV3, and a non-small cell lung cancer cell line, A549, were treated with saikosaponins or cisplatin individually or in combination. Cell death was quantitatively detected by the release of lactate dehydrogenase (LDH using a cytotoxicity detection kit. Cellular ROS was analyzed by flow cytometry. Apoptosis was evaluated by AO/EB staining, flow cytometry after Anexin V and PI staining, and Western blot for caspase activation. ROS scavengers and caspase inhibitor were used to determine the roles of ROS and apoptosis in the effects of saikosaponins on cisplatin-induced cell death. Results Both saikosaponin-a and -d sensitized cancer cells to cisplatin-induced cell death in a dose-dependent manner, which was accompanied with induction of reactive oxygen species (ROS accumulation. The dead cells showed typical apoptotic morphologies. Both early apoptotic and late apoptotic cells detected by flow cytometry were increased in saikosaponins and cisplatin cotreated cells, accompanied by activation of the caspase pathway. The pan-caspase inhibitor z-VAD and ROS scanvengers butylated hydroxyanisole (BHA and N-acetyl-L-cysteine (NAC dramatically suppressed the potentiated cytotoxicity achieved by combination of saikosaponin-a or -d and cisplatin. Conclusions These results suggest that saikosaponins sensitize cancer cells to cisplatin through ROS-mediated apoptosis, and the combination of saikosaponins with cisplatin could be an effective therapeutic strategy.

  7. The Effects of Pretreatment with Various Doses of L-Arginine on Cisplatin-Induced Nephropathy of Male Rats

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    B Rasoulian

    2016-09-01

    Full Text Available Introduction: Cisplatin is a widely used anti-cancer drug, which its application is limited by nephrotoxicity. In this study, the effect of pretreatment with different l-arginine doses on Cisplatin-induced renal functional injury was investigated. Methods: 63 male rats were divided into 7 groups: In groups 3, 4, 5 and 6, 60 min before the Cisplatin injection (5mg/kg; L-Arginine with doses of 50,100,200 or 400mg/kg was injected, respectively. In group7, normal saline was injected before Cisplatin administration. In groups 1 and 2, normal saline was injected instead of Cisplatin. In group 2, 60min before normal saline injection, 400mg/kg L-Arginine was administered and in group1, instead of L-arginine, normal saline was injected too. Injections were intraperitoneal. 72h after Cisplatin injection, blood sampling and plasma separation were done. Urine sample was collected 24 hours before blood sampling by metabolic cage. The mean of plasma urea and creatinine levels and creatinine clearance (ml/day.kg and fractional excretion of Na (FENa, % were compared among different groups as renal functional parameters. Results: In comparison to group 7, L-arginine injection in a dose of 400mg/kg led to significant amelioration of all parameters. 200 mg/kg L-arginine administration led to significant decrease in plasma urea level and FENa. 100mg/kg L-arginine caused significant improvement in fractional excretion of sodium. L-arginine injection with 50mg/kg dose, significantly ameliorate all renal function tests instead of creatinine clearance. Conclusion: Pretreatment with L-arginine administration with 400 or 50 mg/kg doses, respectively, had the highest effect on reducing Cisplatin-induced nephropathy. L-arginine injection with intermediate doses i.e. 200 or 100 mg/kg had less effect in reducing Cisplatin-induced nephropathy and it needs more investigations.

  8. Protective effect of curcumin and vitamin C each alone and in combination on cisplatin-induced sperm abnormalities in male albino rats

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    Sabha Elsayed Elballat

    2016-08-01

    The results of the present investigation concluded that the combination between curcumin and vitamin C in cisplatin treatment afforded the best ameliorative effect on cisplatin induced sperm shape abnormalities. This may be due to the synergistic effect between curcumin and vitamin C as both of them have antioxidant properties which in turn lead to repairing of sperm abnormalities.

  9. Cellular Responses to Cisplatin-Induced DNA Damage

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    Alakananda Basu

    2010-01-01

    Full Text Available Cisplatin is one of the most effective anticancer agents widely used in the treatment of solid tumors. It is generally considered as a cytotoxic drug which kills cancer cells by damaging DNA and inhibiting DNA synthesis. How cells respond to cisplatin-induced DNA damage plays a critical role in deciding cisplatin sensitivity. Cisplatin-induced DNA damage activates various signaling pathways to prevent or promote cell death. This paper summarizes our current understandings regarding the mechanisms by which cisplatin induces cell death and the bases of cisplatin resistance. We have discussed various steps, including the entry of cisplatin inside cells, DNA repair, drug detoxification, DNA damage response, and regulation of cisplatin-induced apoptosis by protein kinases. An understanding of how various signaling pathways regulate cisplatin-induced cell death should aid in the development of more effective therapeutic strategies for the treatment of cancer.

  10. Protective effect of lanostane triterpenoids from the sclerotia of Poria cocos Wolf against cisplatin-induced apoptosis in LLC-PK1 cells.

    Science.gov (United States)

    Lee, Dahae; Lee, Seulah; Shim, Sang Hee; Lee, Hae-Jeung; Choi, Youkyung; Jang, Tae Su; Kim, Ki Hyun; Kang, Ki Sung

    2017-07-01

    Cisplatin-induced nephrotoxicity is a serious adverse effect that limits the use of cisplatin in cancer patients. In the present study, we investigated the protective effect of lanostane triterpenoids (1-10) isolated from the ethanolic extract of Poria cocos Wolf against cisplatin-induced cell death in LLC-PK1 kidney tubular epithelial cells. Treatment of cisplatin induced significant cell death, which was suppressed by treatment with dehydroeburicoic acid monoacetate (1) and 3β-acetoxylanosta-7,9(11),24-trien-21-oic acid (9). Compound 1 exhibited the highest efficacy among the tested compounds and was thus subjected to further mechanistic studies. The increase in the percentage of apoptotic cells induced by cisplatin reduced by 4.3% after co-treatment of cells with compound 1 (50 and 100μM). Furthermore, phosphorylation of the mitogen-activated protein kinases JNK, ERK, and p38, and caspase-3, which characterize oxidative stress-mediated apoptosis, increased significantly after treatment with cisplatin, and decreased after treatment with compound 1. These results indicate that the renoprotective effects of compound 1 may be mediated by its anti-apoptotic activity. Copyright © 2017 Elsevier Ltd. All rights reserved.

  11. Biochemical changes associated with ascorbic acid–cisplatin combination therapeutic efficacy and protective effect on cisplatin-induced toxicity in tumor-bearing mice

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    Amenla Longchar

    2015-01-01

    Full Text Available Cisplatin is one of the well-established anticancer drugs being used against a wide spectrum of cancers. However, full therapeutic efficacy of the drug is limited due to development of various toxicities in the host. This study examines the comparative therapeutic effectiveness and toxicities of cisplatin alone and in combination of dietary ascorbic acid (AA in ascites Dalton's lymphoma-bearing mice. The findings show that the combination treatment of mice with ascorbic acid plus cisplatin has much better therapeutic efficacy against murine ascites Dalton's lymphoma (DL in comparison to cisplatin alone and this may involve a decrease in reduced glutathione (GSH, catalase activity and increased lipid peroxidation (LPO in Dalton's lymphoma tumor cells. At the same time, combination treatment indicates a protective role of ascorbic acid against cisplatin-induced tissue toxicities (side effects in the hosts. Cisplatin-induced histopathological changes in liver, kidney and testes were decreased after combination treatment. The analysis of renal function test (RFT, liver function test (LFT and sperm abnormalities also suggest an improvement in these parameters after combination treatment. Therefore, it may be concluded that the increased GSH level, catalase activity and decreased LPO in the tissues, i.e., liver, kidney and testes after combination treatment may be involved in its protective ability against cisplatin-induced tissue toxicities in the host.

  12. Effect of Nigella sativa L. seed extract on cisplatin-induced delay in gastric emptying in Sprague-Dawley rats.

    Science.gov (United States)

    Riyaz, Ambreena; Nazir, Shahid; Khushtar, Mohammad; Mishra, Anuradha; Jahan, Yasmeen; Ahmad, Asad

    2017-03-01

    The aim of this study was focused on investigating the possible protective effect of Nigella sativa L. seed extract against cisplatin-induced delay in gastric emptying, in a rat model. Twenty-five male Sprague-Dawley rats were divided into five equal groups as follows: Group I or control group, Group II (cisplatin 10 mg/kg, i.p at day 5), Group III (N. sativa L. 250 mg/kg for 5 days + cisplatin 10 mg/kg, i.p on day 5), Group IV (N. sativa L. 500 mg/kg for 5 days + cisplatin 10 mg/kg, i.p on day 5) and Group V (ondansetron 3 mg/kg/day, per os + cisplatin 10 mg/kg, i.p on day 5). Phenol red meal was adopted to estimate gastric emptying in different groups of the rats. Gastric emptying was significantly increased (p cisplatin treatment alone (Group II). However, ondansetron produced significantly (p < 0.01) better reversal than N. sativa L. seed extract.

  13. Post-treatment Effects of Erythropoietin and Nordihydroguaiaretic Acid on Recovery from Cisplatin-induced Acute Renal Failure in the Rat

    OpenAIRE

    Lee, Dong Won; Kwak, Ihm Soo; Lee, Soo Bong; Song, Sang Heon; Seong, Eun Young; Yang, Byeong Yun; Lee, Min Young; SOL, MEE YOUNG

    2009-01-01

    5-Lipoxygenase inhibitor and human recombinant erythropoietin might accelerate renal recovery in cisplatin-induced acute renal failure rats. Male Sprague-Dawley rats were randomized into four groups: 1) normal controls; 2) Cisplatin group-cisplatin induced acute renal failure (ARF) plus vehicle treatment; 3) Cisplatin+nordihydroguaiaretic acid (NDGA) group-cisplatin induced ARF plus 5-lipoxygenase inhibitor treatment; 4) Cisplatin+erythropoietin (EPO) group-cisplatin induced ARF plus erythrop...

  14. Reversible p53 inhibition prevents cisplatin ototoxicity without blocking chemotherapeutic efficacy.

    Science.gov (United States)

    Benkafadar, Nesrine; Menardo, Julien; Bourien, Jérôme; Nouvian, Régis; François, Florence; Decaudin, Didier; Maiorano, Domenico; Puel, Jean-Luc; Wang, Jing

    2017-01-01

    Cisplatin is a widely used chemotherapy drug, despite its significant ototoxic side effects. To date, the mechanism of cisplatin-induced ototoxicity remains unclear, and hearing preservation during cisplatin-based chemotherapy in patients is lacking. We found activation of the ATM-Chk2-p53 pathway to be a major determinant of cisplatin ototoxicity. However, prevention of cisplatin-induced ototoxicity is hampered by opposite effects of ATM activation upon sensory hair cells: promoting both outer hair cell death and inner hair cell survival. Encouragingly, however, genetic or pharmacological ablation of p53 substantially attenuated cochlear cell apoptosis, thus preserving hearing. Importantly, systemic administration of a p53 inhibitor in mice bearing patient-derived triple-negative breast cancer protected auditory function, without compromising the anti-tumor efficacy of cisplatin. Altogether, these findings highlight a novel and effective strategy for hearing protection in cisplatin-based chemotherapy. © 2016 The Authors. Published under the terms of the CC BY 4.0 license.

  15. Effect of geranylgeranylacetone on gentamycin ototoxicity in rat cochlea culture.

    Science.gov (United States)

    Sano, Hajime; Yoneda, Satoshi; Iwase, Hitoo; Itoh, Akihiko; Hashimoto, Daimon; Okamoto, Makito

    2007-03-01

    Geranylgeranylacetone (GGA), an anti-ulcer drug, has been reported to induce heat shock proteins (HSPs) in several animal organs. Purpose of this study was to investigate whether GGA has protective effect on gentamycin (GM) ototoxicity and whether it induces HSP70 in rat cochlea. We used cochlea explant culture from postnatal 5-day rat. Explants were pre-incubated with GGA, then incubated with GM and GGA. The number of surviving outer hair cells (OHCs) labeled by phalloidin was counted to evaluate the protective effect of GGA. The expression of HSP70 in whole cochlea tissue was investigated by immunoblot analysis. The number of surviving OHCs was significantly high in GGA 10(-5)M group compared to GM only group and GGA 10(-6)M group. In the immunoblot analysis, HSP70 levels in GGA added groups were slightly high compared to simple culture group, but much lower than those in heat shock group. It was suggested that GGA-induced HSP70, and had partial protective effects on GM ototoxicity in the cochlea. GGA has possibility to be safe and useful treatment drug for cochlea disorder.

  16. Role of Bone Marrow Derived Mesenchymal Stem Cells and the Protective Effect of Silymarin in Cisplatin-Induced Acute Renal Failure in Rats.

    Science.gov (United States)

    Ibrahim, Mohamed El-Tantawy; Bana, Eman El; El-Kerdasy, Hanan I

    2018-01-01

    Cisplatin is a highly effective antitumor agent whose clinical application is limited by its nephrotoxicity, which is associated with high mortality and morbidity rates. We aimed to study the protective role of silymarin and mesenchymal stem cells as a therapeutic tool of cisplatin nephrotoxicity. We injected rats with cisplatin in a dose of 5mg/kg body weight for 5 days to induce acute renal failure (ARF). Silymarin was administrated 6 hours before cisplatin injection and mesenchymal stem cells were injected 24 hours after cisplatin-induced ARF. We assessed the ARF biochemically by elevation of kidney function tests and histopathologically by an alteration of the histological architecture of the renal cortex in the form of shrinkage of glomeruli, lobulated tufts and glomerular hypertrophy with narrowing capsular space. The tubules showed extensive tubular degeneration with cellular hyaline materials and debris in the lumen of the renal tubules. The renal blood vessels appeared sclerotic with marked thickened walls. When silymarin was given in different doses before cisplatin, it decreased the toxic effect of cisplatin in the kidney but sclerotic blood vessels remained. Injection of mesenchymal stem cells in rats with cisplatin-induced ARF improved the histopathological effects of cisplatin in renal tissues and kidney function tests were significantly improved. There was a significant improvement in kidney function tests and renal histopathology by using silymarin as protective mechanism in cisplatin-induced ARF. Administration of mesenchymal stem cells denoted a more remarkable therapeutic effect in ARF. Copyright © 2018 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.

  17. Dunnione ameliorates cisplatin-induced small intestinal damage by modulating NAD{sup +} metabolism

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    Pandit, Arpana; Kim, Hyung-Jin; Oh, Gi-Su; Shen, AiHua; Lee, Su-Bin; Khadka, Dipendra; Lee, SeungHoon [Center for Metabolic Function Regulation & Department of Microbiology, Wonkwang University, Iksan, Jeonbuk 570-749 (Korea, Republic of); Shim, Hyeok; Yang, Sei-Hoon; Cho, Eun-Young [Department of Internal Medicine, School of Medicine, Wonkwang University, Iksan, Jeonbuk 570-749 (Korea, Republic of); Kwon, Kang-Beom [Department of Oriental Medical Physiology, School of Oriental Medicine, Wonkwang University, Iksan, Jeonbuk 570-749 (Korea, Republic of); Kwak, Tae Hwan [PAEAN Biotechnology, 160 Techno-2 Street, Yuseong-gu, Daejeon 305-500 (Korea, Republic of); Choe, Seong-Kyu; Park, Raekil [Center for Metabolic Function Regulation & Department of Microbiology, Wonkwang University, Iksan, Jeonbuk 570-749 (Korea, Republic of); So, Hong-Seob, E-mail: jeanso@wku.ac.kr [Center for Metabolic Function Regulation & Department of Microbiology, Wonkwang University, Iksan, Jeonbuk 570-749 (Korea, Republic of)

    2015-11-27

    Although cisplatin is a widely used anticancer drug for the treatment of a variety of tumors, its use is critically limited because of adverse effects such as ototoxicity, nephrotoxicity, neuropathy, and gastrointestinal damage. Cisplatin treatment increases oxidative stress biomarkers in the small intestine, which may induce apoptosis of epithelial cells and thereby elicit damage to the small intestine. Nicotinamide adenine dinucleotide (NAD{sup +}) is a cofactor for various enzymes associated with cellular homeostasis. In the present study, we demonstrated that the hyper-activation of poly(ADP-ribose) polymerase-1 (PARP-1) is closely associated with the depletion of NAD{sup +} in the small intestine after cisplatin treatment, which results in downregulation of sirtuin1 (SIRT1) activity. Furthermore, a decrease in SIRT1 activity was found to play an important role in cisplatin-mediated small intestinal damage through nuclear factor (NF)-κB p65 activation, facilitated by its acetylation increase. However, use of dunnione as a strong substrate for the NADH:quinone oxidoreductase 1 (NQO1) enzyme led to an increase in intracellular NAD{sup +} levels and prevented the cisplatin-induced small intestinal damage correlating with the modulation of PARP-1, SIRT1, and NF-κB. These results suggest that direct modulation of cellular NAD{sup +} levels by pharmacological NQO1 substrates could be a promising therapeutic approach for protecting against cisplatin-induced small intestinal damage. - Highlights: • NAD{sup +} acts as a cofactor for numerous enzymes including Sirtuins and PARP. • Up-regulation of SIRT1 could attenuate the cisplatin-induced intestinal damage. • Modulation of the cellular NAD{sup +} could be a promising therapeutic approach.

  18. The protective effect of melanocortins on cisplatin-induced hearing loss

    NARCIS (Netherlands)

    Wolters, Francisca Louisa Carolina

    2003-01-01

    Cisplatin is widely used for the treatment of a variety of tumors. Unfortunately, the therapeutic effect of cisplatin is limited because patients can develop a high frequency hearing loss in both ears. Recovery of this hearing loss is observed sporadically. Animal studies have shown that chronic

  19. Ameliorative effects of pine bark extract on cisplatin-induced acute kidney injury in rats.

    Science.gov (United States)

    Lee, In-Chul; Ko, Je-Won; Park, Sung-Hyeuk; Shin, Na-Rae; Shin, In-Sik; Kim, Yun-Bae; Kim, Jong-Choon

    2017-11-01

    This study investigated the dose-response effects of pine bark extract (PBE, pycnogenol®) on oxidative stress-mediated apoptotic changes induced by cisplatin (Csp) in rats. The ameliorating potential of PBE was evaluated after orally administering PBE at doses of 10 or 20 mg/kg for 10 days. Acute kidney injury was induced by a single intraperitoneal injection of Csp at 7 mg/kg on test day 5. Csp treatment caused acute kidney injury manifested by elevated levels of serum blood urea nitrogen (BUN) and creatinine (CRE) with corresponding histopathological changes, including degeneration of tubular epithelial cells, hyaline casts in the tubular lumen, and inflammatory cell infiltration (interstitial nephritis). Csp also induced significant apoptotic changes in renal tubular cells. In addition, Csp treatment induced high levels of oxidative stress, as evidenced by an increased level of malondialdehyde, depletion of the reduced glutathione (GSH) content, and decreased activities of glutathione S-transferase, superoxide dismutase, and catalase in kidney tissues. On the contrary, PBE treatment lowered BUN and CRE levels and effectively attenuated histopathological alterations and apoptotic changes induced by Csp. Additionally, treatment with PBE suppressed lipid peroxidation, prevented depletion of GSH, and enhanced activities of the antioxidant enzymes in kidney tissue. These results indicate that PBE has a cytoprotective effect against oxidative stress-mediated apoptotic changes caused by Csp in the rat kidney, which may be attributed to both increase of antioxidant enzyme activities and inhibition of lipid peroxidation.

  20. Synergy of Raddeanin A and cisplatin induced therapeutic effect enhancement in human hepatocellular carcinoma.

    Science.gov (United States)

    Li, Jian-Nan; Yu, Ye; Zhang, Yan-Fei; Li, Zhi-Meng; Cai, Guang-Zhi; Gong, Ji-Yu

    2017-04-01

    Cisplatin is a main compound for human hepatocellular carcinoma (HCC) chemotherapies, but it has certain cytotoxicity during applications. To release that, combining with other drugs are being as a regular plan in clinic. In our present study, we are focusing on one of active monomers extracted from Anemone Raddeana Regel, Raddeanin A (RA), which is on behalf of the same character like cisplatin in the tumor remedies. In order to investigate whether combination usage of RA and cisplatin can be priority to the later drug's effect development and its toxicity reduction in HCC, both of two drugs were treated 24 h or 48 h in QGY-7703 cells for estimating their abilities in tumor cell proliferation inhibition. Results show RA makes synergistic functions with cisplatin after measuring and analyzing their combination index (CI) values. Meanwhile it can strengthen cisplatin's effect through arresting the tumor cells in G0/G1 cycle and further promoting their apoptosis. Interestingly, the molecule signals correlated to tumor cell apoptosis containing both of p53 and bax are simultaneously activated, but bcl-2 and survivin are all depressed in mRNA level. Meanwhile, combining usage with RA can even raise the intracellular productions of reactive oxygen species (ROS). All these consequences reflect RA plays an important role in enhancing the therapeutic effect of cisplatin in HCC. This finding may guide for the drug usage of cisplatin in clinic practice. Copyright © 2017 Elsevier Inc. All rights reserved.

  1. Effect of enalapril in cisplatin-induced nephrotoxicity in rats; gender-related difference.

    Science.gov (United States)

    Zamani, Zohreh; Nematbakhsh, Mehdi; Eshraghi-Jazi, Fatemeh; Talebi, Ardeshir; Jilanchi, Sima; Navidi, Mitra; Shirdavani, Soheila; Ashrafi, Farzaneh

    2016-01-01

    The function of renin angiotensin system (RAS) is gender-related, and this system affects cisplatin (CP)-induced nephrotoxicity. In this study, we compared the effect of enalapril as an angiotensin-converting enzyme (ACE) inhibitor on CP-induced nephrotoxicity between male and female rats. Sixty-two adult male and female Wistar rats were divided into eight groups. Both genders received CP (2.5 mg/kg, i.p.) and enalapril (30 mg/kg, i.p.) for 7 days in compared with CP alone or enalapril alone or vehicle alone treated groups. At the end of the experiment, blood samples were obtained, and the kidney tissue was investigated for histopathological changes. CP increased the serum levels of blood urea nitrogen and creatinine as well as kidney weight and kidney tissue damage score in both genders (P only enalapril failed to ameliorate the aforementioned parameters in both genders, but also it intensified nephrotoxicity in females (P genders (P gender-dependent RAS response.

  2. Mechanisms involved in the possible nephroprotective effect of rutin and low dose γ irradiation against cisplatin-induced nephropathy in rats.

    Science.gov (United States)

    Radwan, Rasha R; Abdel Fattah, Salma M

    2017-04-01

    Cisplatin has demonstrated high antitumor efficacy. However, nephrotoxicity is a dose-limiting factor in its clinical use. The present study was designed to investigate the protective effect of rutin and low dose of irradiation (LDR) on cisplatin-induced nephrotoxicity in rats. Rats received rutin (200mg/kg/day, p.o) for 10 consecutive days and subjected to LDR (0.5Gy) 1day prior to cisplatin. Intraperitoneal administration of single dose of cisplatin (7.5mg/kg) was used to induce nephrotoxicity. Data showed that cisplatin caused elevation in serum creatinine and urea, disturbance in blood count, elevation in gene expression of tumor necrosis factor alpha, nuclear factor kappa B, interleukin-1β, caspase-3, mitochondrial cytochrome C and apoptosis-inducing factor in renal tissue. Moreover, it caused elevation in renal malondialdehyde accompanied by reduction in glutathione content. These effects were confirmed by histopathological examination. It was observed that LDR and rutin ameliorated the studied parameters. In conclusion, LDR could be considered as a novel approach for prophylaxis of cisplatin induced renal damage, also it augmented the nephroprotective effect of rutin via modulating the expression of inflammatory, oxidative stress and apoptotic mediators as well as histological changes in rats kidneys and hence might be valuable in improving the therapeutic index of cisplatin. Copyright © 2017 Elsevier B.V. All rights reserved.

  3. Melatonin suppresses cisplatin-induced nephrotoxicity via activation of Nrf-2/HO-1 pathway

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    Kilic Ulkan

    2013-01-01

    Full Text Available Abstract Background Cisplatin, one of the most effective and potent anticancer drugs, is used in the treatment of a wide variety of both pediatric and adult malignancies. However, the chemotherapeutic use of cisplatin is limited by its serious side-effects such as nephrotoxicity and ototoxicity. Cisplatin chemotherapy induces a reduction in the antioxidant status, leading to a failure of the antioxidant defense against free-radical damage generated by antitumor drugs. Cisplatin-induced oxidative stress in the kidney was partially prevented by antioxidant treatments using superoxide dismutase, glutathione, selenium and flavonoids. Melatonin and its metabolites possess free-radical scavenging activity and it has been shown that they protect against cisplatin toxicity. However, the mechanism of the protective effects of melatonin against cisplatin-induced nephrotoxicity is still essentially unknown. We therefore designed this study to investigate the underlying mechanism of the protective effect of melatonin against cisplatin-induced renal damage in a rat nephrotoxicity model in vivo. Methods Twenty eight 8-week-old male Wistar rats were divided into four groups of control, melatonin treatment (4 mg/kg b.w i.p. for 10 days, cisplatin treatment (7 mg/kg b.w., i.p. and melatonin and cisplatin combination treatment. Serum urea nitrogen (urea-N and creatinine levels were measured. Histopathological changes were evaluated. In addition, we analyzed the expression levels of HO-1, Nrf2, NF-κB and AP-1 in Western blot analysis. Results Both serum creatinine and urea nitrogen increased significantly following cisplatin administration alone; these values decreased significantly with melatonin co-treatment of cisplatin-treated rats. Histological analysis showed that cisplatin caused damage in the proximal tubular cells in the kidneys of cisplatin-treated rats; these changes were reversed by melatonin co-treatment. Upon Western blot analysis, melatonin

  4. Mutations in Cockayne Syndrome-Associated Genes (Csa and Csb) Predispose to Cisplatin-Induced Hearing Loss in Mice.

    Science.gov (United States)

    Rainey, Robert N; Ng, Sum-Yan; Llamas, Juan; van der Horst, Gijsbertus T J; Segil, Neil

    2016-04-27

    Cisplatin is a common and effective chemotherapeutic agent, yet it often causes permanent hearing loss as a result of sensory hair cell death. The causes of sensitivity to DNA-damaging agents in nondividing cell populations, such as cochlear hair and supporting cells, are poorly understood, as are the specific DNA repair pathways that protect these cells. Nucleotide excision repair (NER) is a conserved and versatile DNA repair pathway for many DNA-distorting lesions, including cisplatin-DNA adducts. Progressive sensorineural hearing loss is observed in a subset of NER-associated DNA repair disorders including Cockayne syndrome and some forms of xeroderma pigmentosum. We investigated whether either of the two overlapping branches that encompass NER, transcription-coupled repair or global genome repair, which are implicated in Cockayne syndrome and xeroderma pigmentosum group C, respectively, modulates cisplatin-induced hearing loss and cell death in the organ of Corti, the auditory sensory epithelium of mammals. We report that cochlear hair cells and supporting cells in transcription-coupled repair-deficient Cockayne syndrome group A (Csa(-/-)) and group B (Csb(-/-)) mice are hypersensitive to cisplatin, in contrast to global genome repair-deficient Xpc(-/-) mice, both in vitro and in vivo We show that sensory hair cells in Csa(-/-) and Csb(-/-) mice fail to remove cisplatin-DNA adducts efficiently in vitro; and unlike Xpc(-/-) mice, Csa(-/-) and Csb(-/-) mice lose hearing and manifest outer hair cell degeneration after systemic cisplatin treatment. Our results demonstrate that Csa and Csb deficiencies predispose to cisplatin-induced hearing loss and hair/supporting cell damage in the mammalian organ of Corti, and emphasize the importance of transcription-coupled DNA repair in the protection against cisplatin ototoxicity. The utility of cisplatin in chemotherapy remains limited due to serious side effects, including sensorineural hearing loss. We show that mouse

  5. [Treatment effects of electroacupuncture on gentamycin ototoxicity and its mechanism in guinea pigs].

    Science.gov (United States)

    Kang, S J; Shi, X J; Shi, Y Z; Zeng, Z L

    2001-08-01

    To investigate the effects of electroacupuncture on gentamycin (GE) ototoxicity in guinea pigs. Brainstem auditory evoked potential (BAEP) and histochemistry were used in our study. Electroacupuncture reduced the elevated BAEP thresholds and shortened the prolongated BAEP wave latencies and interpeak latencies. It protected the activity of mitochondrial enzyme in the cochlear hair cells and cochlear stria vascularis. Electroacupuncture therapy can reduce GE ototoxicity. The mechanism of electroacupuncture therapy may be associated with its protected activity of mitochondrial enzyme and maintenance of energy metabolism of the cochlear hair cells and cochlear stria vascularis.

  6. Differential susceptibility of rats and guinea pigs to the ototoxic effects of ethyl benzene

    NARCIS (Netherlands)

    Cappaert, NLM; Klis, SFL; Muijser, H; Kulig, BM; Ravensberg, LC; Smoorenburg, GF

    2002-01-01

    The present study was designed to compare the ototoxic effects of volatile ethyl benzene in guinea pigs and rats. Rats showed deteriorated auditory thresholds in the mid-frequency range, based on electrocochleography, after 550-ppm ethyl benzene (8 h/day, 5 days). Outer hair cell (OHC) loss was

  7. Cilastatin attenuates cisplatin-induced proximal tubular cell damage.

    Science.gov (United States)

    Camano, Sonia; Lazaro, Alberto; Moreno-Gordaliza, Estefania; Torres, Ana M; de Lucas, Carmen; Humanes, Blanca; Lazaro, Jose A; Milagros Gomez-Gomez, M; Bosca, Lisardo; Tejedor, Alberto

    2010-08-01

    A major area in cancer therapy is the search for protective strategies against cisplatin-induced nephrotoxicity. We investigated the protective effect of cilastatin on cisplatin-induced injury to renal proximal tubular cells. Cilastatin is a specific inhibitor of renal dehydrodipeptidase I (DHP-I), which prevents hydrolysis of imipenem and its accumulation in the proximal tubule. Primary cultures of proximal cells were treated with cisplatin (1-30 microM) in the presence or absence of cilastatin (200 microg/ml). Apoptosis and mitochondrial injury were assessed by different techniques. Cisplatin uptake and DNA binding were measured by inductively coupled plasma spectrometry. HeLa cells were used to control the effect of cilastatin on the tumoricidal activity of cisplatin. Cisplatin increased cell death, apoptotic-like morphology, caspase activation, and mitochondrial injury in proximal tubular cells in a dose- and time-dependent way. Concomitant treatment with cilastatin reduced cisplatin-induced changes. Cilastatin also reduced the DNA-bound platinum but did not modify cisplatin-dependent up-regulation of death receptors (Fas) or ligands (tumor necrosis factor alpha, Fas ligand). In contrast, cilastatin did not show any effects on cisplatin-treated HeLa cells. Renal DHP-I was virtually absent in HeLa cells. Cilastatin attenuates cisplatin-induced cell death in proximal tubular cells without reducing the cytotoxic activity of cisplatin in tumor cells. Our findings suggest that the affinity of cilastatin for renal dipeptidase makes this effect specific for proximal tubular cells and may be related to a reduction in intracellular drug accumulation. Therefore, cilastatin administration might represent a novel strategy in the prevention of cisplatin-induced acute renal injury.

  8. Role of electrolytes disturbances and Na(+)-K(+)-ATPase in cisplatin - induced renal toxicity and effects of ethanolic extract of Cichorium intybus.

    Science.gov (United States)

    Noori, Shafaq; Mahboob, Tabassum

    2012-10-01

    Cisplatin is known by its toxicity by disturbing electrolytes homeostasis. Thus we aimed to find out the role of herbal plant Cichorium intybus on Cisplatin - induced toxicity. 24 male Albino Wistar rats were randomly divided into 4 groups: Group I is termed as untreated control; Group II is Cisplatin control and received 3 mg/ kg b.w.; i.p.; Group III received C. intybus ethanolic extract at a dose of 500 mg/kg b.w. orally for 10 consecutive days and Group IV is Cisplatin + C. intybus pretreated group. C. intybus is given 30 minutes prior to Cisplatin. Cisplatin - induced electrolytes disturbances is indicated by increase Intra - erythrocyte sodium content, decreased plasma magnesium, calcium and Intra-erythrocyte Na(+)-K(+)-ATPase which implicates the renal toxicity. At a dose of 500 mg/kg b.w. of C. Intybus pretreatment showed partial counter action on the electrolytes imbalances and Na(+)-K(+)-ATPase activity.

  9. Glutamine protects against cisplatin-induced nephrotoxicity by decreasing cisplatin accumulation

    OpenAIRE

    Kim, Hyun-Jung; Park, Dong Jun; Kim, Jin Hyun; Jeong, Eun Young; Jung, Myeong Hee; Kim, Tae-Ho; Yang, Jung Ill; Lee, Gyeong-Won; Chung, Hye Jin; Chang, Se-Ho

    2015-01-01

    Cisplatin is a chemotherapeutic drug but induces acute kidney injury (AKI). Cisplatin-induced AKI depends on several signaling pathways leading to apoptosis in tubular epithelial cells. Glutamine is a substrate for the synthesis of glutathione, the most abundant intracellular thiol and antioxidant, and plays an important role in protecting cells from apoptosis induced by different stimuli. In the present study, we investigated the protective effect of glutamine on cisplatin-induced AKI. Rats ...

  10. Glutamine protects against cisplatin-induced nephrotoxicity by decreasing cisplatin accumulation

    Directory of Open Access Journals (Sweden)

    Hyun-Jung Kim

    2015-01-01

    Full Text Available Cisplatin is a chemotherapeutic drug but induces acute kidney injury (AKI. Cisplatin-induced AKI depends on several signaling pathways leading to apoptosis in tubular epithelial cells. Glutamine is a substrate for the synthesis of glutathione, the most abundant intracellular thiol and antioxidant, and plays an important role in protecting cells from apoptosis induced by different stimuli. In the present study, we investigated the protective effect of glutamine on cisplatin-induced AKI. Rats were divided into control, glutamine, cisplatin, and cisplatin plus glutamine groups. Glutamine ameliorated renal dysfunction, tissue injury, and cisplatin-induced apoptosis. Cisplatin increased cell death, caspase-3 cleavage, activation of MAPKs and p53, oxidative stress, and mRNA expression of TNF-α and TNFR1 in HK-2 cells. Glutamine treatment reduced cisplatin-induced these changes in HK-2 cells. Notably, glutamine reduced the cisplatin-induced expression of organic cation transporter 2 (OCT2 and cisplatin accumulation. Our results suggest that the protective effect of glutamine on cisplatin is specific for proximal tubular cells and the initial effects may be related to attenuation of cisplatin uptake. Thus, glutamine administration might represent a new strategy for the treatment of cisplatin-induced AKI.

  11. Hesperidin protects brain and sciatic nerve tissues against cisplatin-induced oxidative, histological and electromyographical side effects in rats.

    Science.gov (United States)

    Kamisli, Suat; Ciftci, Osman; Kaya, Kursat; Cetin, Asli; Kamisli, Ozden; Ozcan, Cemal

    2015-09-01

    In the present study, the beneficial effect of hesperidin (HP), a citrus flavonoid, on cisplatin (CP)-induced neurotoxicity was investigated. A total of 28 rats were equally divided into four groups; the first group was kept as control. In the second and third groups, CP and HP were given at the doses of 7 and 50 mg/kg/day, respectively. In the fourth group, CP and HP were given together at the same doses. The results indicated that although CP caused significant induction of lipid peroxidations and reduction in the antioxidant defense system potency in the brain and sciatic nerve, HP prevented these effects of CP. Besides, CP led to histopathological damage, mainly apoptosis, as well as electromyographical (EMG) changes in sciatic nerve. On the other hand, HP treatment reversed histopathological and EMG effects of CP. In conclusion, CP had severe dose-limiting neurotoxic effects and these effects of CP can be prevented by HP treatment. Thus, it appears that coadministration of HP with CP may be a useful approach to attenuate the negative effects of CP on the nervous system. © The Author(s) 2013.

  12. Erythropoietin overrides the triggering effect of DNA platination products in a mouse model of Cisplatin-induced neuropathy

    Directory of Open Access Journals (Sweden)

    Egensperger Rupert

    2009-07-01

    Full Text Available Abstract Background Cisplatin mediates its antineoplastic activity by formation of distinct DNA intrastrand cross links. The clinical efficacy and desirable dose escalations of cisplatin are restricted by the accumulation of DNA lesions in dorsal root ganglion (DRG cells leading to sensory polyneuropathy (PNP. We investigated in a mouse model by which mechanism recombinant erythropoietin (rhEPO protects the peripheral nervous system from structural and functional damage caused by cisplatin treatment with special emphasis on DNA damage burden. Results A cumulative dose of 16 mg cisplatin/kg resulted in clear electrophysiological signs of neuropathy, which were significantly attenuated by concomitant erythropoietin (cisplatin 32,48 m/s ± 1,68 m/s; cisplatin + rhEPO 49,66 m/s ± 1,26 m/s; control 55,01 m/s ± 1,88 m/s; p Conclusion The protective effect of recombinant erythropoietin is not mediated by reducing the burden of DNA platination in the target cells, but it is likely to be due to a higher resistance of the target cells to the adverse effect of DNA damage. The increased frequency of intact mitochondria might also contribute to this protective role.

  13. Ameliorative Effects of Chloroform Fraction of Cocos nucifera L. Husk Fiber Against Cisplatin-induced Toxicity in Rats

    Science.gov (United States)

    Adaramoye, Oluwatosin Adekunle; Azeez, Adesola Fausat; Ola-Davies, Olufunke Elizabeth

    2016-01-01

    Background: Cisplatin (Cis) is used in the treatment of solid tumors and is known to elicit serious side effects. Objective: The present study investigated the protective effects of chloroform fraction of Cocos nucifera husk fiber (CFCN) against Cis-induced organs’ damage and chromosomal defect in rats. Quercetin (QUE), standard antioxidant, served as positive control. Materials and Methods: Thirty male Wistar rats were assigned into six groups and treated with corn oil (control), Cis alone, Cis + CFCN, CFCN alone, Cis + QUE, and QUE alone. QUE and CFCN were given at 50 and 200 mg/kg/day, respectively, by oral gavage for 7 days before the rats were exposed to a single dose of Cis (10 mg/kg, intraperitoneal) at the last 36 h of study. Results: Administration of Cis alone caused a significant (P 0.05) affected in Cis-treated rats. Furthermore, the activities of hepatic and renal catalase, superoxide dismutase, glutathione S-transferase, glutathione peroxidase, and levels of reduced glutathione were significantly (P Cocos nucifera husk fiber (CFCN) against Cis-induced organs’ damage while quercetin (QUE) served as standard antioxidant.Thirty male Wistar rats were assigned into six groups and treated with corn oil (Control), Cis alone, Cis + CFCN, CFCN alone, Cis + QUE and QUE alone.QUE and CFCN were given at 50 and 200 mg/kg/day respectively by oral gavage for seven days before the rats were exposed to a single dose of Cis (10mg/kg, i.p.) at the last 36 h of study. Results indicate that administration of Cis caused a significant (P0.05) affected in Cis-treated rats.The activities of hepatic and renal catalase, superoxide dismutase, glutathione-s-transferase, glutathione peroxidase and levels of reduced glutathione were significantly (P<0.05) decreased in Cis-treated rats with concomitant elevation of malondialdehyde.Cis exposure increased the frequency of micronucleated polychromatic erythrocytes (mPCE) by 92%.Pretreatment with CFCN inhibited lipid peroxidation

  14. Pathophysiology of Cisplatin-Induced Acute Kidney Injury

    Directory of Open Access Journals (Sweden)

    Abdullah Ozkok

    2014-01-01

    Full Text Available Cisplatin and other platinum derivatives are the most widely used chemotherapeutic agents to treat solid tumors including ovarian, head and neck, and testicular germ cell tumors. A known complication of cisplatin administration is acute kidney injury (AKI. The nephrotoxic effect of cisplatin is cumulative and dose-dependent and often necessitates dose reduction or withdrawal. Recurrent episodes of AKI may result in chronic kidney disease. The pathophysiology of cisplatin-induced AKI involves proximal tubular injury, oxidative stress, inflammation, and vascular injury in the kidney. There is predominantly acute tubular necrosis and also apoptosis in the proximal tubules. There is activation of multiple proinflammatory cytokines and infiltration of inflammatory cells in the kidney. Inhibition of the proinflammatory cytokines TNF-α or IL-33 or depletion of CD4+ T cells or mast cells protects against cisplatin-induced AKI. Cisplatin also causes endothelial cell injury. An understanding of the pathogenesis of cisplatin-induced AKI is important for the development of adjunctive therapies to prevent AKI, to lessen the need for dose decrease or drug withdrawal, and to lessen patient morbidity and mortality.

  15. Pathophysiology of Cisplatin-Induced Acute Kidney Injury

    Science.gov (United States)

    Ozkok, Abdullah; Edelstein, Charles L.

    2014-01-01

    Cisplatin and other platinum derivatives are the most widely used chemotherapeutic agents to treat solid tumors including ovarian, head and neck, and testicular germ cell tumors. A known complication of cisplatin administration is acute kidney injury (AKI). The nephrotoxic effect of cisplatin is cumulative and dose-dependent and often necessitates dose reduction or withdrawal. Recurrent episodes of AKI may result in chronic kidney disease. The pathophysiology of cisplatin-induced AKI involves proximal tubular injury, oxidative stress, inflammation, and vascular injury in the kidney. There is predominantly acute tubular necrosis and also apoptosis in the proximal tubules. There is activation of multiple proinflammatory cytokines and infiltration of inflammatory cells in the kidney. Inhibition of the proinflammatory cytokines TNF-α or IL-33 or depletion of CD4+ T cells or mast cells protects against cisplatin-induced AKI. Cisplatin also causes endothelial cell injury. An understanding of the pathogenesis of cisplatin-induced AKI is important for the development of adjunctive therapies to prevent AKI, to lessen the need for dose decrease or drug withdrawal, and to lessen patient morbidity and mortality. PMID:25165721

  16. Tomato pomace powder ameliorated cisplatin-induced ...

    African Journals Online (AJOL)

    Tomato (Lycopersicon esculentum) pomace powder (TPP) may be a preventive agent by virtue of its known antioxidant property. The possible protective role of TPP against cisplatin-induced alteration of the microanatomy of rat brain was investigated. Thirty rats were divided equally into five groups: control, propylene glycol ...

  17. Lycium barbarum polysaccharide attenuates cisplatin-induced ...

    African Journals Online (AJOL)

    cisplatin-induced apoptosis in ovary granulosa cells via alleviation of endoplasmic reticulum stress”. Li-Qiong Huang1,2, Yuan-Zhen Zhang1,2*, Bo Zheng3 and Yi He3. 1Department of Obstetrics and Gynecology, Zhongnan Hospital of Wuhan University, 2Hubei Provincial Key Laboratory of. Developmentally Originated ...

  18. An optimized method to assess ototoxic effects in the lateral line of zebrafish (Danio rerio) embryos.

    Science.gov (United States)

    Stengel, Daniel; Zindler, Florian; Braunbeck, Thomas

    2017-03-01

    In order to clarify the suitability of the lateral line of zebrafish (Danio rerio) embryos as a model for the screening of ototoxic (neurotoxic) effects, existing neuromast assays were adapted, improved and validated with a series of chemicals known or unknown for their ototoxic potential (caffeine copper sulfate, dichlorvos, 2.4-dinitrotoluene, neomycin, 4-nonylphenol, perfluorooctanesulfonic acid). Present methods were improved by (1) the introduction of a 4-step scoring system, (2) the selection of neuromasts from both the anterior and posterior lateral line systems, (3) a combined DASPEI/DAPI staining applied after both a continuous and pulse exposure scenario, and (4) an additional screening for nuclear fragmentation. Acute toxicities of the model substances were determined by means of the fish embryo test as specified in OECD TG 236, and EC 10 concentrations were used as the highest test concentration in the neuromast assay. The enhanced neuromast assay identified known ototoxic substances such as neomycin and copper sulfate as ototoxic at sensitivities similar to those of established methods, with pulse exposure leading to stronger effects than continuous exposure. Except for caffeine, all substances tested (dichlorvos, 2.4-dinitrotoluene, 4-nonylphenol, perfluorooctanesulfonic acid) produced significant toxic effects in neuromasts at EC 10 concentrations. Depending on the test substances and their location along the lateral line, specific neuromasts differed in sensitivity. Generally, neuromasts proved more sensitive in the pulse exposure scenario. Whereas for neomycin and copper sulfate neuromasts located along the anterior lateral line were more sensitive, posterior lateral line neuromasts proved more sensitive for the other test substances. Nuclear fragmentation could not only be associated with all test substances, but, albeit at lower frequencies, also with negative controls, and could, therefore, not be assigned specifically to chemical damage. The

  19. Cisplatin induces differentiation of breast cancer cells.

    Science.gov (United States)

    Prabhakaran, Praseetha; Hassiotou, Foteini; Blancafort, Pilar; Filgueira, Luis

    2013-01-01

    Breast tumors are heterogeneous including cells with stem cell properties and more differentiated cells. This heterogeneity is reflected into the molecular breast cancer subtypes. Breast cancer stem cells are resistant to chemotherapy, thus recent efforts are focusing on identifying treatments that shift them toward a more differentiated phenotype, making them more susceptible to chemotherapy. We examined whether the drug cisplatin induces differentiation in breast cancer cell lines that represent different breast cancer subtypes. We used three cell lines representing triple-negative breast cancers, BT-549 and MDA-MB-231 (claudin-low), and MDA-MB-468 (basal-like), along with estrogen and progesterone receptor positive MCF-7 cells (luminal). Cisplatin was applied at 2.5, 5, 10, and 20 μM, and cell viability and proliferation were measured using MTS and BrdU assays, respectively. The effect of cisplatin on the cellular hierarchy was examined by flow cytometry, immunofluorescence and qRT-PCR. Cisplatin treatment of 10 and 20 μM reduced cell viability by 36-51% and proliferation capacity by 36-67%. Treatment with cisplatin resulted in 12-67% down-regulation of stem cell markers (CD49f, SSEA4) and 10-130% up-regulation of differentiation markers (CK18, SMA, β-tubulin). At the mRNA level, CD49f was down-regulated whilst β-tubulin was up-regulated in the claudin-low cell lines. SSEA4 protein expression decreased upon cisplatin treatment, but SSEA4 mRNA expression increased indicating a differential regulation of cisplatin at the post-transcriptional level. It is concluded that cisplatin reduces breast cancer cell survival and induces differentiation of stem/progenitor cell subpopulations within breast cancer cell lines. These effects indicate the potential of this drug to target specific chemotherapy-resistant cells within a tumor.

  20. Hesperidin alleviates cisplatin-induced hepatotoxicity in rats without inhibiting its antitumor activity.

    Science.gov (United States)

    Omar, Hany A; Mohamed, Wafaa R; Arafa, El-Shaimaa A; Shehata, Basim A; El Sherbiny, Gamal A; Arab, Hany H; Elgendy, Abdel Nasser A M

    2016-04-01

    Hesperidin, a naturally occurring flavonoid, exerts many clinically appreciable effects such as anti-oxidant, anti-allergic and anti-inflammatory actions. The present study aimed to investigate the possible protective effects of multiple doses of hesperidin against cisplatin-induced acute hepatotoxicity in rats. Hesperidin (100 or 200mg/kg po) was given to rats one day before cisplatin (7.5mg/kg, ip) injection. All animals were sacrificed 5 days after cisplatin injection and blood samples were collected for determination of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities, triglycerides (TG) and total cholesterol levels. Liver samples were used for the determination of malondialdehyde (MDA), glutathione (GSH), total nitrate and nitrite contents. Western blot analysis was used for the assessment of NF-κB and p-Akt expression and histopathological examination was also performed. Results showed that hesperidin significantly reduced cisplatin-induced elevations in serum ALT and AST activities, TG and total cholesterol levels. It also reduced cisplatin-induced oxidative stress by significant reduction in liver MDA and NO content and elevation of GSH content. In addition, hesperidin significantly counteracted cisplatin-induced increased NF-κB expression and decreased p-Akt expression. Histopathological examination revealed that hesperidin greatly protected liver against cisplatin-induced injury. Moreover hesperidin did not inhibit the cytotoxic effect of cisplatin on cancer cells as determined by MTT assay. Hesperidin decreased cisplatin-induced functional and histopathological liver damage in a dose-dependent manner without affecting its potential cytotoxic effect. Copyright © 2015 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

  1. Mechanisms of cisplatin-induced muscle atrophy

    Energy Technology Data Exchange (ETDEWEB)

    Sakai, Hiroyasu, E-mail: sakai@hoshi.ac.jp [Department of Pharmacology, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 1428501 (Japan); Division of Pharmacy Professional Development and Research, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 1428501 (Japan); Sagara, Atsunobu; Arakawa, Kazuhiko; Sugiyama, Ryoto; Hirosaki, Akiko; Takase, Kazuhide; Jo, Ara [Department of Pharmacology, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 1428501 (Japan); Sato, Ken [Department of Pharmacology, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 1428501 (Japan); Division of Pharmacy Professional Development and Research, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 1428501 (Japan); Chiba, Yoshihiko [Department of Biology, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 1428501 (Japan); Yamazaki, Mitsuaki [Department of Anesthesiology, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, 2630 Sugitani, Toyama-shi, Toyama 9300194 (Japan); Matoba, Motohiro [Department of Palliative Medicine and Psychooncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 1040045 (Japan); Narita, Minoru, E-mail: narita@hoshi.ac.jp [Department of Pharmacology, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 1428501 (Japan)

    2014-07-15

    Fatigue is the most common side effect of chemotherapy. However, the mechanisms of “muscle fatigue” induced by anti-cancer drugs are not fully understood. We therefore investigated the muscle-atrophic effect of cisplatin, a platinum-based anti-cancer drug, in mice. C57BL/6J mice were treated with cisplatin (3 mg/kg, i.p.) or saline for 4 consecutive days. On Day 5, hindlimb and quadriceps muscles were isolated from mice. The loss of body weight and food intake under the administration of cisplatin was the same as those in a dietary restriction (DR) group. Under the present conditions, the administration of cisplatin significantly decreased not only the muscle mass of the hindlimb and quadriceps but also the myofiber diameter, compared to those in the DR group. The mRNA expression levels of muscle atrophy F-box (MAFbx), muscle RING finger-1 (MuRF1) and forkhead box O3 (FOXO3) were significantly and further increased by cisplatin treated group, compared to DR. Furthermore, the mRNA levels of myostatin and p21 were significantly upregulated by the administration of cisplatin, compared to DR. On the other hand, the phosphorylation of Akt and FOXO3a, which leads to the blockade of the upregulation of MuRF1 and MAFbx, was significantly and dramatically decreased by cisplatin. These findings suggest that the administration of cisplatin increases atrophic gene expression, and may lead to an imbalance between protein synthesis and protein degradation pathways, which would lead to muscle atrophy. This phenomenon could, at least in part, explain the mechanism of cisplatin-induced muscle fatigue. - Highlights: • Cisplatin decreased mass and myofiber diameter in quadriceps muscle. • The mRNA of MAFbx, MuRF1 and FOXO3 were increased by the cisplatin. • The mRNA of myostatin and p21 were upregulated by cisplatin. • The phosphorylation of Akt and FOXO3a was decreased by cisplatin.

  2. Pyruvate dehydrogenase kinase 4 deficiency attenuates cisplatin-induced acute kidney injury.

    Science.gov (United States)

    Oh, Chang Joo; Ha, Chae-Myeong; Choi, Young-Keun; Park, Sungmi; Choe, Mi Sun; Jeoung, Nam Ho; Huh, Yang Hoon; Kim, Hyo-Jeong; Kweon, Hee-Seok; Lee, Ji-Min; Lee, Sun Joo; Jeon, Jae-Han; Harris, Robert A; Park, Keun-Gyu; Lee, In-Kyu

    2017-04-01

    Clinical prescription of cisplatin, one of the most widely used chemotherapeutic agents, is limited by its side effects, particularly tubular injury-associated nephrotoxicity. Since details of the underlying mechanisms are not fully understood, we investigated the role of pyruvate dehydrogenase kinase (PDK) in cisplatin-induced acute kidney injury. Among the PDK isoforms, PDK4 mRNA and protein levels were markedly increased in the kidneys of mice treated with cisplatin, and c-Jun N-terminal kinase activation was involved in cisplatin-induced renal PDK4 expression. Treatment with the PDK inhibitor sodium dichloroacetate (DCA) or genetic knockout of PDK4 attenuated the signs of cisplatin-induced acute kidney injury, including apoptotic morphology of the kidney tubules along with numbers of TUNEL-positive cells, cleaved caspase-3, and renal tubular injury markers. Cisplatin-induced suppression of the mitochondrial membrane potential, oxygen consumption rate, expression of electron transport chain components, cytochrome c oxidase activity, and disruption of mitochondrial morphology were noticeably improved in the kidneys of DCA-treated or PDK4 knockout mice. Additionally, levels of the oxidative stress marker 4-hydroxynonenal and mitochondrial reactive oxygen species were attenuated, whereas superoxide dismutase 2 and catalase expression and glutathione synthetase and glutathione levels were recovered in DCA-treated or PDK4 knockout mice. Interestingly, lipid accumulation was considerably attenuated in DCA-treated or PDK4 knockout mice via recovered expression of peroxisome proliferator-activated receptor-α and coactivator PGC-1α, which was accompanied by recovery of mitochondrial biogenesis. Thus, PDK4 mediates cisplatin-induced acute kidney injury, suggesting that PDK4 might be a therapeutic target for attenuating cisplatin-induced acute kidney injury. Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

  3. The ototoxic effect of boric acid solutions applied into the middle ear of guinea pigs.

    Science.gov (United States)

    Oztürkcan, Sedat; Dündar, Riza; Katilmis, Hüseyin; Ilknur, Ali Ekber; Aktaş, Sinem; Haciömeroğlu, Senem

    2009-05-01

    This study analyzed the ototoxic effects of boric acid solutions. Boric acid solutions have been used as otologic preparations for many years. Boric acid is commonly found in solutions prepared with alcohol or distilled water but can also be found in a powder form. These preparations are used for both their antiseptic and acidic qualities in external and middle ear infections. We investigated the ototoxic effect of boric acid solutions on guinea pigs. We are unaware of any similar, previously published study of this subject in English. The study was conducted on 28 young albino guinea pigs. Prior to application of the boric acid solution under general anesthesia, an Auditory Brainstem Response (ABRs) test was applied to the right ear of the guinea pigs. Following the test, a perforation was created on the tympanic membrane of the right ear of each guinea pig and small gelfoam pieces were inserted into the perforated area. Test solutions were administered to the middle ear for 10 days by means of a transcanal route. Fifteen days after inserting the gelfoams in all of the guinea pigs, we anasthesized the guinea pigs and removed the gelfoams from the perforated region of the ear and then performed an ABRs on each guinea pig. The ABRs were within the normal range before the applications. After the application, no significant changes were detected in the ABRs thresholds in neither the saline group nor the group administered boric acid and distilled water solution; however, significant changes were detected in the ABRs thresholds of the Gentamicine and boric acid and alcohol solution groups. We believe that a 4% boric acid solution prepared with distilled water can be a more reliable preparation than a 4% boric acid solution prepared with alcohol.

  4. Drp1-dependent mitophagy protects against cisplatin-induced apoptosis of renal tubular epithelial cells by improving mitochondrial function.

    Science.gov (United States)

    Zhao, Chuanyan; Chen, Zhuyun; Qi, Jia; Duan, Suyan; Huang, Zhimin; Zhang, Chengning; Wu, Lin; Zeng, Ming; Zhang, Bo; Wang, Ningning; Mao, Huijuan; Zhang, Aihua; Xing, Changying; Yuan, Yanggang

    2017-03-28

    Cisplatin chemotherapy often causes acute kidney injury (AKI) in cancer patients. There is increasing evidence that mitochondrial dysfunction plays an important role in cisplatin-induced nephrotoxicity. Degradation of damaged mitochondria is carried out by mitophagy. Although mitophagy is considered of particular importance in protecting against AKI, little is known of the precise role of mitophagy and its molecular mechanisms during cisplatin-induced nephrotoxicity. Also, evidence that activation of mitophagy improved mitochondrial function is lacking. Furthermore, several evidences have shown that mitochondrial fission coordinates with mitophagy. The aim of this study was to investigate whether activation of mitophagy protects against mitochondrial dysfunction and renal proximal tubular cells injury during cisplatin treatment. The effect of mitochondrial fission on mitophagy was also investigated. In cultured human renal proximal tubular cells, we observed that 3-methyladenine, a pharmacological inhibitor of autophagy, blocked mitophagy and exacerbated cisplatin-induced mitochondrial dysfunction and cells injury. In contrast, autophagy activator rapamycin enhanced mitophagy and protected against the harmful effects of cisplatin on mitochondrial function and cells viability. Suppression of mitochondrial fission by knockdown of its main regulator dynamin-related protein-1 (Drp1) decreased cisplatin-induced mitophagy. Meanwhile, Drp1 suppression protected against cisplatin-induced cells injury by inhibiting mitochondrial dysfunction. Our results provide evidence that Drp1-depedent mitophagy has potential as renoprotective targets for the treatment of cisplatin-induced AKI.

  5. Parents are aware of the ototoxic effects of chemotherapy in paediatrics undergoing cancer treatment – Professional versus parental views: A pilot study

    OpenAIRE

    Nomfundo F. Moroe; Kirstie Hughes

    2017-01-01

    Background: The primary goal of chemotherapy is to cure cancer and its symptoms. Hence, in recent years, there has been an increase in cancer paediatric survival rate. However, there have also been adverse side effects such as ototoxic hearing loss because of chemotherapy. Therefore, this study aimed at exploring whether the parents of children undergoing chemotherapy are aware of ototoxic effects of chemotherapy.Methods: A non-experimental quantitative study was conducted to collect data thr...

  6. Effect of Gingerol on Cisplatin-Induced Pica Analogous to Emesis Via Modulating Expressions of Dopamine 2 Receptor, Dopamine Transporter and Tyrosine Hydroxylase in the Vomiting Model of Rats.

    Science.gov (United States)

    Qian, Weibin; Cai, Xinrui; Wang, Yingying; Zhang, Xinying; Zhao, Hongmin; Qian, Qiuhai; Yang, Zhihong; Liu, Zhantao; Hasegawa, Junichi

    2016-06-01

    Gingerol, the generic term for pungent constituents in ginger, has been used for treating vomiting in China. We are going to investigate the mechanisms of inhibitive effect of gingerol on cisplatin-induced pica behaviour by studying on both peripheral and central levels, and the effects of gingerol on homeostasis of dopamine (DA) transmission: dopamine D2 receptor (D2R), dopamine transporter (DAT) and tyrosine hydroxylase (TH). The antiemetic effect of gingerol was investigated on a vomiting model in rats induced by cisplatin 3 mg·kg(-1) intraperitoneal injection (i.p.). Rats were randomly divided into the normal control group (C), simple gingerol control group (CG), cisplatin control group (V), cisplatin + metoclopramide group (M), cisplatin + low-dose gingerol group (GL), cisplatin + middle-dose gingerol group (GM) and cisplatin + high-dose gingerol group (GH). In observation period, rats in Groups C and V were pretreated with sterile saline 3 mL i.g.; rats in Group CG were pretreated with gingerol 40 mg·kg(-1) i.g.; rats in Group M were pretreated with metoclopramide 2.5 mg·kg(-1) i.g.; rats in Groups GL, GM and GH were pretreated with gingerol 10, 20 and 40 mg·kg(-1) i.g. for 3 days, respectively. Cisplatin (3 mg·kg(-1), i.p.) was administered one time after each treatment with the antiemetic agent or its vehicle except the Groups C and CG. The distribution of D2R, DAT and TH in the area postrema and ileum were measured by immunohistochemistry and quantitated based on the image analysis, and the expression of DAT and TH in the area postrema and ileum were measured by RT-PCR. The weights of kaolin eaten of the remaining rats were observed in every 6 h continuously for 72 h. The weight of kaolin eaten in rats induced by cisplatin was significantly reduced by pretreatment with gingerol in a dose-dependent manner during the 0-24 h and 24-72 h periods (P Gingerol markedly improved gastric emptying induced by cisplatin in a dose-dependent manner (P Gingerol is

  7. Differential and additive suppressive effects of 5-HT3 (palonosetron)- and NK1 (netupitant)-receptor antagonists on cisplatin-induced vomiting and ERK1/2, PKA and PKC activation.

    Science.gov (United States)

    Darmani, Nissar A; Zhong, Weixia; Chebolu, Seetha; Mercadante, Frank

    2015-04-01

    To better understand the anti-emetic profile of the 5-HT3 (palonosetron)- and the tachykinin NK1 (netupitant) -receptor antagonists, either alone or in combination, we evaluated the effects of palonosetron and/or netupitant pretreatment on cisplatin-evoked vomiting and changes in the phosphorylation of brainstem kinases such as the extracellular signal-regulated protein kinases 1 and 2 (ERK1/2), protein kinase C alpha/beta (PKCα/β), and protein kinase A (PKA) in the least shrew. Our results demonstrate that cisplatin (10mg/kg, i.p.) causes emesis in the least shrew over 40h with respective peak early- and delayed-phases occurring at 1 - 2 and 32 - 34h post-injection. During the early phase (0 - 16h post cisplatin), palonosetron (0.1mg/kg, s.c.) significantly protected shrews from vomiting with a near complete suppression of vomit frequency. Palonosetron also significantly protected shrews from vomiting during the delayed phase (27 - 40h post cisplatin), but the reduction in mean vomit frequency failed to achieve significance. On the other hand, netupitant (5mg/kg, i.p.) totally abolished vomiting during the delayed phase, and tended to suppress the mean vomit frequency during the acute phase. The combined treatment protected shrews almost completely from vomiting during both phases. Brainstem pERK1/2 levels were significantly elevated at all time-points except at 40h post-cisplatin administration. PKA phosphorylation tended to be elevated throughout the delayed phase, but a significant increase only occurred at 33h. Brainstem pPKCα/β levels were enhanced during acute-phase with a significant elevation at 2h. Palonosetron, netupitant or their combination had no effect on elevated pERK1/2 levels during acute phase, but the combination reversed ERK1/2 phosphorylation at 33h post-cisplatin treatment. In addition, only the combined regimen prevented the cisplatin-induced PKCα/β phosphorylation observed at the acute phase. On the other hand, palonosetron and

  8. Excitatory Hindbrain-Forebrain Communication Is Required for Cisplatin-Induced Anorexia and Weight Loss.

    Science.gov (United States)

    Alhadeff, Amber L; Holland, Ruby A; Zheng, Huiyuan; Rinaman, Linda; Grill, Harvey J; De Jonghe, Bart C

    2017-01-11

    Cisplatin chemotherapy is commonly used to treat cancer despite severe energy balance side effects. In rats, cisplatin activates nucleus tractus solitarius (NTS) projections to the lateral parabrachial nucleus (lPBN) and calcitonin-gene related peptide (CGRP) projections from the lPBN to the central nucleus of the amygdala (CeA). We demonstrated previously that CeA glutamate receptor signaling mediates cisplatin-induced anorexia and body weight loss. Here, we used neuroanatomical tracing, immunofluorescence, and confocal imaging to demonstrate that virtually all NTS→lPBN and lPBN→CeA CGRP projections coexpress vesicular glutamate transporter 2 (VGLUT2), providing evidence that excitatory projections mediate cisplatin-induced energy balance dysregulation. To test whether lPBN→CeA projection neurons are required for cisplatin-induced anorexia and weight loss, we inhibited these neurons chemogenetically using a retrograde Cre-recombinase-expressing canine adenovirus-2 in combination with Cre-dependent inhibitory Designer Receptors Exclusive Activated by Designer Drugs (DREADDs) before cisplatin treatment. Inhibition of lPBN→CeA neurons attenuated cisplatin-induced anorexia and body weight loss significantly. Using a similar approach, we additionally demonstrated that inhibition of NTS→lPBN neurons attenuated cisplatin-induced anorexia and body weight loss significantly. Together, our data support the view that excitatory hindbrain-forebrain projections are necessary for cisplatin's untoward effects on energy intake, elucidating a key neuroanatomical circuit driving pathological anorexia and weight loss that accompanies chemotherapy treatment. Chemotherapy treatments are commonly used to treat cancers despite accompanying anorexia and weight loss that may limit treatment adherence and reduce patient quality of life. Strikingly, we lack a neural understanding of, and effective treatments for, chemotherapy-induced anorexia and weight loss. The current data

  9. Aminoglycoside ototoxicity and the medial efferent system: II. Comparison of acute effects of different antibiotics.

    Science.gov (United States)

    Lima da Costa, D; Erre, J P; Pehourq, F; Aran, J M

    1998-01-01

    Gentamicin (GM) has been shown to reversibly reduce the ability of contralateral noise to suppress ipsilateral cochlear activity, in a dose-dependent manner. However, during chronic administration of lower doses (60 mg/kg) the involvement of medial efferents could not be demonstrated. The purposes of the present study were to determine whether other aminoglycosides would display the same acute effects as GM and whether there was any correlation between their specificity and degree of cochlear and vestibular toxicity and their potency of blockade of the medial efferent system. Thus, we observed changes in ipsilateral ensemble background activity (EBA) of the VIIIth nerve without and with contralateral low level (55 dB SPL) broadband noise stimulation, in awake guinea pigs (GPs), before and after one single high-dose intramuscular injection of different aminoglycoside antibiotics (AAs) (gentamicin, amikacin, neomycin, netilmicin, streptomycin, tobramycin). For comparison, the effects of strychnine, a known antagonist of the efferent transmission and of cisplatin, an antineoplastic agent with cochleotoxic properties were also studied. Netilmicin displayed blocking properties similar to GM, although less pronounced, while amikacin and neomycin had no effect on medial efferent function. With tobramycin and streptomycin a decrease in suppression was usually associated with a reduction of the EBA measured without acoustic stimulation. However, with cisplatin, suppression was still effective when EBA was severely decreased. We could not observe specific effects of strychnine on medial efferent function. In conclusion, no correlation was found between specificity and degree of AA ototoxicity and their action on the medial efferent system.

  10. Cisplatin-induced renal toxicity via tumor necrosis factor-α, interleukin 6, tumor suppressor P53, DNA damage, xanthine oxidase, histological changes, oxidative stress and nitric oxide in rats: protective effect of ginseng.

    Science.gov (United States)

    Yousef, Mokhtar I; Hussien, Hend M

    2015-04-01

    Cisplatin is an effective chemotherapeutic agent successfully used in the treatment of a wide range of solid tumors, while its usage is limited due to its nephrotoxicity. The present study was undertaken to examine the effectiveness of ginseng to ameliorate the renal nephrotoxicity, damage in kidney genomic DNA, tumor necrosis factor-α, interleukin 6, tumor suppressor P53, histological changes and oxidative stress induced by cisplatin in rats. Cisplatin caused renal damage, including DNA fragmentation, upregulates gene expression of tumor suppressor protein p53 and tumor necrosis factor-α and IL-6. Cisplatin increased the levels of kidney TBARS, xanthine oxidase, nitric oxide, serum urea and creatinine. Cisplatin decreased the activities of antioxidant enzymes (GST, GPX, CAT and SOD), ATPase and the levels of GSH. A microscopic examination showed that cisplatin caused kidney damage including vacuolization, severe necrosis and degenerative changes. Ginseng co-treatment with cisplatin reduced its renal damage, oxidative stress, DNA fragmentation and induced DNA repair processes. Also, ginseng diminished p53 activation and improved renal cell apoptosis and nephrotoxicity. It can be concluded that, the protective effects of ginseng against cisplatin induced-renal damage was associated with the attenuation of oxidative stress and the preservation of antioxidant enzymes. Copyright © 2015 Elsevier Ltd. All rights reserved.

  11. Involvement of substance P in the development of cisplatin-induced acute and delayed pica in rats.

    Science.gov (United States)

    Yamamoto, Kouichi; Asano, Keiko; Tasaka, Ayana; Ogura, Yuko; Kim, Seikou; Ito, Yui; Yamatodani, Atsushi

    2014-06-01

    Although substance P (SP) and neurokinin NK1 receptors have been reported to be involved in cisplatin-induced acute and delayed emesis, their precise roles remain unclear. Pica, the consumption of non-nutrient materials such as kaolin in rats, can be used as a model of nausea in humans. We investigated the time-dependent changes in cisplatin-induced pica and the involvement of SP and NK1 receptors in this behaviour. Rats were administered cisplatin with or without a daily injection of a 5-HT3 receptor antagonist (granisetron) or an NK1 receptor antagonist (aprepitant), and kaolin intake was then monitored for 5 days. The effects of granisetron on the cisplatin-induced expression of preprotachykinin-A (PPT-A) mRNA, which encodes mainly for SP, and on SP release in the medulla, measured by in vivo brain microdialysis, were also investigated. Cisplatin induced pica within 8 h of its administration that continued for 5 days. Granisetron inhibited the acute phase (day 1), but not the delayed phase (days 2-5), of pica, whereas aprepitant abolished both phases. Within 24 h of the injection of cisplatin, PPT-A mRNA expression and SP release in the medulla were significantly increased; these findings lasted during the observation period and were inhibited by granisetron for up to 24 h. The profiles of cisplatin-induced pica in rats are similar to clinical findings for cisplatin-induced emesis in humans, and we showed that SP production in the medulla and activation of NK1 receptors are involved in this cisplatin-induced pica. © 2014 The British Pharmacological Society.

  12. Efficacy of safranal to cisplatin-induced nephrotoxicity.

    Science.gov (United States)

    Karafakıoğlu, Yasemin Sunucu; Bozkurt, Mehmet Fatih; Hazman, Ömer; Fıdan, A Fatih

    2017-03-20

    The aim of the present study was to investigate the effects of safranal on cisplatin-induced nephrotoxicity and oxidative stress in rats. Adult male Sprague-Dawley rats were randomly divided into five groups. The control group received physiological saline; animals in Group 2 received only safranal and in Group 3 received only cisplatin; 5 days of safranal treatment was performed following administration of cisplatin for the animals in Group 4; 5 days of safranal pretreatment was applied to the animals in Group 5 before administration of cisplatin. Cisplatin (7 mg/kg) was intraperitoneally injected as a single dose and safranal (200 mg/kg) was administered by gavage. Biochemical and histopathological methods were utilized for evaluation of the nephrotoxicity. The concentrations of creatinine and urea in plasma and levels of malondialdehyde (MDA) and glutathione (GSH) as well as total antioxidant status (TAS) and total oxidant status (TOS) were determined in kidney tissue. Administration of cisplatin to rats induced a marked renal failure, characterized with a significant increase in plasma creatinine and urea concentrations. MDA and TOS levels of rats that received cisplatin alone were not significantly different compared with those of the control group, but GSH and TAS levels in the only cisplatin-administered group were significantly decreased. Safranal administration produced amelioration in biochemical indices of nephrotoxicity in both plasma and kidney tissues when compared with the only cisplatin-administered group, pretreatment with safranal being more effective. As a result, safranal treatment might have a protective effect against cisplatin-induced nephrotoxicity and oxidative stress in rat. © 2017 The Author(s); published by Portland Press Limited on behalf of the Biochemical Society.

  13. Neferine reduces cisplatin-induced nephrotoxicity by enhancing autophagy via the AMPK/mTOR signaling pathway.

    Science.gov (United States)

    Li, Hui; Tang, Yuling; Wen, Long; Kong, Xianglong; Chen, Xuelian; Liu, Ping; Zhou, Zhiguo; Chen, Wenhang; Xiao, Chenggen; Xiao, Ping; Xiao, Xiangcheng

    2017-03-11

    Cisplatin is one of the most effective chemotherapeutic agents; however, its clinical use is limited by serious side effects of which nephrotoxicity is the most important. Nephrotoxicity induced by cisplatin is closely associated with autophagy reduction and caspase activation. In this study, we investigated whether neferine, an autophagy inducer, had a protective effect against cisplatin-induced nephrotoxicity. In an in vitro cisplatin-induced nephrotoxicity model, we determined that neferine was able to induce autophagy and that pretreatment with neferine not only attenuated cisplatin-induced cell apoptosis but further activated cell autophagy. This pro-survival effect was abolished by the autophagic flux inhibitor chloroquine. Furthermore, neferine pretreatment activated the AMPK/mTOR pathway; however, pharmacological inhibition of AMPK abolished neferine-mediated autophagy and nephroprotection against cisplatin-induced apoptosis. Collectively, our findings suggest for the first time the possible protective mechanism of neferine, which is crucial for its further development as a potential therapeutic agent for cisplatin-induced nephrotoxicity. Copyright © 2017 Elsevier Inc. All rights reserved.

  14. Infrasound sensitizes human glioblastoma cells to cisplatin-induced apoptosis.

    Science.gov (United States)

    Rachlin, Kenneth; Moore, Dan H; Yount, Garret

    2013-11-01

    The development of nontoxic agents that can selectively enhance the cytotoxicity of chemotherapy is an important aim in oncology. This study evaluates the ability of infrasound exposure to sensitize glioblastoma cells to cisplatin-induced apoptosis. The infrasound was delivered using a device designed to replicate the unique infrasound emissions measured during external Qigong treatments. Human glioblastoma cell lines harboring wild-type p53 (U87) or mutant p53 (U251, SF210, and SF188) were treated in culture with cisplatin, infrasound emissions, or the combination of the 2 agents. Induction of apoptosis was quantified after 24 hours by flow cytometry following annexin V/propidium iodide staining. Infrasound emissions alone, delivered at moderate levels (~10 mPa) with dynamic frequency content (7-13 Hz), did not induce apoptosis, yet combining infrasound with cisplatin augmented the induction of apoptosis by cisplatin in all the 4 cell lines (P < .05). Increased cellular uptake of the fluorophore calcein associated with infrasound exposure was quantified by fluorescence microscopy as well as flow cytometry, demonstrating increased cell membrane permeability. The 4 cell lines differed in the degree to which infrasound exposure increased calcein uptake, and these differences were predictive of the extent to which infrasound enhanced cisplatin-induced apoptosis. When exposed to specific frequencies, membrane permeabilization also appeared to be differentially responsive for each cell line, suggesting the potential for selective targeting of tissue types using isolated infrasonic frequencies. Additionally, the pressure amplitudes used in this study were several orders of magnitude less than those used in similar studies involving ultrasound and shock waves. The results of this study provide support for using infrasound to enhance the chemotherapeutic effects of cisplatin in a clinical setting.

  15. Cisplatin Induces a Mitochondrial-ROS Response That Contributes to Cytotoxicity Depending on Mitochondrial Redox Status and Bioenergetic Functions

    Science.gov (United States)

    Marullo, Rossella; Werner, Erica; Degtyareva, Natalya; Moore, Bryn; Altavilla, Giuseppe; Ramalingam, Suresh S.; Doetsch, Paul W.

    2013-01-01

    Cisplatin is one of the most effective and widely used anticancer agents for the treatment of several types of tumors. The cytotoxic effect of cisplatin is thought to be mediated primarily by the generation of nuclear DNA adducts, which, if not repaired, cause cell death as a consequence of DNA replication and transcription blockage. However, the ability of cisplatin to induce nuclear DNA (nDNA) damage per se is not sufficient to explain its high degree of effectiveness nor the toxic effects exerted on normal, post-mitotic tissues. Oxidative damage has been observed in vivo following exposure to cisplatin in several tissues, suggesting a role for oxidative stress in the pathogenesis of cisplatin-induced dose-limiting toxicities. However, the mechanism of cisplatin-induced generation of ROS and their contribution to cisplatin cytotoxicity in normal and cancer cells is still poorly understood. By employing a panel of normal and cancer cell lines and the budding yeast Saccharomyces cerevisiae as model system, we show that exposure to cisplatin induces a mitochondrial-dependent ROS response that significantly enhances the cytotoxic effect caused by nDNA damage. ROS generation is independent of the amount of cisplatin-induced nDNA damage and occurs in mitochondria as a consequence of protein synthesis impairment. The contribution of cisplatin-induced mitochondrial dysfunction in determining its cytotoxic effect varies among cells and depends on mitochondrial redox status, mitochondrial DNA integrity and bioenergetic function. Thus, by manipulating these cellular parameters, we were able to enhance cisplatin cytotoxicity in cancer cells. This study provides a new mechanistic insight into cisplatin-induced cell killing and may lead to the design of novel therapeutic strategies to improve anticancer drug efficacy. PMID:24260552

  16. Cisplatin-induced autophagy protects breast cancer cells from apoptosis by regulating yes-associated protein.

    Science.gov (United States)

    Jiang, Yulin; Ji, Feihu; Liu, Yifeng; He, Mengjia; Zhang, Zhiqian; Yang, Junhong; Wang, Nian; Zhong, Changli; Jin, Qianni; Ye, Xiangsen; Chen, Tingmei

    2017-10-16

    Breast cancer is a common cause of cancer‑related deaths in women. Treatment with cisplatin exhibits some therapeutic efficacy. However, treatment optimization is required, and the mechanisms underlying the cisplatin's proapoptotic effects remain unclear. In the present study, we demonstrated that cisplatin induced apoptosis and autophagy in breast cancer cells. Autophagy induced by cisplatin played a protective role in breast cancer cells, which impaired its proapoptotic effect. Mechanistically, for the first time, we found that cisplatin treatment activated the MAPK signaling pathway and promoted autophagy via the ERK signaling pathway. Notably, we found that nuclear translocation of yes-associated protein (YAP) was regulated by cisplatin-induced autophagy, and we identified YAP as a survival input that promoted survival in cisplatin-treated breast cancer cells. These findings revealed that administration of cisplatin along with an autophagy inhibitor is a promising therapeutic strategy for treating breast cancer.

  17. Relative ototoxicity of 21 aromatic solvents

    Energy Technology Data Exchange (ETDEWEB)

    Gagnaire, Francois; Langlais, Cristina [Institut National de Recherche et de Securite, Departement Polluants et Sante, Vandoeuvre (France)

    2005-06-01

    of the ototoxic agents as expressed by the octanol/water partition coefficients. However, it seemed that some structural constraint was essential to induce ototoxicity. It seems there must be a single side-chain on the aromatic ring for ototoxicity, except with p-xylene. The other aromatic solvents with two side-chains were not ototoxic. When the saturated side-chain was branched (isopropylbenzene, isobutylbenzene, sec-butylbenzene, tert-butylbenzene), no ototoxicity was observed. The ototoxic potency increased when the length of the saturated side-chain extended from one carbon atom to two carbon atoms. Beyond that point, the ototoxic effect decreased with n-propylbenzene and disappeared with n-butylbenzene. Moreover, unsaturation of the side-chain of allylbenzene increased the ototoxicity of n-propylbenzene substantially. Branching of the unsaturated chain ({alpha}-methylstyrene and trans-{beta}-methylstyrene) decreased the ototoxicity of styrene. (orig.)

  18. Thalidomide ameliorates cisplatin-induced nephrotoxicity by inhibiting renal inflammation in an experimental model.

    Science.gov (United States)

    Amirshahrokhi, Keyvan; Khalili, Ali-Reza

    2015-04-01

    Cisplatin is a platinum-based chemotherapy drug. However, its chemotherapeutic use is restricted by serious side effects, especially nephrotoxicity. Inflammatory mechanisms have a significant role in the pathogenesis of cisplatin-induced nephrotoxicity. Thalidomide is an immunomodulatory and anti-inflammatory agent and is used for the treatment of various inflammatory diseases. The purpose of this study was to investigate the potential nephroprotective effect of thalidomide in a mouse model of cisplatin-induced nephrotoxicity. Nephrotoxicity was induced in mice by a single injection of cisplatin (15 mg/kg, i.p.) and treated with thalidomide (50 and 100 mg/kg/day, orally) for 4 days, beginning 24 h prior to the cisplatin injection. Renal toxicity induced by cisplatin was demonstrated by increasing plasma levels of creatinine and blood urea nitrogen (BUN). Cisplatin increased the renal production of the proinflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and transforming growth factor (TGF)-β1. In addition, kidney levels of malondialdehyde (MDA), myeloperoxidase (MPO), and nitric oxide (NO) were increased by cisplatin. Biochemical results showed that thalidomide reduced cisplatin-induced increase in plasma creatinine and BUN. Thalidomide treatment also significantly reduced tissue levels of the proinflammatory cytokines, MDA, MPO, and NO and increased anti-inflammatory cytokine IL-10. Furthermore, histological examination indicated that thalidomide ameliorated renal damage caused by cisplatin. These data suggest that thalidomide attenuates cisplatin-induced nephrotoxicity possibly by inhibition of inflammatory reactions. Taken together, our findings indicate that thalidomide might be a valuable candidate for the prevention of nephrotoxicity in patients receiving cisplatin.

  19. Nebivolol Ameliorates Cisplatin-Induced Nephrotoxicity in Rats.

    Science.gov (United States)

    Morsy, Mohamed A; Heeba, Gehan H

    2016-06-01

    Treatment with cisplatin is associated with dose-limiting side effects, mainly nephrotoxicity. On the other hand, nebivolol, a β1 -adrenoceptor antagonist, exhibits vasodilatory and antioxidative properties. This study aimed to determine whether nebivolol possesses a protective effect against cisplatin nephrotoxicity and explore many mechanisms underlying this potential effect. Nephrotoxicity was induced in Wistar rats by a single intraperitoneal injection of cisplatin (6 mg/kg) on day 2. Nebivolol (10 mg/kg) was administered orally for 7 consecutive days. Nebivolol showed a nephroprotective effect as demonstrated by the significant reduction in the elevated levels of serum creatinine and urea as well as renal levels of malondialdehyde, nitric oxide products (nitrite/nitrate), inducible nitric oxide synthase, tumour necrosis factor-alpha, caspase-3, angiotensin II and endothelin-1 with a concurrent increase in renal levels of reduced glutathione and endothelial nitric oxide synthase compared to untreated rats. Histopathological examination confirmed the nephroprotective effect of nebivolol. Pre-treatment with Nω -nitro-L-arginine methyl ester, the non-specific nitric oxide synthase inhibitor, partially altered the protection afforded by nebivolol. In conclusion, nebivolol protects rats against cisplatin-induced nephrotoxicity that is most likely through its antioxidant, anti-inflammatory and antiapoptotic effects as well as by abrogation of the augmented angiotensin II and endothelin-1 levels. © 2015 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

  20. Cisplatin-induced ototoxicity : Morphological evidence of spontaneous outer hair cell recovery in albino guinea pigs?

    NARCIS (Netherlands)

    Cardinaal, RM; de Groot, JCMJ; Huizing, EH; Veldman, JE; Smoorenburg, GF

    Cisplatin is frequently used in the treatment of various forms of malignancies. Its therapeutic efficacy, however, is limited by the occurrence of sensorineural hearing loss. Little is known about the course of hearing loss over longer time intervals after cessation of cisplatin administration.

  1. Blocking junctional adhesion molecule C promotes the recovery of cisplatin-induced acute kidney injury.

    Science.gov (United States)

    Kim, Sun Chul; Ko, Yoon Sook; Lee, Hee Young; Kim, Myung-Gyu; Jo, Sang-Kyung; Cho, Won-Yong

    2017-11-01

    Recent findings have demonstrated the occurrence of neutrophil transendothelial migration in the reverse direction (reverse TEM) and that endothelial junctional adhesion molecule C (JAM-C) is a negative regulator of reverse TEM. In this study, we tested the effects of a JAM-C blocking antibody on the resolution of kidney injuries and inflammation in a mouse model of cisplatin-induced acute kidney injury (AKI). Cisplatin was administered via intraperitoneal injection. A JAM-C blocking antibody or a control immunoglobulin G was administered intraperitoneal at 1.5 mg/kg, with the injection being delayed until day 4 following cisplatin administration to restrict the effect of antibodies on recovery. After cisplatin injection, serum creatinine and histologic injuries peaked on day 4. Treatment with a JAM-C blocking antibody on days 4 and 5 promoted the functional and histologic recovery of cisplatin-induced AKI on days 5 and 6. Facilitating recovery with a JAM-C blocking antibody correlated with significantly increased circulating intercellular adhesion molecule 1+ Tamm-Horsfall protein+ neutrophils and significantly decreased renal neutrophil infiltration, indicating that facilitating reverse the TEM of neutrophils from the kidney to the peripheral circulation partially mediated the resolution of inflammation and recovery. These results demonstrated that reverse TEM is involved in the resolution of neutrophilic inflammation in cisplatin-induced AKI and that JAM-C is an important regulator of this process.

  2. Potential of morin and hesperidin in the prevention of cisplatin-induced nephrotoxicity.

    Science.gov (United States)

    Kaltalioglu, Kaan; Coskun-Cevher, Sule

    2016-09-01

    Oxidative stress is one of the important mechanisms of cisplatin-induced nephrotoxicity. Therefore, this study was designed to explore the potential protective effects of morin and/or hesperidin on oxidative stress in cisplatin-induced nephrotoxicity. This study was performed on 42 Wistar rats. Rats were divided into seven groups: control, morin, hesperidin, cisplatin, cisplatin + morin, cisplatin + hesperidin, and cisplatin + morin + hesperidin. Morin and/or hesperidin were given for 10 consecutive days by oral gavage and on the 4th day a single dose of cisplatin (7 mg/kg) was injected intraperitoneally. After administrations, on the 11th day of the experiment the animals were killed, and malondialdehyde (MDA), nitric oxide (NOx), glutathione (GSH) levels and myeloperoxidase (MPO), catalase (CAT), superoxide dismutase (SOD) activity were measured. Cisplatin-treated rats showed increased levels of MDA, and decreased levels of NOx also activity of CAT. Morin and/or hesperidin pretreatment prevent oxidative stress in kidney tissue, while they increase the NOx level, CAT activity, and decrease MPO activity. In conclusion, morin + hesperidin pretreatment may have a significant potential for protection of cisplatin-induced nephrotoxicity.

  3. Developing better mouse models to study cisplatin-induced kidney injury.

    Science.gov (United States)

    Sharp, Cierra N; Siskind, Leah J

    2017-10-01

    Cisplatin is a potent chemotherapeutic used for the treatment of many types of cancer. However, its dose-limiting side effect is nephrotoxicity leading to acute kidney injury (AKI). Patients who develop AKI have an increased risk of mortality and are more likely to develop chronic kidney disease (CKD). Unfortunately, there are no therapeutic interventions for the treatment of AKI. It has been suggested that the lack of therapies is due in part to the fact that the established mouse model used to study cisplatin-induced AKI does not recapitulate the cisplatin dosing regimen patients receive. In recent years, work has been done to develop more clinically relevant models of cisplatin-induced kidney injury, with much work focusing on incorporation of multiple low doses of cisplatin administered over a period of weeks. These models can be used to recapitulate the development of CKD after AKI and, by doing so, increase the likelihood of identifying novel therapeutic targets for the treatment of cisplatin-induced kidney injury. Copyright © 2017 the American Physiological Society.

  4. Jellyfish model for ototoxicity.

    Science.gov (United States)

    McAfee, Jacob Seth; Benson, Chris; Spangenberg, Dorothy; Lattanzio, Frank; Strasnick, Barry

    2015-02-01

    Pharmacologic ototoxicity is well described in the medical literature, yet efficient screening models are lacking. Aurelia aurita ephyrae, transparent jellyfish with identifiable hair cells, could be an effective model. Structural changes readily manifest behaviorally, and hair cells are easily stained and observed. We treated ephyrae with various gentamicin concentrations, evaluated its motility, and quantified its hair cell loss. Baseline pulsing per minute (P), swimming (S), and orientation (O) values were recorded from cultured ephyrae. Ephyrae were transferred into test tubes containing artificial seawater (ASW), gentamicin, or penicillin. P, S, and O were scored at 0, 24, and 48 hours. Ephyrae were formalin fixed, phalloidin stained, and imaged with confocal microscopy, and hair cells were then counted. P was impaired by gentamicin in a dose-dependent fashion, whereas ASW controls maintained baseline P, S, and O values. Impairment of S and O occurred with 3.5 mmol/L gentamicin at 24 hours. For six experiments each using 40 ephyrae, at 24 hours, average P was reduced from 75.2 in ASW to 28.8, 12.3, and 1.9 for 1, 2, and 3.5 mmol/L gentamicin, respectively (p < 0.05 for all cases). Hair cell loss at 24 and 48 hours was significant (32% and 48% reduction compared with control, p < 0.05) and correlated with motility deficits. Deficits from penicillin exposure were not statistically significant. The ephyra model demonstrated functional and histologic gentamicin-mediated impairments, showing promise as a screening tool for ototoxic agents. The changes in ephyra motility after gentamicin exposure correlated significantly with hair cell loss.

  5. QiShenYiQi Pills, a Compound Chinese Medicine, Prevented Cisplatin Induced Acute Kidney Injury via Regulating Mitochondrial Function

    Directory of Open Access Journals (Sweden)

    Li Zhou

    2017-12-01

    Full Text Available Nephrotoxicity is a serious adverse effect of cisplatin chemotherapy that limits its clinical application, to deal with which no effective management is available so far. The present study was to investigate the potential protective effect of QiShenYiQi Pills (QSYQ, a compound Chinese medicine, against cisplatin induced nephrotoxicity in mice. Pretreatment with QSYQ significantly attenuated the cisplatin induced increase in plasma urea and creatinine, along with the histological damage, such as tubular necrosis, protein cast, and desquamation of epithelial cells, improved the renal microcirculation disturbance as indicated by renal blood flow, microvascular flow velocity, and the number of adherent leukocytes. Additionally, QSYQ prevented mitochondrial dysfunction by preventing the cisplatin induced downregulation of mitochondrial complex activity and the expression of NDUFA10, ATP5D, and Sirt3. Meanwhile, the cisplatin-increased renal thiobarbituric acid-reactive substances, caspase9, cleaved-caspase9, and cleaved-caspase3 were all diminished by QSYQ pretreatment. In summary, the pretreatment with QSYQ remarkably ameliorated the cisplatin induced nephrotoxicity in mice, possibly via the regulation of mitochondrial function, oxidative stress, and apoptosis.

  6. Ancient Chinese Formula Qiong-Yu-Gao Protects Against Cisplatin-Induced Nephrotoxicity Without Reducing Anti-tumor Activity.

    Science.gov (United States)

    Teng, Zhi-Ying; Cheng, Xiao-Lan; Cai, Xue-Ting; Yang, Yang; Sun, Xiao-Yan; Xu, Jin-Di; Lu, Wu-Guang; Chen, Jiao; Hu, Chun-Ping; Zhou, Qian; Wang, Xiao-Ning; Li, Song-Lin; Cao, Peng

    2015-10-29

    Cisplatin is a highly effective anti-cancer chemotherapeutic agent; however, its clinical use is severely limited by serious side effects, of which nephrotoxicity is the most important. In this study, we investigated whether Qiong-Yu-Gao (QYG), a popular traditional Chinese medicinal formula described 840 years ago, exhibits protective effects against cisplatin-induced renal toxicity. Using a mouse model of cisplatin-induced renal dysfunction, we observed that pretreatment with QYG attenuated cisplatin-induced elevations in blood urea nitrogen and creatinine levels, ameliorated renal tubular lesions, reduced apoptosis, and accelerated tubular cell regeneration. Cisplatin-mediated elevations in tumor necrosis factor alpha (TNF-α) mRNA, interleukin-1 beta (IL-1β) mRNA, and cyclooxygenase-2 (COX-2) protein in the kidney were also significantly suppressed by QYG treatment. Furthermore, QYG reduced platinum accumulation in the kidney by decreasing the expression of copper transporter 1 and organic cation transporter 2. An in vivo study using implanted Lewis lung cancer cells revealed that concurrent administration of QYG and cisplatin did not alter the anti-tumor activity of cisplatin. Our findings suggest that the traditional Chinese medicinal formula QYG inhibits cisplatin toxicity by several mechanisms that act simultaneously, without compromising its therapeutic efficacy. Therefore, QYG may be useful in the clinic as a protective agent to prevent cisplatin-induced nephrotoxicity.

  7. Ototoxicity in dogs and cats.

    Science.gov (United States)

    Oishi, Naoki; Talaska, Andra E; Schacht, Jochen

    2012-11-01

    A variety of drugs in veterinary use have side effects that can potentially damage the senses of hearing or balance in animals. A large body of literature exists on the incidence and mechanisms of ototoxicity in experimental animals and in humans, but little is documented in domestic dogs and cats. However, the generality of these adverse actions across species allows one to extrapolate and provide the veterinarian with insight into possible complications of chemotherapy. Copyright © 2012 Elsevier Inc. All rights reserved.

  8. Potential protective role of hydrogen against cisplatin- induced side ...

    African Journals Online (AJOL)

    Yi Lang1. 1Department of Radiation Oncology, Sichuan Cancer Hospital, 2Department of Oncology, Chengdu First People's Hospital,. Chengdu 610041, China ... indiscriminately interact with lipids, proteins, and nucleic acids, thus leading to .... Differential roles of hydrogen peroxide and hydroxyl radical in cisplatin-induced ...

  9. Protective effect of L-N-acetylcysteine against gentamycin ototoxicity in the organ cultures of the rat cochlea.

    Science.gov (United States)

    Maniu, Alma; Perde-Schrepler, Maria; Cosgarea, M

    2011-01-01

    The AIM of this study was to test if L-N-acetylcysteine (L-NAC) can protect hair cells against gentamycin-induced damage in vitro. Mammalian auditory cells are unable to regenerate when affected by several toxic agents. Aminoglycosides are large-scale antibiotics, extremely useful for the treatment of several Gram-negative bacterial infections, but their use is limited by the extremely severe side effects like ototoxicity and nephrotoxicity. 1-4-day-old rat cochlea explants were exposed to different doses of gentamycin. Half of the cochleas were pretreated for 24 hours with different doses of L-NAC. The explants were fixed and stained with phalloidin, and the intact hair cells were counted. GM treatment resulted in the loss of sensorial cells in the organ of Corti explants in a dose-dependent manner. All doses of L-NAC offered significant protection (pgentamycin toxicity.

  10. Protocatechuic aldehyde attenuates cisplatin-induced acute kidney injury by suppressing Nox-mediated oxidative stress and renal inflammation

    Directory of Open Access Journals (Sweden)

    Li Gao

    2016-12-01

    Full Text Available Cisplatin is a classic chemotherapeutic agent widely used to treat different types of cancers including ovarian, head and neck, testicular and uterine cervical carcinomas. However, cisplatin induces acute kidney injury by directly triggering an excessive inflammatory response, oxidative stress and programmed cell death of renal tubular epithelial cells. All of which lead to higher mortality rates in patients. In this study we examined the protective effect of protocatechuic aldehyde (PA in vitro in cisplatin-treated tubular epithelial cells and in vivo in cisplatin nephropathy. PA is a monomer of Traditional Chinese Medicine isolated from the root of S. miltiorrhiza. Results show that PA prevented cisplatin-induced decline of renal function and histological damage, which was confirmed by attenuation of KIM1 in both mRNA and protein levels. Moreover, PA reduced renal inflammation by suppressing oxidative stress and programmed cell death in response to cisplatin, which was further evidenced by in vitro data. Of note, PA suppressed NAPDH oxidases, including Nox2 and Nox4, in a dosage-dependent manner. Moreover, silencing Nox4, but not Nox2, removed the inhibitory effect of PA on cisplatin-induced renal injury, indicating that Nox4 may play a pivotal role in mediating the protective effect of PA in cisplatin-induced acute kidney injury. Collectively, our data indicate that PA largely blocked cisplatin-induced acute kidney injury by suppressing Nox-mediated oxidative stress and renal inflammation without compromising anti-tumor activity of cisplatin. These findings suggest that PA and its derivatives may serve as potential protective agents for cancer patients with cisplatin treatment.

  11. Baicalein, a Bioflavonoid, Prevents Cisplatin-Induced Acute Kidney Injury by Up-Regulating Antioxidant Defenses and Down-Regulating the MAPKs and NF-κB Pathways.

    Directory of Open Access Journals (Sweden)

    Bidya Dhar Sahu

    Full Text Available Acute renal failure is a serious complication of the anticancer drug cisplatin. The potential role of baicalein, a naturally occurring bioflavonoid on cisplatin-induced renal injury is unknown. Here, we assessed the effect of baicalein against a murine model of cisplatin-induced acute renal failure and investigated the underlying possible mechanisms. Renal function, kidney histology, inflammation, oxidative stress, renal mitochondrial function, proteins involved in apoptosis, nuclear translocation of Nrf2 and effects on intracellular signaling pathways such as MAPKs, and NF-κB were assessed. Pretreatment with baicalein ameliorated the cisplatin-induced renal oxidative stress, apoptosis and inflammation and improved kidney injury and function. Baicalein inhibited the cisplatin-induced expression of iNOS, TNF-α, IL-6 and mononuclear cell infiltration and concealed redox-sensitive transcription factor NF-κB activation via reduced DNA-binding activity, IκBα phosphorylation and p65 nuclear translocation in kidneys. Further studies demonstrated baicalein markedly attenuated cisplatin-induced p38 MAPK, ERK1/2 and JNK phosphorylation in kidneys. Baicalein also restored the renal antioxidants and increased the amount of total and nuclear accumulation of Nrf2 and downstream target protein, HO-1 in kidneys. Moreover, baicalein preserved mitochondrial respiratory enzyme activities and inhibited cisplatin-induced apoptosis by suppressing p53 expression, Bax/Bcl-2 imbalance, cytochrome c release and activation of caspase-9, caspase-3 and PARP. Our findings suggest that baicalein ameliorates cisplatin-induced renal damage through up-regulation of antioxidant defense mechanisms and down regulation of the MAPKs and NF-κB signaling pathways.

  12. Galangin ameliorates cisplatin-induced nephrotoxicity by attenuating oxidative stress, inflammation and cell death in mice through inhibition of ERK and NF-kappaB signaling.

    Science.gov (United States)

    Huang, Yu-Ching; Tsai, Ming-Shiun; Hsieh, Pei-Chi; Shih, Jheng-Hong; Wang, Tsu-Shing; Wang, Yi-Chun; Lin, Ting-Hui; Wang, Sue-Hong

    2017-08-15

    Cisplatin is a chemotherapeutic agent widely used in the treatment of various cancers. However, cisplatin can induce nephrotoxicity and neurotoxicity, limiting its dosage and usage. Galangin, a natural flavonol, has been found to exhibit anti-oxidant and anti-inflammatory effects in vivo. Here, we investigated the effects of galangin on cisplatin-induced acute kidney injury (AKI) and its molecular mechanisms in mice. Galangin administration reduced the cisplatin-induced oxidative stress by decreasing renal MDA and 3-NT formations. Galangin administration also increased renal anti-oxidative enzyme activities (SOD, GPx, and CAT) and GSH levels depleted by cisplatin. Furthermore, galangin administration inactivated stress-induced Nrf2 protein and its downstream products, HO-1 and GCLC. In terms of the inflammatory response, galangin administration reduced IκBα phosphorylation, NF-κB phosphorylation and nuclear translocation, and then inhibited cisplatin-induced secretions of pro-inflammatory TNF-α, IL-1β and IL-6. In addition, cisplatin-induced ERK and p38 phosphorylations were inhibited by galangin administration. In terms of cell death, galangin administration reduced levels of p53, pro-apoptotic Bax and activated caspase-3 to inhibit the cisplatin-induced apoptosis. Galangin administration also reduced the expression levels of RIP1 and RIP3 to inhibit cisplatin-induced RIP1/RIP3-dependent necroptosis. Therefore, galangin administration significantly ameliorates cisplatin-induced nephrotoxicity by attenuating oxidative stress, inflammation, and cell death through inhibitions of ERK and NF-κB signaling pathways. Galangin might be a potential adjuvant for clinical cisplatin therapy. Copyright © 2017 Elsevier Inc. All rights reserved.

  13. The Role of Thiamine Pyrophosphate in Prevention of Cisplatin Ototoxicity in an Animal Model

    Directory of Open Access Journals (Sweden)

    Ozan Kuduban

    2013-01-01

    Full Text Available Objective. The aim of this study was to evaluate the effectiveness of thiamine pyrophosphate against cisplatin-induced ototoxicity in guinea pigs. Materials and Methods. Healthy guinea pigs (n=18 were randomly divided into three groups. Group 1 (n=6 received an intraperitoneal injection of saline solution and cisplatin for 7 days, group 2 (n=6 received an intraperitoneal injection of thiamine pyrophosphate and cisplatin for 7 days, and group 3 (n=6 received only intraperitoneal injection of saline for 7 days. The animals in all groups were sacrificed under anesthesia, and their cochleas were harvested for morphological and biochemical observations. Results. In group 1, receiving only cisplatin, cochlear glutathione concentrations, superoxide dismutase, and glutathione peroxidase activities significantly decreased (P<0.05 and malondialdehyde concentrations significantly increased (P<0.05 compared to the control group. In group 2, receiving thiamine pyrophosphate and cisplatin, the concentrations of enzymes were near those of the control group. Microscopic examination showed that outer hair cells, spiral ganglion cells, and stria vascularis were preserved in group 2. Conclusion. Systemic administration of thiamine pyrophosphate yielded statistically significant protection to the cochlea of guinea pigs from cisplatin toxicity. Further experimental animal studies are essential to determine the appropriate indications of thiamine pyrophosphate before clinical use.

  14. L-Carnitine Ameliorates the Decrease of Aquaporin 2 Levels in Rats with Cisplatin-Induced Kidney Injury.

    Science.gov (United States)

    Gao, Jianjun; Gu, Zhaoyan; Li, Min; Xu, Yongxing; Gao, Yuehua; Wei, Jiamei; Liang, Boran; Na, Yu

    2017-01-01

    It has been found that L-carnitine ameliorated cisplatin-induced acute kidney injury (AKI) in rats. However, the detailed role of L-carnitine in improving the renal urinary concentration function in cisplatin-induced AKI is not fully understood. In this study, 30 Sprague-Dawley rats were divided randomly into 5 groups: control, cisplatin (CIS), L-carnitine (CAR), L-carnitine plus cisplatin (CAR + CIS), and cisplatin plus L-carnitine (CIS + CAR) groups. Cisplatin (7 mg/kg) and L-carnitine (300 mg/kg) were injected intraperitoneally. Urine (24 h) and blood samples were collected to analyze renal urinary concentrating function. Immunoblotting, confocal laser microscopy, and enzyme-linked immunosorbent assays were used to assess the level and localization of the water channel aquaporin (AQP) 2, and levels of stimulatory G protein α subunit (GSα protein), arginine vasopressin (AVP) receptor 2, adenylyl cyclase and serum AVP. Renal urinary concentrating function was improved by L-carnitine in rats with cisplatin-induced AKI. AQP2 expression, which decreased after cisplatin treatment, was improved by L-carnitine in different regions of the kidney. Moreover, our data indicated that L-carnitine could increase AQP2 accumulation at the apical plasma membranes of the renal-collecting ducts. Finally, intervention with L-carnitine effectively improved the expression of AQP2 upstream signaling proteins, such as GSα protein, adenylyl cyclase, and serum AVP levels in rats with cisplatin-induced AKI. L-carnitine resolves the cisplatin-induced urinary concentration defect, which may occur by increasing AVP/cyclic adenosine monophosphate/AQP2 levels, indicating the potential use of L-carnitine to ameliorate the renal urinary concentration effect in cancer patients treated with cisplatin. © 2017 S. Karger AG, Basel.

  15. INF-α and Ototoxicity

    Directory of Open Access Journals (Sweden)

    Mohammad Reza Sharifian

    2013-01-01

    Full Text Available Introduction. INF-α is a common drug for the treatment of hepatitis B and C. Although a variety of related complications are discussed, possible ototoxic effects of this mediation are not well described. Methods and Materials. In a before-after control study, 24 patients who received INF-α for the treatment of hepatitis B and C and 30 normal controls were included. Subjective and objective ototoxicity evaluations via questionnaire, high frequency audiometry, and measuring transiently evoked otoacoustic emissions (TEOAEs were performed one week before and one month after the prescription of the drug. Results. Subjective hearing complaint, tinnitus, and vertigo were seen in just 3 cases, which was not statistically significant (. In the frequency range of 4000 to 8000 Hz before (9.38 ± 1.0 and 10.7 ± 1.2, resp. and after (17.9 ± 2.6 and 17.6 ± 2.6, resp. one month of treatment, a significant difference ( was detected. Progressive decreases in amplitude of the OAE during TEOAE measurement in 1, 2, and 4 frequencies among 41.66%, 18.75 %, and 43.75% were observed, respectively. The hearing loss was seen more among older and male cases significantly. Conclusion. The results showed ototoxicity of INF-α that may encourage planning hearing monitoring in patients receiving this drug.

  16. P2X7 receptor blockade protects against cisplatin-induced nephrotoxicity in mice by decreasing the activities of inflammasome components, oxidative stress and caspase-3

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Yuanyuan; Yuan, Fahuan; Cao, Xuejiao [Department of Nephrology, Xinqiao Hospital, PLA, Third Military Medical University, Chongqing 400037 (China); Zhai, Zhifang [Department of Dermatology, Southwest Hospital, Third Military Medical University, Chongqing 400038 (China); Gang Huang [Department of Medical Genetics, Third Military Medical University, Chongqing 430038 (China); Du, Xiang; Wang, Yiqin; Zhang, Jingbo; Huang, Yunjian; Zhao, Jinghong [Department of Nephrology, Xinqiao Hospital, PLA, Third Military Medical University, Chongqing 400037 (China); Hou, Weiping, E-mail: hwp0518@aliyun.com [Department of Nephrology, Xinqiao Hospital, PLA, Third Military Medical University, Chongqing 400037 (China)

    2014-11-15

    Nephrotoxicity is a common complication of cisplatin chemotherapy and thus limits the use of cisplatin in clinic. The purinergic 2X7 receptor (P2X7R) plays important roles in inflammation and apoptosis in some inflammatory diseases; however, its roles in cisplatin-induced nephrotoxicity remain unclear. In this study, we first assessed the expression of P2X7R in cisplatin-induced nephrotoxicity in C57BL/6 mice, and then we investigated the changes of renal function, histological injury, inflammatory response, and apoptosis in renal tissues after P2X7R blockade in vivo using an antagonist A-438079. Moreover, we measured the changes of nod-like receptor family, pyrin domain containing proteins (NLRP3) inflammasome components, oxidative stress, and proapoptotic genes in renal tissues in cisplatin-induced nephrotoxicity after treatment with A-438079. We found that the expression of P2X7R was significantly upregulated in the renal tubular epithelial cells in cisplatin-induced nephrotoxicity compared with that of the normal control group. Furthermore, pretreatment with A-438079 markedly attenuated the cisplatin-induced renal injury while lightening the histological damage, inflammatory response and apoptosis in renal tissue, and improved the renal function. These effects were associated with the significantly reduced levels of NLRP3 inflammasome components, oxidative stress, p53 and caspase-3 in renal tissues in cisplatin-induced nephrotoxicity. In conclusions, our studies suggest that the upregulated activity of P2X7R might play important roles in the development of cisplatin-induced nephrotoxicity, and P2X7R blockade might become an effective therapeutic strategy for this disease. - Highlights: • The P2X7R expression was markedly upregulated in cisplatin-induced nephrotoxicity. • P2X7R blockade significantly attenuated the cisplatin-induced renal injury. • P2X7R blockade reduced activities of NLRP3 inflammasome components in renal tissue. • P2X7R blockade

  17. A new grading system for ototoxicity in adults

    NARCIS (Netherlands)

    Theunissen, Eleonoor A. R.; Dreschler, Wouter A.; Latenstein, Merel N.; Rasch, Coen R. N.; van der Baan, Sieberen; de Boer, Jan Paul; Balm, Alfons J. M.; Zuur, Charlotte L.

    2014-01-01

    This study aimed to propose an ototoxicity grading system sensitive to the effect of ototoxicity on specific daily life situations like speech intelligibility and the perception of ultra-high sounds and to test its feasibility compared to current criteria. Pure tone averages (PTAs) for speech

  18. Pattern of Ototoxicity in a Nigerian Teaching Hospital | Salisu ...

    African Journals Online (AJOL)

    There were no effective audiometric and serum drug monitoring mechanism in place before, during or after therapy with ototoxic medications. Ototoxicity is not uncommon and attempts at prevention are feeble. Increased awareness of this condition is advised. High frequency audiometric assessment, otoacoustic emission ...

  19. Magnesium protects against cisplatin-induced acute kidney injury by regulating platinum accumulation.

    Science.gov (United States)

    Solanki, Malvika H; Chatterjee, Prodyot K; Gupta, Madhu; Xue, Xiangying; Plagov, Andrei; Metz, Margot H; Mintz, Rachel; Singhal, Pravin C; Metz, Christine N

    2014-08-15

    Despite its success as a potent antineoplastic agent, ∼25% of patients receiving cisplatin experience acute kidney injury (AKI) and must discontinue therapy. Impaired magnesium homeostasis has been linked to cisplatin-mediated AKI, and because magnesium deficiency is widespread, we examined the effect of magnesium deficiency and replacement on cisplatin-induced AKI in physiologically relevant older female mice. Magnesium deficiency significantly increased cisplatin-associated weight loss and markers of renal damage (plasma blood urea nitrogen and creatinine), histological changes, inflammation, and renal cell apoptosis and modulated signaling pathways (e.g., ERK1/2, p53, and STAT3). Conversely, these damaging effects were reversed by magnesium. Magnesium deficiency alone significantly induced basal and cisplatin-mediated oxidative stress, whereas magnesium replacement attenuated these effects. Similar results were observed using cisplatin-treated LLC-PK1 renal epithelial cells exposed to various magnesium concentrations. Magnesium deficiency significantly amplified renal platinum accumulation, whereas magnesium replacement blocked the augmented platinum accumulation after magnesium deficiency. Increased renal platinum accumulation during magnesium deficiency was accompanied by reduced renal efflux transporter expression, which was reversed by magnesium replacement. These findings demonstrate the role of magnesium in regulating cisplatin-induced AKI by enhancing oxidative stress and thus promoting cisplatin-mediated damage. Additional in vitro experiments using ovarian, breast, and lung cancer cell lines showed that magnesium supplementation did not compromise cisplatin's chemotherapeutic efficacy. Finally, because no consistently successful therapy to prevent or treat cisplatin-mediated AKI is available for humans, these results support developing more conservative magnesium replacement guidelines for reducing cisplatin-induced AKI in cancer patients at risk for

  20. Pre-incubation with hucMSC-exosomes prevents cisplatin-induced nephrotoxicity by activating autophagy.

    Science.gov (United States)

    Wang, Bingying; Jia, Haoyuan; Zhang, Bin; Wang, Juanjuan; Ji, Cheng; Zhu, Xueming; Yan, Yongmin; Yin, Lei; Yu, Jing; Qian, Hui; Xu, Wenrong

    2017-04-08

    The administration of cisplatin is limited due to its nephrotoxic side effects, and prevention of this nephrotoxicity of cisplatin is difficult. Mesenchymal stem cell (MSC)-derived exosomes have been implicated as a novel therapeutic approach for tissue injury. In this study, we demonstrated that the pretreatment of human umbilical cord MSC-derived exosomes (hucMSC-Ex) can prevent the development of cisplatin-induced renal toxicity by activation of autophagy in vitro and in vivo. In vitro, rat renal tubular epithelial (NRK-52E) cells were pre-incubated with exosomes from hucMSC or HFL1 (human lung fibroblast cells; as control) for 30 min, and 3-methyladenine (an autophagic inhibitor) and rapamycin (an autophagic inducer) for 1 h before cisplatin treatment for 8 h, respectively. Cells were harvested for apoptosis assay, enzyme-linked immunosorbent assay (ELISA), Western blot, and quantitative real-time polymerase chain reaction (qRT-PCR). In vivo, we constructed cisplatin-induced acute kidney injury rat models. Prior to treatment with cisplatin for 0.5 h, hucMSC-Ex or HFL1-Ex were injected into the kidneys via the renal capsule. 3-methyladenine and rapamycin were injected under the kidney capsule before hucMSC-Ex. All animals were sacrificed at 3 days after cisplatin injection. Renal function, Luminex assay, tubular apoptosis and proliferation, and autophagy response were evaluated. hucMSC-Ex inhibited cisplatin-induced mitochondrial apoptosis and secretion of inflammatory cytokines in renal tubular epithelial cells in vitro. hucMSC-Ex increased the expression of the autophagic marker protein LC3B and the autophagy-related genes ATG5 and ATG7 in NRK-52E cells. Rapamycin mimicked the effects of hucMSC-Ex in protecting against cisplatin-induced renal injury, while the effects were abrogated by the autophagy inhibitor 3-methyladenine in the animals. Our findings indicate that the activation of autophagy induced by hucMSC-Ex can effectively relieve the nephrotoxicity of

  1. Breast cancer cells with acquired antiestrogen resistance are sensitized to cisplatin-induced cell death

    DEFF Research Database (Denmark)

    Yde, Christina Westmose; Gyrd-Hansen, Mads; Lykkesfeldt, Anne E

    2007-01-01

    with parental MCF-7 cells. Our data show that Bcl-2 can protect antiestrogen-resistant breast cancer cells from cisplatin-induced cell death, indicating that the reduced expression of Bcl-2 in the antiestrogen-resistant cells plays a role in sensitizing the cells to cisplatin treatment....... for future breast cancer treatment. In this study, we have investigated the effect of the chemotherapeutic compound cisplatin using a panel of antiestrogen-resistant breast cancer cell lines established from the human breast cancer cell line MCF-7. We show that the antiestrogen-resistant cells...

  2. Hexokinase 2 confers resistance to cisplatin in ovarian cancer cells by enhancing cisplatin-induced autophagy.

    Science.gov (United States)

    Zhang, Xiao-Yan; Zhang, Meng; Cong, Qing; Zhang, Ming-Xing; Zhang, Meng-Yu; Lu, Ying-Ying; Xu, Cong-Jian

    2018-02-01

    The high mortality rate of ovarian cancer is connected with the development of acquired resistance to multiple cancer drugs, especially cisplatin. Activation of cytoprotective autophagy has been implicated as a contributing mechanism for acquired cisplatin resistance in ovarian cancer cells. Hexokinase 2 (HK2) phosphorylates glucose to generate glucose-6-phosphate, the rate-limiting step in glycolysis. Higher HK2 expression has been associated with chemoresistance in ovarian cancer. However, whether HK2 functionally contributes to cisplatin resistance in ovarian cancer is unclear. In this study, we investigated the role of HK2 in regulating ovarian cancer cisplatin resistance. Increased HK2 levels were detected in drug-resistant human ovarian cancer cells and tissues. Cisplatin downregulated HK2 in cisplatin-sensitive but not in resistant ovarian cancer cells. HK2 knockdown sensitized resistant ovarian cancer cells to cisplatin-induced cell death and apoptosis. Conversely, HK2 overexpression in cisplatin-sensitive cells induced cisplatin resistance. Mechanistically, cisplatin increased ERK1/2 phosphorylation as well as autophagic activity. Blocking autophagy with the autophagy inhibitor 3-MA sensitized resistant ovarian cancer cells to cisplatin. HK2 overexpression enhanced cisplatin-induced ERK1/2 phosphorylation and autophagy while HK2 knockdown showed the opposite effects. Blocking the MEK/ERK pathway using the MEK inhibitor U0126 prevented cisplatin-induced autophagy enhanced by HK2 overexpression. Furthermore, HK2 knockdown sensitized resistance ovarian tumor xenografts to cisplatin in vivo. In conclusion, our data supported that HK2 promotes cisplatin resistance in ovarian cancer by enhancing drug-induced, ERK-mediated autophagy. Therefore, targeting HK2 may be a new therapeutic strategy to combat chemoresistance in ovarian cancer. Copyright © 2017 Elsevier Ltd. All rights reserved.

  3. Effects of Intratympanic Dexamethasone on High-Dose Radiation Ototoxicity In Vivo.

    Science.gov (United States)

    Dinh, Christine T; Chen, Si; Dinh, John; Goncalves, Stefania; Bas, Esperanza; Padgett, Kyle; Johnson, Perry; Elsayyad, Nagy; Telischi, Fred; Van De Water, Thomas

    2017-02-01

    Stereotactic radiosurgery for lateral skull base tumors can cause hearing loss when the cochleae are exposed to high doses of single-fraction radiation. Currently, there are no known nondosimetric preventative treatments for radiation-induced ototoxicity. Intratympanic (IT) dexamethasone (DXM), a synthetic steroid, protects against radiation-induced auditory hair cell (HC) and hearing losses in rats in vivo. Seven rats received radiation (12 Gy) to both cochleae. In irradiated rats and six nonirradiated rats, IT DXM was randomized to one ear, while tympanic puncture without DXM was performed on the contralateral ear. Baseline and 4-week postradiation auditory-evoked potential tests were performed. The cochleae were processed for HC viability. Cochleae exposed to radiation demonstrated more outer HC (OHC) loss in all turns than nonirradiated ears (p <0.05). OHCs were more susceptible to radiation injury than inner HCs in the middle and basal turns (p <0.05). In irradiated cochleae, there was a nonsignificant trend for less OHC loss with IT DXM in the basal turn when compared with placebo. IT DXM did not improve radiation-induced hearing threshold shifts; however, a high rate of tympanic membrane perforations occurred with irradiated ears which may contribute to this finding. Radiation induced loss of OHCs in all turns of the cochlea. IT DXM reduced OHC loss in the basal turn of irradiated ears; however, this finding did not achieve statistical significance. Although IT DXM did not affect radiation-induced hearing threshold shifts in adult rats in vivo, this may be due to a high rate of tympanic membrane perforations.

  4. Xiao-Ban-Xia-Tang inhibits cisplatin-induced pica by down regulating obestatin in rats.

    Science.gov (United States)

    Qian, Qiuhai; Chen, Wenhui; Guo, Chunfang; Wu, Wenguang; Qian, Weibin; Li, Shuanglei

    2011-04-26

    Xiao-Ban-Xia-Tang (XBXT), a traditional Chinese herbal medicine, has been used in China for more than 2000 years, and proved to be effective in various cases of vomiting in the clinic. To investigate the inhibitive effect of XBXT on cisplatin-induced pica behaviour and its effective mechanism on obestatin, CCK and CGRP in the pica model of rat. The inhibitive effect of XBXT was investigated in the pica model of rats induced by cisplatin (3mg kg(-1), i.p.) in 72h observation, the expression of obestatin in the area postrema and ileum was measured by immunohistochemistry and PCR, and the levels of CCK and CGRP in blood were measured by Elisa. The weight of kaolin eaten in rats induced by cisplatin was significantly reduced by pretreatment with XBXT in a dose-dependent manner during the 0-24h and 24-72h periods (P<0.05). XBXT exhibited effective dose-dependent (P<0.05) inhibition on the increase of expression levels of obestatin in both the ileum and area postrema, and markedly suppressed the increase levels of CCK and CGRP in blood induced by cisplatin in a dose-dependent manner (P<0.05). XBXT has good activity against cisplatin-induced eating kaolin in rats possibly by inhibiting central or peripheral increase of obestatin, or the levels of CCK and CGRP in blood. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  5. Targeting Oct2 and P53: Formononetin prevents cisplatin-induced acute kidney injury.

    Science.gov (United States)

    Huang, Di; Wang, Chuangyuan; Duan, Yingjie; Meng, Qiang; Liu, Zhihao; Huo, Xiaokui; Sun, Huijun; Ma, Xiaodong; Liu, Kexin

    2017-07-01

    Nephrotoxicity is one of major side effects of cisplatin in chemotherapy. Therefore, there is an urgent medical need to develop drugs that may protect kidney from toxicity. In previous study, we found that it showed the protective effects of formononetin against apoptosis by upregulating Nrf2. In this study, we investigated the renoprotective effect of formononetin against cisplatin-induced AKI and tried to elucidate the possible mechanisms. The amelioration of renal function, histopathological changes, and apoptosis in tubular cells was observed after formononetin treatment. Formononetin decreased expression of organic cation transporter 2 (Oct2) and increased the expressions of multidrug resistance-associated proteins (Mrps), which might result in a decrease accumulation of cisplatin in tubular cells after AKI. 5-Bromo-2-deoxyuridine (BrdU) and Ki-67 staining assay indicated that formononetin could promote the renal tubular cells proliferation after cisplatin nephrotoxicity. Moreover, formononetin regulated cyclins and pro-apoptotic proteins to involve the regulation of cell cycle. Furthermore, formononetin decreased p53 expression via promoting the overexpression of murine double minute 2 (MDM2) and MDMX. Taken together, formononetin provided protective effects by promoting proliferation of surviving renal tubular cells and inhibiting apoptosis after cisplatin-induced AKI. Copyright © 2017 Elsevier Inc. All rights reserved.

  6. Biliverdin protects against cisplatin-induced apoptosis of renal tubular epithelial cells.

    Science.gov (United States)

    Lv, Qian; Yao, Ying; Wang, Wei; Xiong, Wei; Liao, Wen-hui

    2016-02-01

    Biliverdin (BV) has long been thought to be a cytotoxic metabolic waste product. It has also been demonstrated to have important cytoprotective functions during oxidative stress. The present study aimed to examine the cytoprotective effect of BV on NRK-52E cells, a proximal tubular cell line derived from rat kidney. Cells were treated with 50 µmol/L cisplatin for 24 h (cisplatin group) or pre-treated with BV for 30 min, then with 50 µmol/L cisplatin for 24 h (cisplatin+BV group). Those given no treatment served as a control. Cell apoptosis was evaluated by flow cytometry and cell viability by Cell Counting Kit-8 (CCK-8). The protein expressions of cleaved caspase3, Bax and Bcl-2 were assessed by Western blotting. Reactive oxygen species (ROS) levels were measured using carboxydichlorodihydrofluorescein diacetate (H2DCF). The results showed that cisplatin induced the apoptosis of NRK-52E cells, decreased cell viability, and increased the formation of ROS by upregulating the expression of cleaved caspase3 and Bax and decreasing Bcl-2 protein expression. These effects could be significantly reversed by pretreatment with BV. It was concluded that BV can protect against cisplatin-induced cell apoptosis through the anti-oxidative effects.

  7. SIRT1 overexpression decreases cisplatin-induced acetylation of NF-{kappa}B p65 subunit and cytotoxicity in renal proximal tubule cells

    Energy Technology Data Exchange (ETDEWEB)

    Jung, Yu Jin; Lee, Jung Eun; Lee, Ae Sin [Department of Internal Medicine, Chonbuk National University Medical School, Jeonju (Korea, Republic of); Kang, Kyung Pyo; Lee, Sik; Park, Sung Kwang [Department of Internal Medicine, Chonbuk National University Medical School, Jeonju (Korea, Republic of); Institute for Medical Sciences, Chonbuk National University Medical School, Jeonju (Korea, Republic of); Lee, Sang Yong [Department of Diagnostic Radiology, Chonbuk National University Medical School, Jeonju (Korea, Republic of); Institute for Medical Sciences, Chonbuk National University Medical School, Jeonju (Korea, Republic of); Han, Myung Kwan [Department of Microbiology, Institute for Medical Sciences, Chonbuk National University Medical School, Jeonju (Korea, Republic of); Kim, Duk Hoon [Division of Forensic Medicine, National Forensic Service, Seoul (Korea, Republic of); Kim, Won, E-mail: kwon@jbnu.ac.kr [Department of Internal Medicine, Chonbuk National University Medical School, Jeonju (Korea, Republic of); Institute for Medical Sciences, Chonbuk National University Medical School, Jeonju (Korea, Republic of)

    2012-03-09

    Highlights: Black-Right-Pointing-Pointer Cisplatin increases acetylation of NF-{kappa}B p65 subunit in HK2 cells. Black-Right-Pointing-Pointer SIRT1 overexpression decreases cisplatin-induced p65 acetylation and -cytotoxicity. Black-Right-Pointing-Pointer Resveratrol decreased cisplatin-induced cell viability through deacetylation of p65. -- Abstract: As the increased acetylation of p65 is linked to nuclear factor-{kappa}B (NF-{kappa}B) activation, the regulation of p65 acetylation can be a potential target for the treatment of inflammatory injury. Cisplatin-induced nephrotoxicity is an important issue in chemotherapy of cancer patients. SIRT1, nicotinamide adenine dinucleotide (NAD{sup +})-dependent protein deacetylase, has been implicated in a variety of cellular processes such as inflammatory injury and the control of multidrug resistance in cancer. However, there is no report on the effect of SIRT1 overexpression on cisplatin-induced acetylation of p65 subunit of NF-{kappa}B and cell injury. To investigate the effect of SIRT1 in on cisplatin-induced acetylation of p65 subunit of NF-{kappa}B and cell injury, HK2 cells were exposed with SIRT1 overexpression, LacZ adenovirus or dominant negative adenovirus after treatment with cisplatin. While protein expression of SIRT1 was decreased by cisplatin treatment compared with control buffer treatment, acetylation of NF-{kappa}B p65 subunit was significantly increased after treatment with cisplatin. Overexpression of SIRT1 ameliorated the increased acetylation of p65 of NF-{kappa}B during cisplatin treatment and cisplatin-induced cytotoxicity. Further, treatment of cisplatin-treated HK2 cells with resveratrol, a SIRT1 activator, also decreased acetylation of NF-{kappa}B p65 subunit and cisplatin-induced increase of the cell viability in HK2 cells. Our findings suggests that the regulation of acetylation of p65 of NF-{kappa}B through SIRT1 can be a possible target to attenuate cisplatin-induced renal cell damage.

  8. Urolithin A Mitigates Cisplatin-Induced Nephrotoxicity by Inhibiting Renal Inflammation and Apoptosis in an Experimental Rat Model.

    Science.gov (United States)

    Guada, Melissa; Ganugula, Raghu; Vadhanam, Manicka; Ravi Kumar, Majeti N V

    2017-10-01

    Cumulative kidney toxicity associated with cisplatin is severe and there is no clear consensus on the therapeutic management of the same. The pathogenesis involves activation of inflammatory and apoptotic pathways; therefore, regulating these pathways offers protection. Given the anti-inflammatory and antioxidant effects of urolithin A, a gut microbial metabolite of ellagic acid, our aim was to explore the potential use of urolithin A in the prevention of cisplatin-induced nephrotoxicity in an experimental rat model. For this purpose, animals received a single intraperitoneal dose of cisplatin (5 mg/kg body weight). Six hours prior to cisplatin administration, rats were orally treated with either ellagic acid or urolithin A (50 mg/kg body weight), followed by a daily dose of these compounds during the next 5 days. At the end, plasma and kidneys were collected for analysis. Cisplatin-induced kidney damage was revealed by a significant rise in the plasma creatinine levels accompanied by significant morphologic changes in tubules, T cell Ig and mucin domain-containing protein-1, ionized calcium-binding adapter molecule 1, as well as a marked increase in the number of apoptotic cells localized in tubules. Cisplatin also reduced nitric oxide synthase 3 and nuclear factor kappa-light-chain-enhancer of activated B cells resulting in regulation of various inflammatory cytokines. Urolithin A effectively attenuated cisplatin-induced kidney damage and showed significantly greater effect than its precursor ellagic acid on preserving the normal kidney architecture by downregulating the proinflammatory cytokines. In summary, urolithin A mitigates cisplatin-induced nephrotoxicity in rats by modulation of the inflammatory cascade and inhibition of the proapoptotic pathway. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

  9. Cilastatin protects against cisplatin-induced nephrotoxicity without compromising its anticancer efficiency in rats.

    Science.gov (United States)

    Humanes, Blanca; Lazaro, Alberto; Camano, Sonia; Moreno-Gordaliza, Estefanía; Lazaro, Jose A; Blanco-Codesido, Montserrat; Lara, Jose M; Ortiz, Alberto; Gomez-Gomez, Maria M; Martín-Vasallo, Pablo; Tejedor, Alberto

    2012-09-01

    Cisplatin is an anticancer agent marred by nephrotoxicity; however, limiting this adverse effect may allow the use of higher doses to improve its efficacy. Cilastatin, a small molecule inhibitor of renal dehydropeptidase I, prevents proximal tubular cells from undergoing cisplatin-induced apoptosis in vitro. Here, we explored the in vivo relevance of these findings and the specificity of protection for kidney cells in cisplatin-treated rats. Cisplatin increased serum blood urea nitrogen and creatinine levels, and the fractional excretion of sodium. Cisplatin decreased the glomerular filtration rate, promoted histological renal injury and the expression of many pro-apoptotic proteins in the renal cortex, increased the Bax/Bcl2 ratio, and oxidative stress in kidney tissue and urine. All these features were decreased by cilastatin, which preserved renal function but did not modify the pharmacokinetics of cisplatin area under the curve. The cisplatin-induced death of cervical, colon, breast, and bladder-derived cancer cell lines was not prevented by cilastatin. Thus, cilastatin has the potential to prevent cisplatin nephrotoxicity without compromising its anticancer efficacy.

  10. Antioxidant action of bixin against cisplatin-induced chromosome aberrations and lipid peroxidation in rats.

    Science.gov (United States)

    Silva, C R; Antunes, L M; Bianchi, M L

    2001-06-01

    Cisplatin is one of the most active cytotoxic agents in the treatment of cancer, but has serious side effects, inducing nephrotoxicity and chromosome aberrations. In this study we evaluated the role of the carotenoid bixin on cisplatin-induced oxidative stress in Wistar rats through three markers of oxidative damage: chromosome aberrations, glutathione depletion and lipid peroxidation. The animals were divided into six treatment groups with six rats in each (n= 6). The dose of cisplatin (5.0 mg kg(-1)body wt.) was injected i.p. and bixin (2.5 or 5.0 mg kg(-1)body wt.) was given by gavage at 48, 24 h and 10 min before the cisplatin injection. The treatment with the highest dose of bixin resulted in a statistically significant reduction, by about 33%, in cisplatin-induced abnormal metaphases (P< 0.05). A single dose of cisplatin enhanced the formation of lipid peroxides in 29% and resulted in a 29% depletion in renal glutathione 24 h after cisplatin administration (P< 0.05). The pretreatment with bixin reduced the total number of chromosome aberrations, inhibited the increase in lipid peroxidation, and inhibited renal glutathione depletion induced by cisplatin. Since the pretreatment with bixin alone was safe, under the present experimental conditions, the results suggest that bixin may have future clinical application after further studies. Copyright 2001 Academic Press.

  11. Sorghum [Sorghum bicolor (L.) Moench] leaf sheath dye protects against cisplatin-induced hepatotoxicity and oxidative stress in rats.

    Science.gov (United States)

    Ademiluyi, Adedayo O; Oboh, Ganiyu; Agbebi, Oluwaseun J; Boligon, Aline A; Athayde, Margareth L

    2014-12-01

    This study sought to determine the protective effect of dietary inclusion of sorghum leaf sheath dye on cisplatin-induced hepatotoxicity and oxidative stress in rats. Adult male rats were randomly divided into four groups with six animals in each group. Groups I and II were fed a basal diet, while groups III and IV were fed diets containing 0.5% and 1% sorghum leaf sheath dye, respectively, for 20 days before cisplatin administration. Hepatotoxicity was induced by a single dose of cisplatin (7 mg/kg body weight, i.p.), and the experiment was terminated at 3 days after cisplatin injection. The liver and plasma were studied for hepatotoxicity and antioxidant capacity. Cisplatin caused a significant (Psorghum leaf sheath dye. Furthermore, dietary inclusion of sorghum leaf sheath dye caused a marked reduction in the activities of alanine aminotransferase and aspartate aminotransferase after cisplatin administration. However, the ability of the dye to prevent significant cisplatin-induced alteration of both plasma and liver antioxidant indices suggests an antioxidant mechanism of action. Hence, this protective effect of Sorghum bicolor leaf sheath dye against cisplatin-induced hepatotoxicity in rats reflects its potential and beneficial role in the prevention of liver damage associated with cisplatin administration.

  12. Apaf-1 Inhibitors Protect from Unwanted Cell Death in In Vivo Models of Kidney Ischemia and Chemotherapy Induced Ototoxicity

    Science.gov (United States)

    Orzáez, Mar; Marchán, Sandra; Mondragón, Laura; Montava, Rebeca; Valero, Juan García; Landeta, Olatz; Basañez, Gorka; Carbajo, Rodrigo J.; Pineda-Lucena, Antonio; Bujons, Jordi; Moure, Alejandra; Messeguer, Angel; Lagunas, Carmen; Herrero, Carmen; Pérez-Payá, Enrique

    2014-01-01

    Background Excessive apoptosis induces unwanted cell death and promotes pathological conditions. Drug discovery efforts aimed at decreasing apoptotic damage initially targeted the inhibition of effector caspases. Although such inhibitors were effective, safety problems led to slow pharmacological development. Therefore, apoptosis inhibition is still considered an unmet medical need. Methodology and Principal Findings The interaction between Apaf-1 and the inhibitors was confirmed by NMR. Target specificity was evaluated in cellular models by siRNa based approaches. Cell recovery was confirmed by MTT, clonogenicity and flow cytometry assays. The efficiency of the compounds as antiapoptotic agents was tested in cellular and in vivo models of protection upon cisplatin induced ototoxicity in a zebrafish model and from hypoxia and reperfusion kidney damage in a rat model of hot ischemia. Conclusions Apaf-1 inhibitors decreased Cytc release and apoptosome-mediated activation of procaspase-9 preventing cell and tissue damage in ex vivo experiments and in vivo animal models of apoptotic damage. Our results provide evidence that Apaf-1 pharmacological inhibition has therapeutic potential for the treatment of apoptosis-related diseases. PMID:25330150

  13. Lycium barbarum polysaccharide attenuates cisplatin- induced ...

    African Journals Online (AJOL)

    Purpose: To investigate the effect of Lycium barbarum polysaccharide (LBP) on apoptosis of ovary granulose cells (GCs), as well as its underlying mechanism. Methods: GCs were isolated from Sprague Dawley (SD) rats and divided into three groups: control group, model group (DDP) and LBP group. Cell morphology was ...

  14. Tetrathiomolybdate mediates cisplatin-induced p38 signaling and EGFR degradation and enhances response to cisplatin therapy in gynecologic cancers

    Science.gov (United States)

    Kim, Kyu Kwang; Han, Alex; Yano, Naohiro; Ribeiro, Jennifer R.; Lokich, Elizabeth; Singh, Rakesh K.; Moore, Richard G.

    2015-01-01

    Cisplatin and its analogs are among the most widely used chemotherapeutic agents against various types of cancer. It is known that cisplatin can activate epidermal growth factor receptor (EGFR), which may provide a survival benefit in cancers. Tetrathiomolybdate (TM) is a potent anti-cancer and anti-angiogenic agent and has been investigated in a number of clinical trials for cancer. In this study, we explore the therapeutic potential of TM on cisplatin-mediated EGFR regulation. Our study shows that TM is not cytotoxic, but exerts an anti-proliferative effect in ECC-1 cells. However, TM treatment prior to cisplatin markedly improves cisplatin-induced cytotoxicity. TM suppressed cisplatin-induced activation of EGFR while potentiating activation of p38; the activation of p38 signaling appeared to promote cisplatin-induced EGFR degradation. These results are in contrast to what we saw when cells were co-treated with cisplatin plus an EGFR tyrosine kinase inhibitor, where receptor activation was inhibited but receptor degradation was also blocked. Our current study is in agreement with previous findings that TM may have a therapeutic benefit by inhibiting EGFR activation. We furthermore provide evidence that TM may provide an additional benefit by potentiating p38 activation following cisplatin treatment, which may in turn promote receptor degradation by cisplatin. PMID:26568478

  15. Identification of small molecule inhibitors of cisplatin-induced hair cell death: results of a 10,000 compound screen in the zebrafish lateral line.

    Science.gov (United States)

    Thomas, Andrew J; Wu, Patricia; Raible, David W; Rubel, Edwin W; Simon, Julian A; Ou, Henry C

    2015-03-01

    The zebrafish lateral line can be used to identify small molecules that protect against cisplatin-induced hair cell death. Cisplatin is a commonly used chemotherapeutic agent, which causes hearing loss by damaging hair cells of the inner ear. There are currently no FDA-approved pharmacologic strategies for preventing this side effect. The zebrafish lateral line has been used successfully in the past to study hair cell death and protection. In this study, we used the zebrafish lateral line to screen a library of 10,000 small molecules for protection against cisplatin-induced hair cell death. Dose-response relationships for identified protectants were determined by quantifying hair cell protection. The effect of each protectant on uptake of a fluorescent cisplatin analog was also quantified. From this screen, we identified 2 compounds exhibiting dose-dependent protection: cisplatin hair cell protectant 1 and 2 (CHCP1 and 2). CHCP1 reduced the uptake of a fluorescent cisplatin analog, suggesting its protective effects may be due to decreased cisplatin uptake. CHCP2 did not affect uptake, which suggests an intracellular mechanism of action. Evaluation of analogs of CHCP2 revealed 3 additional compounds that significantly reduced cisplatin-induced hair cell death, although none exceed the effectiveness or potency of the parent compound. The zebrafish lateral line was used to identify 2 small molecules that protected against cisplatin-induced hair cell death.

  16. Synthetic and natural antioxidants attenuate cisplatin-induced vomiting.

    Science.gov (United States)

    Alam, Javaid; Subhan, Fazal; Ullah, Ihsan; Shahid, Muhammad; Ali, Gowhar; Sewell, Robert D E

    2017-01-13

    Synthetic and natural antioxidants including Bacopa monnieri (L.) Pennell (Scrophulariaceae) which also possess anti-dopaminergic properties, have been proposed to be useful for emetogenic chemotherapy. In this study, synthetic [N-(2-mercaptopropionyl) glycine (MPG), vitamin C (Vit-C)] and natural [grape seed proanthocyanidin (GP), B. monnieri n-butanolic fraction (BM-ButFr)] antioxidants and their combinations were evaluated against cisplatin-induced emesis in pigeons during a 24 h observation period. Emesis was induced using cisplatin (7.0 mg/kg, i.v). MPG (10, 20, 30 mg/kg), Vit-C (100, 200, 300 mg/kg), GP (50, 100, 150 mg/kg) and BM-ButFr (5, 10, 20 mg/kg) and their combinations were administered i.m., 15 min before cisplatin administration. The number of vomiting bouts, retching, emetic latency and % weight loss were recorded to assess antiemetic potential. Antioxidant activity was evaluated by the DPPH free radical scavenging assay (FRSA). Significant attenuation of vomiting bouts, retching, % weight loss along with an increase in latency was produced by all the antioxidants and their combinations compared to cisplatin alone and this is the first report of this activity of GP in pigeons. Low EC50 values in the FRSA for MPG (67.66 μg/mL), Vit-C (69.42 μg/mL), GP (6.498 μg/mL) and BM-ButFr (55.61 μg/mL) compared to BHT standard (98.17 μg/mL) demonstrated their radical scavenging capacity. Correlation between the antioxidant activity and antiemetic efficacy disclosed a high degree of correlation for the tested antioxidants. The selected synthetic and natural antioxidants and their combinations were able to attenuate cisplatin-induced vomiting, which correlated with their potent in vitro antioxidant activity.

  17. Transient Receptor Potential Vanilloid 1 is essential for cisplatin-induced heat hyperalgesia in mice

    Directory of Open Access Journals (Sweden)

    Carlton Susan M

    2010-03-01

    Full Text Available Abstract Background Cisplatin is primarily used for treatment of ovarian and testicular cancer. Oxaliplatin is the only effective treatment for metastatic colorectal cancer. Both are known to cause dose related, cumulative toxic effects on the peripheral nervous system and thirty to forty percent of cancer patients receiving these agents experience painful peripheral neuropathy. The mechanisms underlying painful platinum-induced neuropathy remain poorly understood. Previous studies have demonstrated important roles for TRPV1, TRPM8, and TRPA1 in inflammation and nerve injury induced pain. Results In this study, using real-time, reverse transcriptase, polymerase chain reaction (RT-PCR, we analyzed the expression of TRPV1, TRPM8, and TRPA1 induced by cisplatin or oxaliplatin in vitro and in vivo. For in vitro studies, cultured E15 rat dorsal root ganglion (DRG neurons were treated for up to 48 hours with cisplatin or oxaliplatin. For in vivo studies, trigeminal ganglia (TG were isolated from mice treated with platinum drugs for three weeks. We show that cisplatin and oxaliplatin-treated DRG neurons had significantly increased in TRPV1, TRPA1, and TRPM8 mRNA expression. TG neurons from cisplatin treated mice had significant increases in TRPV1 and TRPA1 mRNA expression while oxaliplatin strongly induced only TRPA1. Furthermore, compared to the cisplatin-treated wild-type mice, cisplatin-treated TRPV1-null mice developed mechanical allodynia but did not exhibit enhancement of noxious heat- evoked pain responses. Immunohistochemistry studies showed that cisplatin-treated mice had no change in the proportion of the TRPV1 immunopositive TG neurons. Conclusion These results indicate that TRPV1 and TRPA1 could contribute to the development of thermal hyperalgesia and mechanical allodynia following cisplatin-induced painful neuropathy but that TRPV1 has a crucial role in cisplatin-induced thermal hyperalgesia in vivo.

  18. Magnesium improves cisplatin-mediated tumor killing while protecting against cisplatin-induced nephrotoxicity.

    Science.gov (United States)

    Kumar, Gopal; Solanki, Malvika H; Xue, Xiangying; Mintz, Rachel; Madankumar, Swati; Chatterjee, Prodyot K; Metz, Christine N

    2017-08-01

    Approximately 30% of all cancer patients treated with cisplatin, a widely used broad-spectrum chemotherapeutic agent, experience acute kidney injury (AKI). Almost all patients receiving cisplatin have magnesium (Mg) losses, which are proposed to aggravate AKI. Currently, there are no methods to successfully treat or prevent cisplatin-AKI. Whereas Mg supplementation has been shown to reduce AKI in experimental models and several small clinical trials, the effects of Mg status on tumor outcomes in immunocompetent tumor-bearing mice and humans have not been investigated. The purpose of this study was to further examine the effects of Mg deficiency (±Mg supplementation) on cisplatin-mediated AKI and tumor killing in immunocompetent mice bearing CT26 colon tumors. Using a model where cisplatin alone (20 mg/kg cumulative dose) produced minimal kidney injury, Mg deficiency significantly worsened cisplatin-mediated AKI, as determined by biochemical markers (blood urea nitrogen and plasma creatinine) and histological renal changes, as well as markers of renal oxidative stress, inflammation, and apoptosis. By contrast, Mg supplementation blocked cisplatin-induced kidney injury. Using LLC-PK1 renal epithelial cells, we observed that Mg deficiency or inhibition of Mg uptake significantly enhanced cisplatin-induced cytotoxicity, whereas Mg supplementation protected against cytotoxicity. However, neither Mg deficiency nor inhibition of Mg uptake impaired cisplatin-mediated killing of CT26 tumor cells in vitro. Mg deficiency was associated with significantly larger CT26 tumors in BALB/c mice when compared with normal-fed control mice, and Mg deficiency significantly reduced cisplatin-mediated tumor killing in vivo. Finally, Mg supplementation did not compromise cisplatin's anti-tumor efficacy in vivo. Copyright © 2017 the American Physiological Society.

  19. Antioxidant treatment with coenzyme Q-ter in prevention of gentamycin ototoxicity in an animal model

    OpenAIRE

    Fetoni, A. R.; Eramo, S L M; Rolesi, R; TROIANI, D.; PALUDETTI, G.

    2012-01-01

    SUMMARY Aminoglycosides, such as gentamycin, are well known ototoxic agents. Toxicity occurs via an activation process involving the formation of an iron-gentamycin complex with free radical production. Antioxidants like Q-ter (a soluble formulation of coenzyme Q10, CoQ10), can limit or prevent cellular ototoxic damage. The present study was designed to investigate the possible protective effects of Q-ter on gentamycin ototoxicity in albino guinea pigs (250-300 g). Animals were divided into f...

  20. Functional mechanotransduction is required for cisplatin-induced hair cell death in the zebrafish lateral line

    Science.gov (United States)

    Thomas, Andrew J.; Hailey, Dale W.; Stawicki, Tamara M.; Wu, Patricia; Coffin, Allison B.; Rubel, Edwin W.; Raible, David W.; Simon, Julian A.; Ou, Henry C.

    2013-01-01

    Cisplatin, one of the most commonly used anti-cancer drugs, is known to cause inner ear hair cell damage and hearing loss. Despite much investigation into mechanisms of cisplatin-induced hair cell death, little is known about the mechanism whereby cisplatin is selectively toxic to hair cells. Using hair cells of the zebrafish lateral line, we found that chemical inhibition of mechanotransduction with quinine and EGTA protected against cisplatin-induced hair cell death. Furthermore, we found that the zebrafish mutants mariner (myo7aa) and sputnik (cad23) that lack functional mechanotransduction were resistant to cisplatin-induced hair cell death. Using a fluorescent analogue of cisplatin, we found that chemical or genetic inhibition of mechanotransduction prevented its uptake. These findings demonstrate that cisplatin-induced hair cell death is dependent on functional mechanotransduction in the zebrafish lateral line. PMID:23467357

  1. miR-203 inhibits cell proliferation and promotes cisplatin induced cell death in tongue squamous cancer

    Energy Technology Data Exchange (ETDEWEB)

    Lin, Jiong; Lin, Yao [Guangdong Provincial Key Laboratory of Stomatology, Department of Orthodontics, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangzhou, 510055 (China); Fan, Li [Department of Pharmaceutical Analysis, School of Pharmacy, The Fourth Military Medical University, Xi' an, Shaanxi, 710032 (China); Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, 510055 (China); Kuang, Wei [Department of Stomatology, Guangzhou General Hospital of Guangzhou Military Command, 111 Liuhua Road, Guangzhou, 510010 (China); Zheng, Liwei [State Key Laboratory of Oral Diseases, Sichuan University, Wuhou District, Chengdu, 610041 (China); Wu, Jiahua [Guangdong Provincial Key Laboratory of Stomatology, Department of Orthodontics, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangzhou, 510055 (China); Shang, Peng [Patient-specific Orthopedic Technology Research Center in GuangDong Research Centre for Neural Engineering, 1068 Xueyuan Boulevard, University Town of Shenzhen, Xili, Nanshan, Shenzhen, 518055 (China); Wang, Qiaofeng [Department of Pharmaceutical Chemistry, School of Pharmacy, The Fourth Military Medical University, Xi' an, Shanxi, 710032 (China); Tan, Jiali, E-mail: jasminenov@163.com [Guangdong Provincial Key Laboratory of Stomatology, Department of Orthodontics, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangzhou, 510055 (China)

    2016-04-29

    Oral squamous cell carcinoma (OSCC) is one of the most common types of the head and neck cancer. Chemo resistance of OSCC has been identified as a substantial therapeutic hurdle. In this study, we analyzed the role of miR-203 in the OSCC and its effects on cisplatin-induced cell death in an OSCC cell line, Tca8113. There was a significant decrease of miR-203 expression in OSCC samples, compared with the adjacent normal, non-cancerous tissue. After 3 days cisplatin treatment, the survived Tca8113 cells had a lower expression of miR-203 than that in the untreated control group. In contrast, PIK3CA showed an inverse expression in cancer and cisplatin survived Tca8113 cells. Transfection of Tca8113 cells with miR-203 mimics greatly reduced PIK3CA expression and Akt activation. Furthermore, miR-203 repressed PIK3CA expression through targeting the 3′UTR. Restoration of miR-203 not only suppressed cell proliferation, but also sensitized cells to cisplatin induced cell apoptosis. This effect was absent in cells that were simultaneously treated with PIK3CA RNAi. In summary, these findings suggest miR-203 plays an important role in cisplatin resistance in OSCC, and furthermore delivery of miR-203 analogs may serve as an adjuvant therapy for OSCC. - Highlights: • Much lower miR-203 expression in cisplatin resistant Tca8113 cells is discovered. • Delivery of miR-203 can sensitize the Tca8113 cells to cisplatin induced cell death. • MiR-203 can downregulate PIK3CA through the 3′UTR. • The effects of miR-203 on cisplatin sensitivity is mainly through PIK3CA pathway.

  2. Pre-treatment with cardamonin protects against cisplatin-induced nephrotoxicity in rats: Impact on NOX-1, inflammation and apoptosis

    Energy Technology Data Exchange (ETDEWEB)

    El-Naga, Reem N., E-mail: reemelnaga@hotmail.com

    2014-01-01

    Cisplatin is an effective anti-cancer drug; however, its clinical use is usually associated with nephrotoxicity as a dose-limiting side effect. Several molecular mechanisms have been found to be involved in this nephrotoxicity such as oxidative stress, inflammation and apoptosis. The aim of this study was to explore the potential nephroprotective effect of cardamonin, a flavone found in Alpinia plant, in a rat model of cisplatin-induced nephrotoxicity. The possible mechanisms underlying this nephroprotective effect were investigated. Cardamonin was given at two different doses; 10 and 30 mg/kg orally for two weeks, starting one week before giving a single nephrotoxic dose of cisplatin (7 mg/kg). Acute nephrtoxicity was evident by significantly increased blood urea nitrogen and serum creatinine levels. Also, cisplatin increased lipid peroxidation and depleted reduced glutathione level and superoxide dismutase. Additionally, cisplatin showed a marked pro-inflammatory response as evidenced by significant increase in tissue levels of IL-1β, TNF-α, NF-kB, iNOS, ICAM-1 and MCP-1. Pre-treatment with cardamonin significantly attenuated the nephrotoxic effects, oxidative stress and inflammation induced by cisplatin, in a dose-dependent manner. Also, cardamonin decreased caspase-3 expression and Bax/Bcl-2 ratio as compared to cisplatin group. Besides, cradamonin reversed cisplatin-induced decrease in EGF. Furthermore, up-regulation of NOX-1 was found to be involved in cisplatin-induced nephrotoxicity and its expression was significantly reduced by cardamonin. Histopathological examination further confirmed the nephroprotective effect of cardamonin. Moreover, pre-treatment with subtoxic concentration of cardamonin has significantly enhanced cisplatin cytotoxic activity in four different human cancer cell lines; hela, hepG2, PC3 and HCT116 cancer cell lines. In conclusion, these findings suggest that cardamonin improves therapeutic index of cisplatin and that NOX-1 is

  3. Paracrine Activation of the Wnt/β-Catenin Pathway by Bone Marrow Stem Cell Attenuates Cisplatin-Induced Kidney Injury

    Directory of Open Access Journals (Sweden)

    Xiaoyan Jiao

    2017-12-01

    Full Text Available Background/Aims: Cisplatin-induced acute kidney injury (AKI involves damage to tubular cells via excess reactive oxygen species (ROS generation. Stem cell-based therapies have shown great promise in AKI treatment. In this study, we aimed to assess the protective effect and mechanism of bone marrow mesenchymal stem cell (BMSC-derived conditioned medium (CM against cisplatin-induced AKI. Methods: In vitro, NRK-52E cells were incubated with cisplatin in the presence or absence of CM, followed by the assessment of cell viability, apoptosis and cell cycle distribution. Then, ICG-001 and IWR-1 were used to inhibit the wnt/β-catenin pathway. Furthermore, intracellular and mitochondrial ROS levels were evaluated using DCFH-DA and MitoSOX, respectively. In vivo, after cisplatin injection, rats were intravenously injected with CM or BMSCs. Sera and kidney tissues were collected on day 3 after cisplatin injection to evaluate changes in renal function and histology. Western blotting and qRT-PCR were employed to determine the expression of wnt/β-catenin pathway-related genes and proteins. Immunohistochemical staining was used to evaluate tubular β-catenin expression in kidney biopsy from AKI patients. Results: CM protected NRK-52E cells from cisplatin-induced injury by restoring the wnt4/β-catenin pathway. In response to ICG-001 and IWR-1, the protective effect of CM was attenuated, characterized by a decrease in cell proliferation and an increase in cell apoptosis and intracellular and mitochondrial ROS levels. Knockdown of β-catenin using siRNAs also suppressed the mitochondrial biogenesis regulators PGC-1α, TFAM and NRF-1. In the rat model, CM significantly alleviated renal function and histology associated with tubular injury and upregulated wnt4 and β-catenin. However, the renoprotective effect of CM was blocked by ICG-001, characterized by exacerbated renal function, suppressed PGC-1α expression and increased mitochondrial ROS. Clinical data

  4. Isoliquiritigenin pretreatment attenuates cisplatin induced proximal tubular cells (LLC-PK1) death and enhances the toxicity induced by this drug in bladder cancer T24 cell line.

    Science.gov (United States)

    Patricia Moreno-Londoño, Angela; Bello-Alvarez, Claudia; Pedraza-Chaverri, José

    2017-11-01

    Cisplatin is an effective antineoplastic agent widely used in the treatment of solid tumors, however, it induces nephrotoxicity. Cisplatin-induced nephrotoxicity is associated with increased reactive oxygen species (ROS) production and decreased antioxidant system defense in kidney. Isoliquiritigenin (IsoLQ) is a chalcone, which is characterized by its antioxidant and antiinflammatory properties. Herein, we investigated the protective effect of IsoLQ on LLC-PK1 proximal tubular cells against cisplatin-induced death and its effect on the antineoplastic activity of cisplatin on bladder cancer T24 cell line. It was found that pretreatment with IsoLQ attenuates cisplatin-induced cell death, ROS production, and activation of caspase-3. IsoLQ also induced heme oxygenase-1 (HO-1) expression that may be associated with nuclear factor (erythroid-derived 2)-like 2 (Nrf2) nuclear translocation. The protective effect of IsoLQ was abrogated by tin mesoporphyrin (SnMP), an HO inhibitor. Further, bilirubin and carbon monoxide releasing molecule-2 also showed a protective effect against cisplatin-induced cell death. In addition, IsoLQ induced in a dose-dependent way, death of T24 cells and exacerbated cisplatin-induced cell death. These results suggest that IsoLQ has a protective effect on cisplatin-induced toxicity in LLC-PK1 cells, in part through induction of HO-1, without interfering with the antineoplastic activity of this agent in T24 cells. Copyright © 2017. Published by Elsevier Ltd.

  5. Vestibular damage in chronic ototoxicity: a mini-review.

    Science.gov (United States)

    Sedó-Cabezón, Lara; Boadas-Vaello, Pere; Soler-Martín, Carla; Llorens, Jordi

    2014-07-01

    Ototoxicity is a major cause of the loss of hearing and balance in humans. Ototoxic compounds include pharmaceuticals such as aminoglycoside antibiotics, anti-malarial drugs, loop diuretics and chemotherapeutic platinum agents, and industrial chemicals including several solvents and nitriles. Human and rodent data indicate that the main target of toxicity is hair cells (HCs), which are the mechanosensory cells responsible for sensory transduction in both the auditory and the vestibular system. Nevertheless, the compounds may also affect the auditory and vestibular ganglion neurons. Exposure to ototoxic compounds has been found to cause HC apoptosis, HC necrosis, and damage to the afferent terminals, of differing severity depending on the ototoxicity model. One major pathway frequently involved in HC apoptosis is the c-jun N-terminal kinase (JNK) signaling pathway activated by reactive oxygen species, but other apoptotic pathways can also play a role in ototoxicity. Moreover, little is known about the effects of chronic low-dose exposure. In rodent vestibular epithelia, extrusion of live HCs from the sensory epithelium may be the predominant form of cell demise during chronic ototoxicity. In addition, greater involvement of the afferent terminals may occur, particularly the calyx units contacting type I vestibular HCs. As glutamate is the neurotransmitter in this synapse, excitotoxic phenomena may participate in afferent and ganglion neuron damage. Better knowledge of the events that take place in chronic ototoxicity is of great interest, as it will increase understanding of the sensory loss associated with chronic exposure and aging. Copyright © 2013 Elsevier Inc. All rights reserved.

  6. Candesartan Mediated Amelioration of Cisplatin-Induced Testicular Damage Is Associated with Alterations in Expression Patterns of Nephrin and Podocin

    Science.gov (United States)

    Enatsu, Noritoshi; Miyake, Hideaki; Chiba, Koji; Fujisawa, Masato

    2015-01-01

    Nephrin and podocin are known to be closely related to the pharmacological effects of angiotensin-II receptor blocker (ARB). The objectives of this study were to investigate the role of nephrin and podocin using cisplatin-induced testicular damage and to evaluate the effect of ARB. At first, we evaluated the effects of cisplatin either alone or in combination with ARB candesartan on changes in expression patterns of nephrin and podocin in the rat testes. We then conducted in vitro studies to investigate the effects of angiotensin using cultured Sertoli cells, line TM4. As a result, the expression of nephrin and podocin was shown to localize around the basal membrane of seminiferous tubules. Treatment with cisplatin resulted in a marked decrease in the expression of nephrin and podocin and induced a shift of both proteins from linear to granular expression patterns, accompanying the increased apoptotic index in the testes; these changes were partially restored by the additional administration of candesartan. In vitro studies with TM4 revealed the angiotensin-II mediated expression changes of nephrin and podocin. These findings suggest that candesartan can prevent cisplatin-induced testicular damage by regulating expression patterns of the nephrin-podocin complex in the testes. PMID:26539476

  7. Propofol enhances the cisplatin-induced apoptosis on cervical cancer cells via EGFR/JAK2/STAT3 pathway.

    Science.gov (United States)

    Li, Haoran; Lu, Yan; Pang, Yangyang; Li, Mengjiao; Cheng, Xi; Chen, Jiawei

    2017-02-01

    The main purpose of this study was to evaluate propofol and its combined effect with cisplatin on apoptosis of cervical cancer cells and molecular mechanisms of this phenomenon. The effects of propofol and cisplatin on cell viability and apoptosis were detected by cell counting kit-8 (CCK-8) assay, colony formation assay and flow cytometry assay. Besides, protein expression of EGFR/JAK2/STAT3 pathway was determined by western blot. STAT3 was over-expressed in cervical cancer cells by STAT3 cDNA. Expression of EGFR and STAT3 protein of human tissues was evaluated by immunohistochemistry (IHC) assay. In this study, we found that not only propofol alone could inhibit cervical cancer cells viability but also could increase the inhibitory effect of cisplatin on cervical cancer cells growth. Meanwhile, propofol sensitized cervical cancer cells to cisplatin-induced apoptosis but not affected normal cervical cells. In genetic level, propofol could enhance the anti-tumor effect of cisplatin through EGFR/JAK2/STAT3 pathway. Further studies indicated that overexpression of EGFR and STAT3 is related to poor prognoses in cervical cancer patients, which contributed to confirm the clinical role of combined application of propofol and cisplatin. Propofol enhances the cisplatin-induced cell apoptosis cervical cancer cells via EGFR/JAK2/STAT3 pathway and may be developed as a potential therapeutic agent to treat cervical cancer. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  8. The role of high-frequency audiometry in early detection of ototoxicity

    NARCIS (Netherlands)

    Dreschler, W. A.; vd Hulst, R. J.; Tange, R. A.; Urbanus, N. A.

    1985-01-01

    Ototoxicity is one of the unwanted side-effects of a number of medical drugs. As ototoxicity appears to be most pronounced in the higher frequencies, it can be assessed at an earlier stage by using high-frequency audiometry from 8 to 20 kHz. We have investigated the precision of these measurements.

  9. High frequency audiometry in prospective clinical research of ototoxicity due to platinum derivatives

    NARCIS (Netherlands)

    van der Hulst, R. J.; Dreschler, W. A.; Urbanus, N. A.

    1988-01-01

    The results of clinical use of routine high frequency audiometry in monitoring the ototoxic side effects of platinum and its derivatives are described in this prospective study. After demonstrating the reproducibility of the technique, we discuss the first results of an analysis of ototoxic side

  10. Cisplatin-Associated Ototoxicity: A Review for the Health Professional

    Directory of Open Access Journals (Sweden)

    Jessica Paken

    2016-01-01

    Full Text Available Cisplatin is an effective drug used in the treatment of many cancers, yet its ototoxic potential places cancer patients, exposed to this drug, at risk of hearing loss, thus negatively impacting further on a patient’s quality of life. It is paramount for health care practitioners managing such patients to be aware of cisplatin’s ototoxic properties and the clinical signs to identify patients at risk of developing hearing loss. English peer-reviewed articles from January 1975 to July 2015 were assessed from PubMed, Science Direct, and Ebscohost. Seventy-nine articles and two books were identified for this review, using MeSH terms and keywords such as “ototoxicity”, “cisplatin”, “hearing loss”, and “ototoxicity monitoring”. This review provides an up-to-date overview of cisplatin-associated ototoxicity, namely, its clinical features, incidence rates, and molecular and cellular mechanisms and risk factors, to health care practitioners managing the patient with cancer, and highlights the need for a team-based approach to complement an audiological monitoring programme to mitigate any further loss in the quality of life of affected patients, as there is currently no otoprotective agent recommended routinely for the prevention of cisplatin-associated ototoxicity. It also sets the platform for effective dialogue towards policy formulation and strengthening of health systems in developing countries.

  11. S-Allylmercaptocysteine Attenuates  Cisplatin-Induced Nephrotoxicity through  Suppression of Apoptosis, Oxidative Stress, and  Inflammation.

    Science.gov (United States)

    Zhu, Xiaosong; Jiang, Xiaoyan; Li, Ang; Zhao, Zhongxi; Li, Siying

    2017-02-20

    Cisplatin is a potent chemotherapeutic agent, but its clinical usage is limited by nephrotoxicity. S-allylmercaptocysteine (SAMC), one of the water-soluble organosulfur garlic derivatives, has antioxidant and anti-inflammatory properties and plays an important role in protecting cells from apoptosis. This study aims to examine the protective effects of SAMC on cisplatin nephrotoxicity and to explore the mechanism of its renoprotection. Rats were treated with cisplatin with or without pre-treatment with SAMC. Renal function, histological change, oxidative stress markers and antioxidant enzyme activities were investigated. Apoptotic marker, nuclearfactor (NF)-κB activity, expression of nuclear factor erythroid 2-related factor 2 (Nrf2), NAD(P)H:quinone oxidoreductase 1 (NQO1) and inflammatory cytokines were also examined. The effect of SAMC on cell viability and apoptosis was examined in cultured human kidney (HK-2) cells. SAMC was confirmed to significantly attenuate cisplatin-induced renal damage by using histological pathology and molecular biological method. Pre-treatment with SAMC reduced NF-κB activity, up-regulated Nrf2 and NQO1 expression and down-regulated inflammatory cytokine levels after cisplatin administration. Cisplatin-induced apoptosis in HK-2 cells was significantly attenuated by SAMC. Thus our results suggest that SAMC could be a potential therapeutic agent in the treatment of the cisplatin-induced nephrotoxicity through its anti-apoptotic, anti-oxidant and anti-inflammatory effects.

  12. An integrative view of cisplatin-induced renal and cardiac toxicities: molecular mechanisms, current treatment challenges and potential protective measures

    Science.gov (United States)

    Dugbartey, George J.; Peppone, Luke J.; de Graaf, Inge A.M.

    2017-01-01

    Cisplatin is currently one of the most widely-used chemotherapeutic agents against various malignancies. Its clinical application is limited, however, by inherent renal and cardiac toxicities and other side effects, of which the underlying mechanisms are only partly understood. Experimental studies show cisplatin generates reactive oxygen species, which impair the cell’s antioxidant defense system, causing oxidative stress and potentiating injury, thereby culminating in kidney and heart failure. Understanding the molecular mechanisms of cisplatin-induced renal and cardiac toxicities may allow clinicians to prevent or treat this problem better and may also provide a model for investigating drug-induced organ toxicity in general. This review discusses some of the major molecular mechanisms of cisplatin-induced renal and cardiac toxicities including disruption of ionic homeostasis and energy status of the cell leading to cell injury and cell death. We highlight clinical manifestations of both toxicities as well as (novel)biomarkers such as kidney injury molecule-1 (KIM-1), tissue inhibitor of metalloproteinase-1 (TIMP-1) and N-terminal pro-B-type natriuretic peptide (NT-proBNP). We also present some current treatment challenges and propose potential protective strategies with novel pharmacological compounds that might mitigate or prevent these toxicities, which include the use of hydrogen sulfide. PMID:27717837

  13. Protection against salicylate ototoxicity by zinc.

    Science.gov (United States)

    Günther, T; Rebentisch, E; Vormann, J

    1989-03-01

    One day after oral application of 700 mg (5.5 mmol)/kg salicylic acid given as Na salicylate, hearing thresholds in rats, measured by acoustically evoked responses at 10 and 20 kHz, were increased. Salicylate-induced hearing loss was completely prevented by simultaneous s.c. injection of 6 mg (92 mumol)/kg Zn, whereas simultaneous s.c. injection of 1.5 mmol/kg MgCl2 had no effect. Simultaneous s.c. injection of 100 mg (152 mumol)/kg desferrioxamine had only a minor beneficial effect indicating that salicylate-induced Fe accumulation plays no significant role in salicylate ototoxicity.

  14. Allicin protects auditory hair cells and spiral ganglion neurons from cisplatin - Induced apoptosis.

    Science.gov (United States)

    Wu, Xianmin; Li, Xiaofei; Song, Yongdong; Li, He; Bai, Xiaohui; Liu, Wenwen; Han, Yuechen; Xu, Lei; Li, Jianfeng; Zhang, Daogong; Wang, Haibo; Fan, Zhaomin

    2017-04-01

    Cisplatin is a broad-spectrum anticancer drug that is commonly used in the clinic. Ototoxicity is one of the major side effects of this drug, which caused irreversible sensorineural hearing loss. Allicin, the main biologically active compound derived from garlic, has been shown to exert various anti-apoptotic and anti-oxidative activities in vitro and in vivo studies. We took advantage of C57 mice intraperitoneally injected with cisplatin alone or with cisplatin and allicin combined, to investigate whether allicin plays a protective role in vivo against cisplatin ototoxicity. The result showed that C57 mice in cisplatin group exhibited increased shift in auditory brainstem response, whereas the auditory fuction of mice in allicin + cisplatin group was protected in most frequencies, which was accordance with observed damages of outer hair cells (OHCs) and spiral ganglion neurons (SGNs) in the cochlea. Allicin markedly protected SGN mitochondria from damage and releasing cytochrome c, and significantly reduced pro-apoptosis factor expressions activated by cisplatin, including Bax, cleaved-caspase-9, cleaved-caspase-3and p53. Furthermore, allicin reduced the level of Malondialdehyde (MDA), but increased the level of superoxide dismutase (SOD). All data suggested that allicin could prevent hearing loss induced by cisplatin effectively, of which allicin protected SGNs from apoptosis via mitochondrial pathway while protected OHCs and supporting cells (SCs) from apoptosis through p53 pathway. Copyright © 2017 Elsevier Ltd. All rights reserved.

  15. Curcumin Ameliorates Functional and Structural Abnormalities in Cisplatin-induced Neuropathy.

    Science.gov (United States)

    Agthong, Sithiporn; Kaewsema, Athitaya; Charoensub, Thuntawat

    2015-06-01

    Peripheral neuropathy is one of the major side effects of cisplatin; however, effective treatments are lacking. Curcumin is a polyphenol found in the root of Curcuma longa and has been shown neuroprotective against several neurological diseases. Nevertheless, its effects on cisplatin neuropathy remain unclear. This study aimed to clarify this issue by inducing neuropathy in the rats with intraperitoneal injection of cisplatin 2 mg/kg twice a week for 5 consecutive weeks. Curcumin 200 mg/kg/day was given by gavage to a group of cisplatin-treated rats during these five weeks. The results showed that cisplatin induced thermal hypoalgesia in the 5(th) week which could be prevented by curcumin. In the 5(th) and 8(th) weeks, sciatic motor nerve conduction velocity was reduced in the cisplatin compared with the control groups. Curcumin significantly attenuated this deficit. Morphometric analysis of L4 dorsal root ganglia from the cisplatin group revealed nuclear and nucleolar atrophy including loss of neurons in the 8(th) week. These alterations were significantly blocked by curcumin. Moreover, curcumin also ameliorated the reduced myelin thickness in the sciatic nerve of cisplatin-treated rats. Taken together, our findings suggest the favorable effects of curcumin on both functional and structural abnormalities in cisplatin neuropathy. Future studies are needed to clarify the exact underlying mechanisms.

  16. Allicin protects against cisplatin-induced vestibular dysfunction by inhibiting the apoptotic pathway.

    Science.gov (United States)

    Wu, Xianmin; Cai, Jing; Li, Xiaofei; Li, He; Li, Jianfeng; Bai, Xiaohui; Liu, Wenwen; Han, Yuechen; Xu, Lei; Zhang, Daogong; Wang, Haibo; Fan, Zhaomin

    2017-06-15

    Cisplatin is an anticancer drug that causes the impairment of inner ear function as side effects, including hearing loss and balance dysfunction. The purpose of this study was to investigate the effects of allicin against cisplatin-induced vestibular dysfunction in mice and to make clear the mechanism underlying the protective effects of allicin on oto-vestibulotoxicity. Mice intraperitoneally injected with cisplatin exhibited vestibular dysfunction in swimming test, which agreed with impairment in vestibule. However, these impairments were significantly prevented by pre-treatment with allicin. Allicin markedly reduced cisplatin-activated expression of cleaved-caspase-3 in hair cells and vascular layer cells of utricule, saccule and ampulla, but also decreased AIF nuclear translocation of hair cells in utricule, saccule and ampulla. These results showed that allicin played an effective role in protecting vestibular dysfunction induced by cisplatin via inhibiting caspase-dependent and caspase-independent apoptotic pathways. Therefore, allicin may be useful in preventing oto-vestibulotoxicity mediated by cisplatin. Copyright © 2017. Published by Elsevier B.V.

  17. Assessment of D-methionine protecting cisplatin-induced otolith toxicity by vestibular-evoked myogenic potential tests, ATPase activities and oxidative state in guinea pigs.

    Science.gov (United States)

    Lo, Wu-Chia; Chang, Chih-Ming; Liao, Li-Jen; Wang, Chi-Te; Young, Yi-Ho; Chang, Yih-Leong; Cheng, Po-Wen

    2015-01-01

    To date, inadequate study has been devoted to the toxic vestibular effects caused by cisplatin. In addition, no electrophysiological examination has been conducted to assess cisplatin-induced otolith toxicity. The purposes of this study are thus two-fold: 1) to determine whether cervical vestibular-evoked myogenic potentials (VEMPs) and ocular VEMPs are practical electrophysiological methods of testing for cisplatin-induced otolith toxicity and 2) to examine if D-methionine (D-met) pre-injection would protect the otolith organs against cisplatin-induced changes in enzyme activities and/or oxidative status. Guinea pigs were intraperitoneally treated once daily with the following injections for seven consecutive days: sterile 0.9% saline control, cisplatin (5 mg/kg) only, D-met (300 mg/kg) only, or a combination of d-met (300 mg/kg) and cisplatin (5 mg/kg), respectively, with a 30 minute window in between. Each animal underwent the oVEMP and cVEMP tests before and after treatment. The changes in the biochemistry of the otolith organs, including membranous Na(+), K(+)-ATPase and Ca(2+)-ATPase, lipid peroxidation (LPO) levels and nitric oxide (NO) levels, were also evaluated. In the cisplatin-only treated guinea pigs, the mean amplitudes of the oVEMP tests were significantly (poxidative stress induced by cisplatin toxicity in the otolith organs. Copyright © 2015 Elsevier Inc. All rights reserved.

  18. Cisplatin-induced gastrointestinal dysmotility is aggravated after chronic administration in the rat. Comparison with pica.

    Science.gov (United States)

    Cabezos, P A; Vera, G; Martín-Fontelles, M I; Fernández-Pujol, R; Abalo, R

    2010-07-01

    Chemotherapy induces nausea/emesis and gastrointestinal dysmotility. Pica, the ingestion of non-nutritive substances, is considered as an indirect marker of nausea/emesis in non-vomiting species, like the rat. Cisplatin is the most emetogenic antitumoral drug. In the rat, acute cisplatin induces pica and gastric dysmotility in a temporally related manner, but the effects of chronic cisplatin are not well known. This study analyzed the effects of chronic cisplatin on pica and on gastrointestinal motor function in the rat, using radiographic, non-invasive methods. Rats received saline or cisplatin (1-3 mg kg(-1), i.p.) once a week for four consecutive weeks. Serial X-rays were taken 0-8 h after administration of barium sulfate, which was given intragastrically immediately after the first and last cisplatin administrations and 1 week after treatment finalization. Pica (i.e., kaolin intake) was measured in isolated rats. Cisplatin delayed gastric emptying and induced acute (during the 24 h following each administration) pica. Upon chronic administration, these effects were exacerbated. In addition, basal kaolin intake was enhanced (facilitated) and gastric distension induced. Delayed gastric emptying and gastric distension were not apparent 1 week after treatment, but basal kaolin intake was still elevated. Whereas gastric dysmotility induced by cisplatin is parallel to the development of acute pica and might underlie facilitation of pica throughout chronic treatment, it does not explain its long-term maintenance. These findings should be taken into account in the search for new antiemetic strategies.

  19. The ability of mannitol to decrease cisplatin-induced nephrotoxicity in children: real or not?

    Science.gov (United States)

    Ruggiero, Antonio; Rizzo, Daniela; Trombatore, Giovanna; Maurizi, Palma; Riccardi, Riccardo

    2016-01-01

    Platinum compounds are very effective drugs for the treatment of childhood malignancies, and their use has contributed to an increase in the long-term survival of children with cancer. Unfortunately, the risk of severe disabling effects such as nephrotoxicity is well known among children receiving cisplatin-based chemotherapy. The main pharmacodynamics and clinical characteristics of cisplatin nephrotoxicity are described in order to explore the real ability of mannitol to prevent cisplatin-related nephrotoxicity. Currently, the choice of hydration alone or hydration plus mannitol to prevent nephrotoxicity is controversial. No guidelines are available to provide recommendations on this issue either in adults or in children. Appropriate hydration remains the main fundamental strategy for reducing the risk of cisplatin-induced nephrotoxicity. In conventional treatment regimens employing doses of cisplatin of less than 100 mg/m(2) in patients with normal renal function, pre- and post-hydration (3 l/m(2) at least 12 h pre-cisplatin and 24 h post-cisplatin) alone should be routinely used. In higher doses, pre- and post-hydration plus mannitol should be considered in order to ensure a valid diuresis.

  20. Central Diabetes Insipidus and Cisplatin-Induced Renal Salt Wasting Syndrome: A Challenging Combination.

    Science.gov (United States)

    Cortina, Gerard; Hansford, Jordan R; Duke, Trevor

    2016-05-01

    We describe a 2-year-old female with a suprasellar primitive neuroectodermal tumor and central diabetes insipidus (DI) who developed polyuria with natriuresis and subsequent hyponatremia 36 hr after cisplatin administration. The marked urinary losses of sodium in combination with a negative sodium balance led to the diagnosis of cisplatin-induced renal salt wasting syndrome (RSWS). The subsequent clinical management is very challenging. Four weeks later she was discharged from ICU without neurological sequela. The combination of cisplatin-induced RSWS with DI can be confusing and needs careful clinical assessment as inaccurate diagnosis and management can result in increased neurological injury. © 2016 Wiley Periodicals, Inc.

  1. Review: ototoxic characteristics of platinum antitumor drugs.

    Science.gov (United States)

    Ding, Dalian; Allman, Brian L; Salvi, Richard

    2012-11-01

    Cisplatin, carboplatin, nedaplatin, and oxaliplatin are widely used in contemporary oncology; however, their ototoxic and neurotoxic side effects are quite different as discussed in this review. Cisplatin is considered the most ototoxic, but despite its reputation, the magnitude of hair cell loss that occurs with a single, large drug bolus is limited and confined to the base of the cochlea. For all of these platinum compounds, a major factor limiting damage is drug uptake from stria vascularis into the cochlear fluids. Disrupting the blood-labyrinth barrier with diuretics or noise exposure enhances drug uptake and significantly increases the amount of damage. Combined treatment with ethacrynic acid (a loop diuretic) and cisplatin results in rapid apoptotic hair cell death characterized by upregulation of initiator caspase-8 and membrane death receptor, TRADD, followed by downstream executioners, caspase-3 and caspase-6. Unlike cisplatin, nedaplatin and oxaliplatin are highly neurotoxic when applied to cochlear cultures preferentially damaging auditory nerve fibers at low concentrations and hair cells at high concentrations. Carboplatin, considered far less ototoxic than cisplatin, is paradoxically highly toxic to chinchilla inner hair cells and type I spiral ganglion neurons; however, at high doses it also damages outer hair cells. Hair cell death from cisplatin and carboplatin is characterized in its early stages by upregulation of p53; blocking p53 expression with pifithrin-α prevents hair cell death. Major differences in the toxicity of these four platinum compounds may arise from several different metal transporters that selectively regulate the influx, efflux, and sequestration of these drugs. Copyright © 2012 Wiley Periodicals, Inc.

  2. Ototoxicity in children receiving cisplatin chemotherapy

    Directory of Open Access Journals (Sweden)

    Hee Jin Jang

    2010-02-01

    Full Text Available Purpose : Cisplatin is highly effective for the treatment of solid tumors in children. However, the clinical use of cisplatin is limited by its ototoxicity. The aim of this study was to evaluate the ototoxicity in children treated with cisplatin. Methods : We performed a single institution retrospective analysis of pediatric oncology patients who received cisplatin therapy between January 2001 and January 2008. Thirty-seven patients with sufficient medical and audiologic data were included in this study. Results : The median age at the time of diagnosis was 10.7 (range 3.8&#8211;16.7 years. There were 16 males and 21 females. The underlying diseases were osteosarcoma (15 cases, medulloblastoma (14 cases, germ cell tumors (7 cases, and hepatoblastoma (1 case. The median individual dose was 100 mg/m2/cycle (56-200. The median cumulative dose was 480 mg/m2 (200-1,490. Sixteen patients (43% received cranial radiotherapy. Of the 37 patients, 17 developed hearing loss, leading to an overall incidence of 46%. Logistic regression showed that age at treatment (P=0.04 and cumulative dose of cisplatin (P=0.005 were the significant risk factors in predicting hearing loss in children treated with cisplatin. In all the patients who had hearing loss, there was neither improvement nor aggravation during the follow-up (3&#8211;68 months. Conclusion : The cumulative dose of cisplatin (&gt;500 mg/m2 and younger age at treatment (&lt;12 years were 2 most important risk factors for ototoxicity in patients treated with cisplatin. Serial audiometric evaluations are needed in the patients with risk factors during and after cisplatin treatment.

  3. Mechanism of Cisplatin-Induced Cytotoxicity Is Correlated to Impaired Metabolism Due to Mitochondrial ROS Generation

    Science.gov (United States)

    Shim, Wooyoung; Anwar, Muhammad Ayaz; Kwon, Ji-Woong; Kwon, Hyuk-Kwon; Kim, Hyung Joong; Jeong, Hyobin; Kim, Hwan Myung; Hwang, Daehee; Kim, Hyung Sik; Choi, Sangdun

    2015-01-01

    The chemotherapeutic use of cisplatin is limited by its severe side effects. In this study, by conducting different omics data analyses, we demonstrated that cisplatin induces cell death in a proximal tubular cell line by suppressing glycolysis- and tricarboxylic acid (TCA)/mitochondria-related genes. Furthermore, analysis of the urine from cisplatin-treated rats revealed the lower expression levels of enzymes involved in glycolysis, TCA cycle, and genes related to mitochondrial stability and confirmed the cisplatin-related metabolic abnormalities. Additionally, an increase in the level of p53, which directly inhibits glycolysis, has been observed. Inhibition of p53 restored glycolysis and significantly reduced the rate of cell death at 24 h and 48 h due to p53 inhibition. The foremost reason of cisplatin-related cytotoxicity has been correlated to the generation of mitochondrial reactive oxygen species (ROS) that influence multiple pathways. Abnormalities in these pathways resulted in the collapse of mitochondrial energy production, which in turn sensitized the cells to death. The quenching of ROS led to the amelioration of the affected pathways. Considering these observations, it can be concluded that there is a significant correlation between cisplatin and metabolic dysfunctions involving mROS as the major player. PMID:26247588

  4. Voluntary exercise prevents cisplatin-induced muscle wasting during chemotherapy in mice.

    Directory of Open Access Journals (Sweden)

    Pernille Hojman

    Full Text Available Loss of muscle mass related to anti-cancer therapy is a major concern in cancer patients, being associated with important clinical endpoints including survival, treatment toxicity and patient-related outcomes. We investigated effects of voluntary exercise during cisplatin treatment on body weight, food intake as well as muscle mass, strength and signalling. Mice were treated weekly with 4 mg/kg cisplatin or saline for 6 weeks, and randomized to voluntary wheel running or not. Cisplatin treatment induced loss of body weight (29.8%, P < 0.001, lean body mass (20.6%, P = 0.001, as well as anorexia, impaired muscle strength (22.5% decrease, P < 0.001 and decreased glucose tolerance. In addition, cisplatin impaired Akt-signalling, induced genes related to protein degradation and inflammation, and reduced muscle glycogen content. Voluntary wheel running during treatment attenuated body weight loss by 50% (P < 0.001, maintained lean body mass (P < 0.001 and muscle strength (P < 0.001, reversed anorexia and impairments in Akt and protein degradation signalling. Cisplatin-induced muscular inflammation was not prevented by voluntary wheel running, nor was glucose tolerance improved. Exercise training may preserve muscle mass in cancer patients receiving cisplatin treatment, potentially improving physical capacity, quality of life and overall survival.

  5. Anti-emetic mechanisms of Zingiber officinale against cisplatin induced emesis in the pigeon; behavioral and neurochemical correlates.

    Science.gov (United States)

    Ullah, Ihsan; Subhan, Fazal; Ayaz, Muhammad; Shah, Rehmat; Ali, Gowhar; Haq, Ikram Ul; Ullah, Sami

    2015-02-26

    Zingiber officinale (ZO, family Zingiberaceae) has been reported for its antiemetic activity against cancer chemotherapy induced emesis in animal models and in clinics. Current study was designed to investigate ZO for potential usefulness against cisplatin induced vomiting in pigeon and its effects on central and peripheral neurotransmitters involved in the act of vomiting. Zingiber officinale acetone fraction (ZO-ActFr) was investigated for attenuation of emesis induced by cisplatin in healthy pigeons. Neurotransmitters DA, 5HT and their metabolites DOPAC, HVA and 5HIAA were analyzed using High Performance Liquid Chromatography system coupled with electrochemical detector in area postrema, brain stem and intestine. Antiemetic effect of ZO-ActFr was correlated with central and intestinal neurotransmitters levels in pigeon. Cisplatin (7 mg/kg i.v.) induced emesis without lethality upto the observation period. ZO-ActFr (25, 50 & 100 mg/kg) attenuated cisplatin induced emesis ~ 44.18%, 58.13% (P MCP; 30 mg/kg), produced ~ 48.83% reduction (P < 0.05). ZO-ActFr reduced (P < 0.05 - 0.001) 5-hydroxytryptamine (5HT) concentration in the area postrema, brain stem and intestine at 3(rd) hour of cisplatin administration, while at the 18(th) hour ZO treatments attenuated the dopamine upsurge (P < 0.001) caused by cisplatin in the area postrema and 5HT concentration (P < 0.01 - 0.001) in the brain stem and intestine. ZO treatments alone did not altered the basal neurotransmitters and their metabolites in the brain areas and intestine. The behavioral study verify the antiemetic profile of ZO against cisplatin induced emesis in the pigeon, where central and peripheral neural evidences advocate the involvement of serotonergic mechanism at initial time point (3(rd) hr), while the later time point (18(th) hr) is associated with serotonergic and dopaminergic component in the mediation of its antiemetic effect.

  6. Pharmacological inhibition of NADPH oxidase protects against cisplatin induced nephrotoxicity in mice by two step mechanism.

    Science.gov (United States)

    Wang, Yimin; Luo, Xiao; Pan, Hao; Huang, Wei; Wang, Xueping; Wen, Huali; Shen, Kezhen; Jin, Baiye

    2015-09-01

    Cisplatin induced nephrotoxicity is primarily caused by ROS (Reactive Oxygen Species) induced proximal tubular cell death. NADPH oxidase is major source of ROS production by cisplatin. Here, we reported that pharmacological inhibition of NADPH oxidase by acetovanillone (obtained from medicinal herb Picrorhiza kurroa) led to reduced cisplatin nephrotoxicity in mice. In this study we used various molecular biology and biochemistry methods a clinically relevant model of nephropathy, induced by an important chemotherapeutic drug cisplatin. Cisplatin-induced nephrotoxicity was evident by histological damage from loss of the tubular structure. The damage was also marked by the increase in blood urea nitrogen, creatinine, protein nitration as well as cell death markers such as caspase 3/7 activity and DNA fragmentation. Tubular cell death by cisplatin led to pro-inflammatory response by production of TNFα and IL1β followed by leukocyte/neutrophil infiltration which resulted in new wave of ROS involving more NADPH oxidases. Cisplatin-induced markers of kidney damage such as oxidative stress, cell death, inflammatory cytokine production and nephrotoxicity were attenuated by acetovanillone. In addition to that, acetovanillone enhanced cancer cell killing efficacy of cisplatin. Thus, pharmacological inhibition of NADPH oxidase can be protective for cisplatin-induced nephrotoxicity in mice. Copyright © 2015. Published by Elsevier Ltd.

  7. Ototoxicity in the South African mining industry: a position paper

    CSIR Research Space (South Africa)

    Edwards, AL

    2013-02-01

    Full Text Available identified in the last century. We now know that the effects of noise and the interaction of noise with many other factors results in a complex pattern of individual susceptibility and a wide variety in the rate of development of NIHL. Ototoxicity or what has...

  8. Effects of combined treatment of α-tocopherol, L-ascorbic acid, selenium and zinc on bleomycin, etoposide and cisplatin-induced alterations in testosterone synthesis pathway in rats.

    Science.gov (United States)

    Kilarkaje, Narayana

    2014-12-01

    To investigate the effects of therapeutically relevant dose levels of bleomycin, etoposide and cisplatin (BEP) on testicular steroidogenic enzymes, and possible protective effects of an antioxidant cocktail (AC). Adult Sprague-Dawley rats received BEP with or without the AC (α-tocopherol, L-ascorbic acid, selenium and zinc) for either (a) 4 days (short term; 1.5, 15 and 3 mg/kg), or (b) three cycles of 21 days each (0.75, 7.5 and 1.5 mg/kg), or (c) the three cycles with a 63-day recovery period. The expression of steroidogenic enzymes were measured in the testes by Western blotting and immunofluorescent labeling. The short-term BEP exposure resulted in a decrease in scavenger receptor class-B1 and an increase in luteinizing hormone receptor (LHR). The AC with or without BEP has increased the levels of LHR, 3β-hydroxysteroid dehydrogenase (3β-HSD) and 17β-HSD, but without significant changes in testosterone levels. The three cycles of BEP up-regulated the expression of steroidogenic acute regulatory protein (StAR) and down-regulated that of cholesterol side chain cleavage enzyme (P450scc), cytochrome p450 17A1 (Cyp17A1, recovered by the AC) and 17β-HSD, associated with significant reduction in testosterone levels. The three cycles with the recovery time led to decreases in LHR, StAR, P450scc and Cyp17A1 and increases in 3β-HSD and 17β-HSD. The AC did not enhance the recovery of the enzyme levels. The three cycles of BEP treatment inhibit the testosterone synthesis pathway even after the recovery time. The AC recovers the effects of BEP chemotherapy on a few steroidogenic enzymes.

  9. Cisplatin induced arrhythmia; electrolyte imbalance or disturbance of the SA node?

    Science.gov (United States)

    Oun, Rabbab; Rowan, Edward

    2017-09-15

    Since its approval in 1979 cisplatin has become one of the most extensively used chemotherapeutics in the clinic and although cell resistance and toxicity hinder its efficacy it continues to be a gold standard regimen. Cisplatin's side effects primarily include nephrotoxicity, gastrointestinal toxicity, neurotoxicity and ototoxicity. Cardiotoxicity is generally not defined as a side effect of cisplatin. However, over the past decade there has been a surge in the amount of clinical cases reporting a vast array of cardio-toxic events occurring during or shortly after cisplatin infusion, these range from angina to cardiac ischemia and chronic heart failure. This review intends to discuss the clinical cardiac manifestations of cisplatin specifically tachycardia and bradycardia which can be lethal and the possible mechanisms of action. Crown Copyright © 2017. Published by Elsevier B.V. All rights reserved.

  10. The flavonoid 6-methoxyflavone allays cisplatin-induced neuropathic allodynia and hypoalgesia.

    Science.gov (United States)

    Shahid, Muhammad; Subhan, Fazal; Ahmad, Nisar; Sewell, Robert D E

    2017-11-01

    Chemotherapy-induced peripheral neuropathy (CIPN) is a major dose limiting side-effect of several commonly used chemotherapeutic agents (such as cisplatin) that profoundly impairs patient quality of life. Unfortunately, neither prophylactic strategies nor symptomatic treatments have proven useful in this condition. Flavonoids are found ubiquitously in fruits and vegetables and exert a multiplicity of beneficial effects. In this study, the antinociceptive activity of 6-methoxyflavone (6-MF) was investigated and evaluated in comparison with gabapentin in a rat model of CIPN. The effect on motor balance was also assessed using the rotarod and footprint analysis paradigms. 6-MF possessed both peripheral and central antinociceptive activities against tonic and phasic nociceptive stimuli. Cisplatin administration (3.0mg/kg/week, i.p.) for four consecutive weeks generated temporal mechanical allodynia (decreased paw withdrawal threshold; PWT) and thermal hypoalgesia (increased paw thermal threshold; PTT) in the bilateral hindpaws. Daily treatment with 6-MF (25, 50 and 75mg/kg/day, i.p) for four weeks attenuated the cisplatin-induced expression of nocifensive behaviors observed as a significant increase in PWT and alleviation of PTT during the third and fourth weeks of cisplatin administration. Accordingly, daily gabapentin (75mg/kg, i.p) suppressed the expression of CIPN by normalizing the PWT and hotplate response latency. However, these antinociceptive actions were associated with motor impairment exemplified by a significant decrease in rotarod endurance latency and a deficit in the uniformity of step alternation. In contrast, 6-MF was devoid of these adverse side-effects. These findings suggested that 6-MF afforded desirable neuropathic pain alleviating effects in CIPN and it was devoid of gabapentin-like unwanted motor side-effects. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  11. Modulation of cisplatin-induced reactive oxygen species production by fullerene C(60 in normal and transformed lymphoid cells

    Directory of Open Access Journals (Sweden)

    D. V. Franskevych

    2016-02-01

    Full Text Available The early response of normal (Wistar rat thymocytes and transformed (mice lymphoid leukemia L1210 cells to treatment with anticancer drug cisplatin or to combined treatment with cisplatin and carbon nanostructure fullerene C60 was studied. We demonstrated with fluorescent probes DCFH-DA and TMRE that cisplatin at concentration 1 μg/ml induced reactive oxygen species (ROS production and decreased the value of mitochondrial membrane potential in both cell types. The combined treatment with cisplatin (1 μg/ml and fullerene C60 (7.2 μg/ml was shown to be followed by oppositely directed modulation of ROS production in thymocytes and L1210 cells. Cisplatin-induced ROS production was intensified in L1210 cells, while in thymocytes it was decreased. It is supposed that the different effects of combined treatment are associated with peculiarities of fullerene C60 accumulation and localization in normal and cancer cells.

  12. Anthocyanin – Rich Red Dye of Hibiscus Sabdariffa Calyx Modulates Cisplatin-induced Nephrotoxicity and Oxidative Stress in Rats

    Science.gov (United States)

    Ademiluyi, Adedayo O.; Oboh, Ganiyu; Agbebi, Oluwaseun J.; Akinyemi, Ayodele J.

    2013-01-01

    This study sought to investigate the protective effect of dietary inclusion of Hibiscus sabdariffa calyx red dye on cisplatin-induced nephrotoxicity and antioxidant status in rats. Adult male rats were randomly divided into four groups of six animals each. Groups I and II were fed basal diet while groups III and IV were fed diets containing 0.5% and 1% of the dye respectively for 20 days prior to cisplatin administration. Nephrotoxicity was induced by a single dose intraperitoneal administration of cisplatin (7 mg/kg b.w) and the experiment was terminated 3 days after. The kidney and plasma were studied for nephrotoxicity and oxidative stress indices. Cisplatin administration caused a significant (Psabdariffa dye could be attributed to its anthocyanin content. PMID:24711761

  13. Effects of zerumbone on cisplatin-induced clastogenesis in Sprague ...

    African Journals Online (AJOL)

    Administrator

    2011-06-20

    Jun 20, 2011 ... synthetic substances are of great interest because of the widespread and often chronic use of herbal remedies, modern medicinal products, food ingredients, as well as other household and environmental chemicals. Many plant products contain compounds known to cause various diseases or even death ...

  14. Chemopreventive Effect of Tadalafil in Cisplatin-Induced ...

    African Journals Online (AJOL)

    olayemitoyin

    % of patients on high-dose ... NADPH oxidase and stimulates ROS (such superoxide anion, hydrogen peroxide and hydroxyl .... decomposition of hydrogen peroxidase (H₂O₂) in UV recording spectrophotometer. The reaction mixture (3.

  15. Growth hormone secretagogues prevent dysregulation of skeletal muscle calcium homeostasis in a rat model of cisplatin-induced cachexia.

    Science.gov (United States)

    Conte, Elena; Camerino, Giulia Maria; Mele, Antonietta; De Bellis, Michela; Pierno, Sabata; Rana, Francesco; Fonzino, Adriano; Caloiero, Roberta; Rizzi, Laura; Bresciani, Elena; Ben Haj Salah, Khoubaib; Fehrentz, Jean-Alain; Martinez, Jean; Giustino, Arcangela; Mariggiò, Maria Addolorata; Coluccia, Mauro; Tricarico, Domenico; Lograno, Marcello Diego; De Luca, Annamaria; Torsello, Antonio; Conte, Diana; Liantonio, Antonella

    2017-06-01

    Cachexia is a wasting condition associated with cancer types and, at the same time, is a serious and dose-limiting side effect of cancer chemotherapy. Skeletal muscle loss is one of the main characteristics of cachexia that significantly contributes to the functional muscle impairment. Calcium-dependent signaling pathways are believed to play an important role in skeletal muscle decline observed in cachexia, but whether intracellular calcium homeostasis is affected in this situation remains uncertain. Growth hormone secretagogues (GHS), a family of synthetic agonists of ghrelin receptor (GHS-R1a), are being developed as a therapeutic option for cancer cachexia syndrome; however, the exact mechanism by which GHS interfere with skeletal muscle is not fully understood. By a multidisciplinary approach ranging from cytofluorometry and electrophysiology to gene expression and histology, we characterized the calcium homeostasis in fast-twitch extensor digitorum longus (EDL) muscle of adult rats with cisplatin-induced cachexia and established the potential beneficial effects of two GHS (hexarelin and JMV2894) at this level. Additionally, in vivo measures of grip strength and of ultrasonography recordings allowed us to evaluate the functional impact of GHS therapeutic intervention. Cisplatin-treated EDL muscle fibres were characterized by a ~18% significant reduction of the muscle weight and fibre diameter together with an up-regulation of atrogin1/Murf-1 genes and a down-regulation of Pgc1-a gene, all indexes of muscle atrophy, and by a two-fold increase in resting intracellular calcium, [Ca2+ ]i , compared with control rats. Moreover, the amplitude of the calcium transient induced by caffeine or depolarizing high potassium solution as well as the store-operated calcium entry were ~50% significantly reduced in cisplatin-treated rats. Calcium homeostasis dysregulation parallels with changes of functional ex vivo (excitability and resting macroscopic conductance) and in vivo

  16. Ghrelin Partially Protects Against Cisplatin-Induced Male Murine Gonadal Toxicity in a GHSR-1a-Dependent Manner1

    Science.gov (United States)

    Whirledge, Shannon D.; Garcia, Jose M.; Smith, Roy G.; Lamb, Dolores J.

    2015-01-01

    ABSTRACT The chemotherapeutic drug cisplatin causes a number of dose-dependent side effects, including cachexia and testicular damage. Patients receiving a high cumulative dose of cisplatin may develop permanent azoospermia and subsequent infertility. Thus, the development of chemotherapeutic regimens with the optimal postsurvival quality of life (fertility) is of high importance. This study tested the hypothesis that ghrelin administration can prevent or minimize cisplatin-induced testicular damage and cachexia. Ghrelin and its receptor, the growth hormone secretagogue receptor (GHSR-1a), are expressed and function in the testis. Targeted deletion of ghrelin, or its receptor, significantly increases the rate of cell death in the testis, suggesting a protective role. Intraperitoneal administration of vehicle, ghrelin, or cisplatin alone or in combination with ghrelin, in cycles of 9 or 18 days, to adult male C57Bl/6 mice was performed. Body weight was measured daily and testicular and epididymal weight, sperm density and motility, testicular histology, and testicular cell death were analyzed at the time of euthanization. Ghrelin coadministration decreased the severity of cisplatin-induced cachexia and gonadal toxicity. Body, testicular, and epididymal weights significantly increased as testicular cell death decreased with ghrelin coadministration. The widespread damage to the seminiferous epithelium induced by cisplatin administration was less severe in mice simultaneously treated with ghrelin. Furthermore, ghrelin diminished the deleterious effects of cisplatin on testis and body weight homeostasis in wild-type but not Ghsr−/− mice, showing that ghrelin's actions are mediated via GHSR. Ghrelin or more stable GHSR agonists potentially offer a novel therapeutic approach to minimize the testicular damage that occurs after gonadotoxin exposure. PMID:25631345

  17. Alpha2,3-sialyltransferase III knockdown sensitized ovarian cancer cells to cisplatin-induced apoptosis.

    Science.gov (United States)

    Wang, Xiaoyu; Zhang, Yiting; Lin, Haiyingjie; Liu, Yan; Tan, Yi; Lin, Jie; Gao, Fenze; Lin, Shaoqiang

    2017-01-22

    Emerging evidence indicates that β-galactoside-α2,3-sialyltransferase III (ST3Gal3) involves in development, inflammation, neoplastic transformation, and metastasis. However, the role of ST3Gal3 in regulating cancer chemoresistance remains elusive. Herein, we investigated the functional effects of ST3Gal3 in cisplatin-resistant ovarian cancer cells. We found that the levels of ST3Gal3 mRNA differed significantly among ovarian cancer cell lines. HO8910PM cells that have high invasive and metastatic capacity express elevated ST3Gal3 mRNA and are resistant to cisplatin, comparing to SKOV3 cells that have a lower level of ST3Gal3 expression and are more chemosensitive to cisplatin. We found that the expression of ST3Gal3 has reverse correlation with the dosage of cisplatin used in both SKOV3 and HO8910PM cells, and high dose of cisplatin could down-regulate ST3Gal3 expression. We then examined the functional effects of ST3Gal3 knockdown in cancer cell lines using FACS analysis. The number of apoptotic cells was much higher in cells if ST3Gal3 expression was knocked down by siRNA and/or by treating cells with higher dosage of cisplatin in comparison to control cells. Interestingly, in HO8910PM cells with ST3Gal3 knockdown, the levels of caspase 8 and caspase 3 proteins increased, which was more obvious in cells treated with both ST3Gal3 knockdown and cisplatin, suggesting that ST3Gal3 knockdown synergistically enhanced cisplatin-induced apoptosis in ovarian cancer cells. Taken together, these results uncover an alternative mechanism of cisplatin-resistance through ST3Gal3 and open a window for effective prevention of chemoresistance and relapse of ovarian cancer by targeting ST3Gal3. Copyright © 2016 Elsevier Inc. All rights reserved.

  18. A retrospective evaluation of furosemide and mannitol for prevention of cisplatin-induced nephrotoxicity.

    Science.gov (United States)

    Mach, C M; Kha, C; Nguyen, D; Shumway, J; Meaders, K M; Ludwig, M; Williams-Brown, M Y; Anderson, M L

    2017-06-01

    Nephrotoxicity is a recognized side effect of cisplatin chemotherapy. However, the optimal strategy for preventing cisplatin-induced nephrotoxicity, if any, remains unclear. The primary objective for this study was to determine whether mannitol or furosemide provides better nephroprotection when administered with hydration prior to weekly, low-dose cisplatin concurrently with whole pelvic radiotherapy. Clinical data were abstracted from all women who underwent chemoradiation for FIGO IB2-IVA cervical cancer at a regional safety net health system between January 2009 and December 2014. Creatinine clearance was estimated using the IDMS-traceable MDRD Study Equation. Descriptive statistics were used to summarize patient demographics. Cox proportional hazard models were used to identify factors associated with hypomagnesemia and survival. A total of 133 women received 656 weekly doses of single-agent cisplatin (40 mg/m 2 ) concomitant with whole pelvic radiation. Furosemide (20 mg) was administered intravenously prior to 341 cisplatin doses, whereas mannitol (24 g) was administered prior to 315 doses. Significant magnesium wasting was observed after the second weekly cisplatin infusion regardless of whether furosemide or mannitol was utilized. Repetitive low-dose cisplatin infusion had no impact on measured levels of serum creatinine or estimated glomerular filtration rate. Prior history of hypertension, diabetes mellitus, hepatitis C infection and acute gastrointestinal toxicity were each associated with early onset of hypomagnesemia. Repetitive administration of low-dose cisplatin concurrent with whole pelvic radiation is associated with magnesium wasting. However, choice of diuretic with pretreatment hydration had no significant impact on the severity of this adverse effect. © 2017 John Wiley & Sons Ltd.

  19. Spongean alkaloids protect rat kidney cells against cisplatin-induced cytotoxicity.

    Science.gov (United States)

    Funk, Florian; Krüger, Katharina; Henninger, Christian; Wätjen, Wim; Proksch, Peter; Thomale, Jürgen; Fritz, Gerhard

    2014-09-01

    Nephrotoxicity is the major dose-limiting adverse effect of cisplatin (CisPt) and results from CisPt-induced damage of tubular cells. Nephroprotective strategies are preferential to improve supportive care in cancer. We investigated a subset of purified substances originating from various plants or from marine sponges as to their potency to protect rat renal tubular cells (NRK-52E) against the cytotoxic and genotoxic effects of cisplatin. Cotreatment with a substance pool containing five purified substances originating from marine sponges increased the viability of NRK-52E cells following cisplatin treatment. Cytoprotection was accompanied by a reduced level of DNA damage as indicated by a lower amount of S139 phosphorylated histone H2AX (γH2AX) 24 h after treatment. Cytoprotection and genoprotection by the sponge substance pool did not comprise the anthracycline derivative doxorubicin. The spongean alkaloid aaptamine was identified as major bioactive compound that mediates cisplatin resistance. Aeroplysinin-1 was less cytoprotective than aaptamine. Notably, aaptamine preferentially conferred resistance to cisplatin, but not to oxaliplatin. Cytoprotection by aaptamine was also observed in rat glomerular endothelial cells, but not in RT-112 bladder cancer cells. Protection by aaptamine does not rest on a reduced formation of DNA damage caused by cisplatin treatment. Aaptamine and aeroplysinin-1 affected cisplatin-stimulated DDR as reflected on the level of S15-phosphorlyated p53 and S345-phosphorylated checkpoint kinase-1. Summarizing, the spongean alkaloid aaptamine alleviates cisplatin-induced damage in tubular and glomerular rat kidney cells. Therefore, we hypothesize that aaptamine might be useful to widen the therapeutic window of a cisplatin-based therapeutic regimen.

  20. Dietary inclusion of sorghum (Sorghum bicolour) straw dye protects against cisplatin-induced nephrotoxicity and oxidative stress in rats.

    Science.gov (United States)

    Ademiluyi, Adedayo O; Oboh, Ganiyu; Agbebi, Oluwaseun J; Oyeleye, Sunday I

    2014-07-01

    Sorghum straw (dried leaves and stem fiber) extracts and infusion are employed in the management of several ailments in folklore, and it is also a natural dye source used in food preparation. This study sought to investigate the modulatory effect of dietary inclusion of Sorghum straw dye on cisplatin-induced nephrotoxicity and antioxidant status in rats. Adult male rats were randomly divided into four groups of six animals each. Groups I (normal rats) and II (control rats) were fed with basal diet while Groups III and IV were fed with diets containing 0.5% and 1% sorghum straw dye, respectively. Nephrotoxicity was induced in Groups I-IV on the 20th day by the administration of a single dose of cisplatin solution (7 mg/kg body weight, i.p.) and the experiment was terminated 3 d after. Thereafter, the kidney and plasma of the rats were analyzed for kidney function (creatinine, urea, uric acid, and blood urea nitrogen) and antioxidant indices [superoxide dismutase (SOD), catalase, glutathione-S-transferase (GST), malondialdehyde (MDA), vitamin C, and reduced glutathione (GSH)]. The average feed intake of the rats in all the groups ranged from 9.0 to 9.5 (g/rat/day). Furthermore, the result indicated that administration of cisplatin caused significant (p sorghum straw dye significantly reversed the plasma creatinine and the kidney antioxidant indices to near normal levels. The study suggests that dietary inclusion of sorghum straw dye as colorants could protect against oxidative stress and cisplatin-induced nephrotoxicity.

  1. The incidence of ototoxicity in child malignancy cases that received carboplatin therapy with otoacoustic emission (OAE) examination

    Science.gov (United States)

    Wibowo, J. K.; Zizlavsky, S.; Suwento, R.; Sjakti, H. A.; Prihartono, J.

    2017-08-01

    Malignancy is a significant public health problem, both globally and in Indonesia. Chemotherapy is one of the modality in malignancy cases. Carboplatin (cis-diammine-cyclobutanedi-carboxylato platinum) is a second-generation platinum compound that has often been used in the management of cases of malignancies. On the other hand, side effects of cytotoxic drugs need to be considered, especially ototoxic effects. Ototoxicity is dysfunction and damage to the structure of the inner ear that has been caused by drugs or other certain chemicals. The aim of this study is to assess ototoxic effects due to the influence of carboplatin in the cases of children with malignancy. This study uses a serial cross-sectional design to evaluate otoacoustic emission (OAE) signal-to-noise ratio (SNR) change as a result of ototoxic effects and risk factors due to the use of ototoxic carboplatin in the Division of Hematology-Oncology of the Department of Pediatrics at Cipto Mangunkusumo General Hospital in Jakarta, where two of 52 studies’ subjects experienced ototoxicity. In the group were receiving chemotherapy, two (5%) of the 40 subjects has experienced ototoxic events characterized by SNR values less than six, whereas SNR values were not less than six in the group that had not received chemotherapy. Risk factors such as gender, age, carboplatin dose, and cycles of chemotherapy did not have a statistically significant relationship to ototoxity.

  2. Hydroxyl radical scavenger ameliorates cisplatin-induced nephrotoxicity by preventing oxidative stress, redox state unbalance, impairment of energetic metabolism and apoptosis in rat kidney mitochondria.

    Science.gov (United States)

    Santos, N A G; Bezerra, C S Catão; Martins, N M; Curti, C; Bianchi, M L P; Santos, A C

    2008-01-01

    Nephrotoxicity is the major dose-limiting factor of cisplatin chemotherapy. Reactive oxygen species generated in mitochondria are thought to be the main cause of cellular damage in such injury. The present study examined, in vivo, the protective potential of the hydroxyl radical scavenger dimethylthiourea (DMTU) against cisplatin-induced effects on renal mitochondrial bioenergetics, redox state and oxidative stress. Adult male Wistar rats (200 to 220 g) were divided into four groups of eight animals each. The control group was treated only with an intraperitoneal (i.p.) injection of saline solution (1 ml/100 g body weight). The second group was given only DMTU (500 mg/kg body weight, i.p, followed by 125 mg/Kg, i.p., twice a day until they were killed). The third group was given a single injection of cisplatin (10 mg/kg body weight, i.p.). The fourth group was given DMTU (500 mg/kg body weight, i.p.), just before the cisplatin injection (10 mg/kg body weight, i.p.), followed by injections of DMTU (125 mg/kg body weight, i.p.) twice a day until they were killed. Animals were killed 72 h after the treatment. Besides not presenting any direct effect on mitochondria, DMTU substantially inhibited cisplatin-induced mitochondrial injury and cellular death by apoptosis, suppressing the occurrence of acute renal failure. All the following cisplatin-induced effects were prevented by DMTU: (1) increased plasmatic levels of creatinine and blood urea nitrogen (BUN); (2) decreased ATP content, calcium uptake and electrochemical potential; (3) oxidation of lipids, including cardiolipin; and oxidation of proteins, including sulfhydryl, and aconitase enzyme, as well as accumulation of carbonyl proteins; (4) depletion of the antioxidant defense (NADPH and GSH) and (5) increased activity of the apoptosis executioner caspase-3. Our findings show the important role played by mitochondria and hydroxyl radicals in cisplatin-induced nephrotoxicity, as well as the effectiveness of DMTU in

  3. Real-time single cell analysis of Bid cleavage and translocation in cisplatin-induced apoptosis

    Science.gov (United States)

    Liu, Lei; Xing, Da; Pei, Yihui; Chen, Wei R.

    2007-02-01

    Cancer cell apoptosis can be induced by cisplatin, an efficient anticancer agent. However, its mechanism is not fully understood. Bcl-2 homology domain (BH) 3-only proteins couple stress signals to mitochondrial apoptotic pathways. Calpain-mediated cleavage of the BH3-only protein Bid into a 14 kD truncated protein (tBid) has been implicated in cisplatin-induced apoptotic pathway. We utilized a recombinant fluorescence resonance energy transfer (FRET) Bid probe to determine the kinetics of Bid cleavage during cisplatin-induced apoptosis in ASTC-a-1 cells. The cells were also co-transfected with Bid-CFP and DsRed-Mit to dynamically detect tBid translocation. Cells showed a cleavage of the Bid-FRET probe occurring at about 4-5 h after treated with 20 µM cisplatin. Cleavage of the Bid-FRET probe coincided with a translocation of tBid from the cytosolic to the mitochondria, and the translocation lasted about 1.5 h. Using real-time single-cell analysis, we first observed the kinetics of Bid cleavage and translocation to mitochondria in living cells during cisplatin-induced apoptosis.

  4. VCC-1 over-expression inhibits cisplatin-induced apoptosis in HepG2 cells

    Energy Technology Data Exchange (ETDEWEB)

    Zhou, Zhitao; Lu, Xiao; Zhu, Ping [School of Biotechnology, Southern Medical University, Guangzhou 510515 (China); Zhu, Wei [Department of Toxicology, Guangzhou Center for Disease Control and Prevention, Guangzhou 510440 (China); Mu, Xia [Guizhou Provincial People' s Hospital, Guiyang 550004 (China); Qu, Rongmei [School of Biotechnology, Southern Medical University, Guangzhou 510515 (China); Li, Ming, E-mail: limimg2010@yahoo.cn [School of Biotechnology, Southern Medical University, Guangzhou 510515 (China)

    2012-04-06

    Highlights: Black-Right-Pointing-Pointer VCC-1 is hypothesized to be associated with carcinogenesis. Black-Right-Pointing-Pointer Levels of VCC-1 are increased significantly in HCC. Black-Right-Pointing-Pointer Over-expression of VCC-1 could promotes cellular proliferation rate. Black-Right-Pointing-Pointer Over-expression of VCC-1 inhibit the cisplatin-provoked apoptosis in HepG2 cells. Black-Right-Pointing-Pointer VCC-1 plays an important role in control the tumor growth and apoptosis. -- Abstract: Vascular endothelial growth factor-correlated chemokine 1 (VCC-1), a recently described chemokine, is hypothesized to be associated with carcinogenesis. However, the molecular mechanisms by which aberrant VCC-1 expression determines poor outcomes of cancers are unknown. In this study, we found that VCC-1 was highly expressed in hepatocellular carcinoma (HCC) tissue. It was also associated with proliferation of HepG2 cells, and inhibition of cisplatin-induced apoptosis of HepG2 cells. Conversely, down-regulation of VCC-1 in HepG2 cells increased cisplatin-induced apoptosis of HepG2 cells. In summary, these results suggest that VCC-1 is involved in cisplatin-induced apoptosis of HepG2 cells, and also provides some evidence for VCC-1 as a potential cellular target for chemotherapy.

  5. Selenium and high dose vitamin E administration protects cisplatin-induced oxidative damage to renal, liver and lens tissues in rats.

    Science.gov (United States)

    Naziroglu, Mustafa; Karaoğlu, Aziz; Aksoy, Asude Orhan

    2004-02-15

    Cisplatin is one of the most active cytotoxic agents in the treatment of cancer but its clinical use is associated with nephrotoxicity. Several studies suggest that supplementation with antioxidant can influence cisplatin induced nephrotoxicity. In the present study, we investigated the effect of selenium with high dose vitamin E administration on lipid peroxidation (MDA) and scavenging enzyme activity in kidneys, liver and lens of cisplatin-induced toxicity in rats. Forty female Wistar rats were used. They were randomly divided into five groups. The first and second groups were used as control and cisplatin (6 mg/kg BW) intraperitoneally administrated groups. Groups III, IV and V received intraperitoneally five doses of selenium (1.5 mg/kg BW) and a high dose of vitamin E (1000 mg/kg BW) combination before, simultaneously and after with cisplatin, respectively. Glutathione peroxidase (GSH-Px), vitamin E and beta-carotene levels in the kidney, lens and liver, vitamin A and reduced glutathione (GSH) levels in the kidney were significantly (Pselenium and a high dose vitamin E injection. In conclusion, this data demonstrates that there is an increase in lipid peroxidation in the kidney, liver and lens of animals administered with cisplatin whereas there is a decrease in antioxidant vitamins and enzymes. However, intraperitoneally injected selenium combined with a high dose of vitamin E seem to produce a significant improvement on antioxidants concentrations in rats treated before, simultaneously and after with cisplatin. The selenium with high dose vitamin E injection may play a role in preventing cisplatin-induced nephropathy and cataract formation in cancer patient.

  6. MicroRNA-140-5p attenuated oxidative stress in Cisplatin induced acute kidney injury by activating Nrf2/ARE pathway through a Keap1-independent mechanism.

    Science.gov (United States)

    Liao, Weitang; Fu, Zongjie; Zou, Yanfang; Wen, Dan; Ma, Hongkun; Zhou, Fangfang; Chen, Yongxi; Zhang, Mingjun; Zhang, Wen

    2017-11-15

    Oxidative stress was predominantly involved in the pathogenesis of acute kidney injury (AKI). Recent studies had reported the protective role of specific microRNAs (miRNAs) against oxidative stress. Hence, we investigated the levels of miR140-5p and its functional role in the pathogenesis of Cisplatin induced AKI. A mice Cisplatin induced-AKI model was established. We found that miR-140-5p expression was markedly increased in mice kidney. Bioinformatics analysis revealed nuclear factor erythroid 2-related factor (Nrf2) was a potential target of miR-140-5p, We demonstrated that miR-140-5p did not affect Kelch-like ECH-associated protein 1 (Keap1) level but directly targeted the 3'-UTR of Nrf2 mRNA and played a positive role in the regulation of Nrf2 expression which was confirmed by luciferase activity assay and western blot. What was more, consistent with miR140-5p expression, the mRNA and protein levels of Nrf2, as well as antioxidant response element (ARE)-driven genes Heme Oxygenase-1 (HO-1) and NAD(P)H:quinone oxidoreductase l (NQO1) were significantly increased in mice kidney tissues. In vitro study, Enforced expression of miR-140-5p in HK2 cells significantly attenuated oxidative stress by decreasing ROS level and increasing the expression of manganese superoxide dismutase (MnSOD). Simultaneously, miR-140-5p decreased lactate dehydrogenase (LDH) leakage and improved cell vitality in HK2 cells under Cisplatin-induced oxidative stress. However, HK2 cells transfected with a siRNA targeting Nrf2 abrogated the protective effects of miR-140-5p against oxidative stress. These results indicated that miR-140-5p might exert its anti-oxidative stress function via targeting Nrf2. Our findings showed the novel transcriptional role of miR140-5p in the expression of Nrf2 and miR-140-5p protected against Cisplatin induced oxidative stress by activating Nrf2-dependent antioxidant pathway, providing a potentially therapeutic target in acute kidney injury. Copyright © 2017

  7. A prospective study of gentamicin ototoxicity

    DEFF Research Database (Denmark)

    Winkel, O; Hansen, M M; Kaaber-Bühler, Søren

    1978-01-01

    Twenty patients were included in a prospective otoneurological study performed to assess the ototoxicity in gentamicin therapy. Gentamicin was administered intravenously, and the serum level was currently determined. Audiographic and electronystagmographic studies were carried out at the institut...

  8. Drug Induced Hearing Loss: What Is Ototoxicity?

    Science.gov (United States)

    ... page please turn JavaScript on. Feature: Drug-Induced Hearing Loss What Is Ototoxicity? Past Issues / Spring 2016 Table ... of patients taking these drugs." "Antibiotics Caused My Hearing Loss..." Gulab Lalwani Photo Courtesy of: Gulab Lalwani When ...

  9. Ondansetron can enhance cisplatin-induced nephrotoxicity via inhibition of multiple toxin and extrusion proteins (MATEs)

    Energy Technology Data Exchange (ETDEWEB)

    Li, Qing [Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland at Baltimore, MD (United States); Institute of Clinical Pharmacology, Central South University, Hunan 410078 (China); Guo, Dong [Institute of Clinical Pharmacology, Central South University, Hunan 410078 (China); Dong, Zhongqi [Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland at Baltimore, MD (United States); Zhang, Wei [Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland at Baltimore, MD (United States); Institute of Clinical Pharmacology, Central South University, Hunan 410078 (China); Zhang, Lei; Huang, Shiew-Mei [Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD (United States); Polli, James E. [Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland at Baltimore, MD (United States); Shu, Yan, E-mail: yshu@rx.umaryland.edu [Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland at Baltimore, MD (United States)

    2013-11-15

    The nephrotoxicity limits the clinical application of cisplatin. Human organic cation transporter 2 (OCT2) and multidrug and toxin extrusion proteins (MATEs) work in concert in the elimination of cationic drugs such as cisplatin from the kidney. We hypothesized that co-administration of ondansetron would have an effect on cisplatin nephrotoxicity by altering the function of cisplatin transporters. The inhibitory potencies of ondansetron on metformin accumulation mediated by OCT2 and MATEs were determined in the stable HEK-293 cells expressing these transporters. The effects of ondansetron on drug disposition in vivo were examined by conducting the pharmacokinetics of metformin, a classical substrate for OCTs and MATEs, in wild-type and Mate1−/− mice. The nephrotoxicity was assessed in the wild-type and Mate1−/− mice received cisplatin with and without ondansetron. Both MATEs, including human MATE1, human MATE2-K, and mouse Mate1, and OCT2 (human and mouse) were subject to ondansetron inhibition, with much greater potencies by ondansetron on MATEs. Ondansetron significantly increased tissue accumulation and pharmacokinetic exposure of metformin in wild-type but not in Mate1−/− mice. Moreover, ondansetron treatment significantly enhanced renal accumulation of cisplatin and cisplatin-induced nephrotoxicity which were indicated by increased levels of biochemical and molecular biomarkers and more severe pathohistological changes in mice. Similar increases in nephrotoxicity were caused by genetic deficiency of MATE function in mice. Therefore, the potent inhibition of MATEs by ondansetron enhances the nephrotoxicity associated with cisplatin treatment in mice. Potential nephrotoxic effects of combining the chemotherapeutic cisplatin and the antiemetic 5-hydroxytryptamine-3 (5-HT{sub 3}) receptor antagonists, such as ondansetron, should be investigated in patients. - Highlights: • Nephrotoxicity significantly limits clinical use of the chemotherapeutic

  10. Neo-adjuvant chemotherapy with cisplatin induces low expression of NMDA receptors and postoperative cognitive impairment.

    Science.gov (United States)

    Cheng, Jing; Liu, Xiaoqing; Cao, Longhui; Zhang, Tianhua; Li, Huiting; Lin, Wenqian

    2017-01-10

    Whether Neo-adjuvant chemotherapy can affect patients' postoperative brain function is not clear. In this study, we investigated the effect of preoperative cisplatin treatment on postoperative cognitive function and its possible mechanism in rats. Moreover, we also tested whether the NMDAR inhibitor memantine could attenuate cisplatin-induced alterations. 12-month-oldSprague-Dawley rats randomly received an intraperitoneal injection of either cisplatin once a week at a dose of 3mg/kg for three consecutive weeks or an equivalent volume of normal saline. After the injections, the normal saline injection group was divided into 3 groups (n=5 each): a normal saline group (group S), normal saline+pentobarbital group (group SP), and normal saline+pentobarbital+operation group (group SPO).The cisplatin injection group was divided into 3 groups: a cisplatin group (group C), cisplatin+pentobarbital group (group CP), and cisplatin+pentobarbital+operation group (group CPO).Rats in the group SP, SPO,CP and CPO were anaesthetized with sodium pentobarbital and then the SPO and CPO groups underwent a simple laparotomy operation. The effects of memantine were tested through two additional groups of rats (cisplatin+memantine group (group CM) and cisplatin+pentobarbital+operation+memantine group (group CPOM)). A Morris water maze test was performed to evaluate the spatial learning and memory ability five days after anesthesia or operation. After the test, the hippocampi were removed for detection of the expression of NMDAR by western bloting. The relevant protein expression levels of PSD95 and ERK1/2 were detected by western blot analysis. Rats treated with cisplatin had a longer mean escape latency and spent a shorter amount of time in the target quadrant than did the normal saline injection rats. Furthermore, the protein expression levels of NMDA receptors, PSD95 and ERK1/2 were decreased in cisplatin group and memantine could up-regulate their expression. These results suggest

  11. Antioxidantes da dieta como inibidores da nefrotoxicidade induzida pelo antitumoral cisplatina Dietary antioxidants as inhibitors of cisplatin-induced nephrotoxicity

    Directory of Open Access Journals (Sweden)

    Lusânia Maria Greggi Antunes

    2004-03-01

    Full Text Available A cisplatina é uma droga antineoplásica altamente efetiva contra vários tipos de cânceres humanos, tais como tumores do testículo e ovário, câncer da cabeça e pescoço e câncer do pulmão. Entretanto, a nefrotoxicidade é um dos principais efeitos colaterais da terapia com a cisplatina. A gravidade da nefrotoxicidade induzida pela cisplatina está relacionada com a concentração de platina nos rins. As evidências mostram que a nefrotoxicidade induzida pela cisplatina é atribuída ao dano oxidativo resultante da geração de radicais livres, e que a administração de antioxidantes é eficiente na inibição destes efeitos colaterais. Uma abordagem alternativa para proteger os roedores dos efeitos colaterais da cisplatina é o uso de conhecidos antioxidantes da dieta. Alguns estudos têm sido realizados para diminuir a peroxidação lipídica e os efeitos citotóxicos induzidos pela cisplatina, com o emprego de antioxidantes da dieta, tais como, selenito de sódio, vitaminas C e E, curcumina e o carotenóide bixina. Nós sugerimos que aqueles antioxidantes da dieta têm efeito nefroprotetor, e que os mecanismos antioxidantes destes compostos deveriam ser explorados durante a quimioterapia com a cisplatina.Cisplatin is a highly effective antineoplastic drug used against several types of human cancers, such as testicular and ovarian tumors; head and neck; and lung cancer. However, nephrotoxicity is one of the most important side-effects of cisplatin therapy. The severity of cisplatin nephrotoxicity is related to platinum concentration in the kidneys. There is a growing amount of evidence that cisplatin-induced nephrotoxicity is ascribed to oxidative damage resulting from free radical generation and that the administration of antioxidants is efficient in inhibiting these side effects. An alternative approach aiming to protect rodents against cisplatin side-effects is the introduction of known dietary antioxidants. Some studies have been

  12. Cisplatin induces protective autophagy through activation of BECN1 in human bladder cancer cells

    Directory of Open Access Journals (Sweden)

    Lin JF

    2017-05-01

    Full Text Available Ji-Fan Lin,1 Yi-Chia Lin,2 Te-Fu Tsai,2,3 Hung-En Chen,2 Kuang-Yu Chou,2,3 Thomas I-Sheng Hwang2–4 1Central Laboratory, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, 2Division of Urology, School of Medicine, Fu-Jen Catholic University, New Taipei, 3Division of Urology, Department of Surgery, Shin Kong Wu Ho-Su Memorial Hospital, 4Department of Urology, Taipei Medical University, Taipei, Taiwan Purpose: Cisplatin-based chemotherapy is the first line treatment for several cancers including bladder cancer (BC. Autophagy induction has been implied to contribute to cisplatin resistance in ovarian cancer; and a high basal level of autophagy has been demonstrated in human bladder tumors. Therefore, it is reasonable to speculate that autophagy may account for the failure of cisplatin single treatment in BC. This study investigated whether cisplatin induces autophagy and the mechanism involved using human BC cell lines.Materials and methods: Human BC cells (5637 and T24 were used in this study. Cell viability was detected using water soluble tetrazolium-8 reagents. Autophagy induction was detected by monitoring the levels of light chain 3 (LC3-II and p62 by Western blot, LC3-positive puncta formation by immunofluorescence, and direct observation of the autophagolysosome (AL formation by transmission electron microscopy. Inhibitors including bafilomycin A1 (Baf A1, chloroquine (CQ, and shRNA-based lentivirus against autophagy-related genes (ATG7 and ATG12 were utilized. Apoptosis level was detected by caspase 3/7 activity and DNA fragmentation.Results: Cisplatin decreased cell viability and induced apoptosis of 5637 and T24 cells in a dose- and time-dependent manner. The increased LC3-II accumulation, p62 clearance, the number of LC3-positive puncta, and ALs in cisplatin-treated cells suggested that cisplatin indeed induces autophagy. Inhibition of cisplatin-induced autophagy using Baf A1, CQ, or ATG7/ATG12 shRNAs significantly enhanced cytotoxicity of

  13. Pathophysiology of cisplatin-induced acute kidney injury

    National Research Council Canada - National Science Library

    Ozkok, Abdullah; Edelstein, Charles L

    2014-01-01

    .... A known complication of cisplatin administration is acute kidney injury (AKI). The nephrotoxic effect of cisplatin is cumulative and dose-dependent and often necessitates dose reduction or withdrawal...

  14. Pinpointing differences in cisplatin-induced apoptosis in adherent and non-adherent cancer cells

    DEFF Research Database (Denmark)

    Tastesen, Hanne Sørup; Holm, Jacob Bak; Poulsen, Kristian Arild

    2010-01-01

    Platinum compounds are used in the treatment of cancer. We demonstrate that cisplatin-induced (10 µM) apoptosis (caspase-3 activity) is pronounced within 18 hours in non-adherent Ehrlich ascites tumour cells (EATC), whereas there is no increase in caspase-3 activity in the adherent Ehrlich Lettré...... to a significant increase in apoptosis in ELA following cisplatin exposure. We find that cytosolic accumulation of cisplatin is similar in EATC and ELA. However, the nuclear accumulation and DNA-binding of cisplatin is significant lower in ELA compared to EATC. We suggest three putative reasons for the observed...

  15. Amelioration of cisplatin-induced nephrotoxicity in rats by curcumin ...

    African Journals Online (AJOL)

    Unfortunately, it exerts various side effects in several organs particularly in the kidney [2]. Only days after ..... respiratory chain, xanthine and NADPH oxidase) and exogenous sources (cigarette smoke, exogenous toxins ... insufficiency of antioxidant defense system are concerned in some pathological conditions induced by ...

  16. Effect of low-level laser treatment on cochlea hair-cell recovery after ototoxic hearing loss

    Science.gov (United States)

    Rhee, Chung-Ku; He, Peijie; Jung, Jae Yun; Ahn, Jin-Chul; Chung, Phil-Sang; Lee, Min Young; Suh, Myung-Whan

    2013-12-01

    The primary cause of hearing loss includes damage to cochlear hair cells. Low-level laser therapy (LLLT) has become a popular treatment for damaged nervous systems. Based on the idea that cochlea hair cells and neural cells are from same developmental origin, the effect of LLLT on hearing loss in animal models is evaluated. Hearing loss animal models were established, and the animals were irradiated by 830-nm diode laser once a day for 10 days. Power density of the laser treatment was 900 mW/cm2, and the fluence was 162 to 194 J. The tympanic membrane was evaluated after LLLT. Thresholds of auditory brainstem responses were evaluated before treatment, after gentamicin, and after 10 days of LLLT. Quantitative scanning electron microscopic (SEM) observations were done by counting remaining hair cells. Tympanic membranes were intact at the end of the experiment. No adverse tissue reaction was found. On SEM images, LLLT significantly increased the number of hair cells in middle and basal turns. Hearing was significantly improved by laser irradiation. After LLLT treatment, both the hearing threshold and hair-cell count significantly improved.

  17. Novel herbal medicine LA16001 ameliorates cisplatin-induced anorexia.

    Science.gov (United States)

    Woo, Sang-Mi; Lee, Kang Min; Lee, Gyu Ri; Park, Ji Youn; Lee, Hee Jae; Bahn, Hyo-Jung; Yoon, Hyun Seok; Kim, Jem Yung; Shin, Young Cheol; Cho, Sung-Gook; Ko, Seong-Gyu

    2018-02-01

    Chemotherapy frequently causes anorexia in cancer patients, which has been associated with poor disease prognosis. Several therapeutic strategies for the treatment of chemotherapy‑induced anorexia are available; however, their adverse effects limit their clinical use. Herbal medicines have a long history of use for the treatment of various diseases, including cancer, and recent research has demonstrated their safety and efficacy. In the present study, combinations of herbal medicines were designed based on traditional Korean medicine, and their effects were investigated on chemotherapy‑induced anorexia. Herbal mixtures were extracted, composed of Atractylodes japonica, Angelica gigas, Astragalus membranaceus, Lonicera japonica Thunb., Taraxacum platycarpum H. Dahlstedt and Prunella vulgaris var. asiatica (Nakai) Hara. The mixtures were termed LCBP‑Anocure‑16001‑3 (LA16001, LA16002, LA16003). A cisplatin‑induced anorexic mouse model was used to evaluate the putative effects of the extracts on chemotherapy‑induced anorexia. Treatment with LA16001 was revealed to prevent body weight loss, and all three extracts were demonstrated to improve food intake. When the molecular mechanisms underlying the orexigenic effects of LA16001 were investigated, altered expression levels of ghrelin, leptin and interleukin‑6 were revealed. Furthermore, LA16001 was reported to induce phosphorylation of Janus kinase 1 and signal transducer and activator of transcription 3. In addition, LA16001 administration increased the number of white blood cells and neutrophils. These results suggested that the herbal formula LA16001 may be able to prevent chemotherapy‑induced anorexia and may have potential as a novel therapeutic strategy for the adjuvant treatment of patients with cancer.

  18. Mechanical Stress Promotes Cisplatin-Induced Hepatocellular Carcinoma Cell Death

    Science.gov (United States)

    Riad, Sandra; Bougherara, Habiba

    2015-01-01

    Cisplatin (CisPt) is a commonly used platinum-based chemotherapeutic agent. Its efficacy is limited due to drug resistance and multiple side effects, thereby warranting a new approach to improving the pharmacological effect of CisPt. A newly developed mathematical hypothesis suggested that mechanical loading, when coupled with a chemotherapeutic drug such as CisPt and immune cells, would boost tumor cell death. The current study investigated the aforementioned mathematical hypothesis by exposing human hepatocellular liver carcinoma (HepG2) cells to CisPt, peripheral blood mononuclear cells, and mechanical stress individually and in combination. HepG2 cells were also treated with a mixture of CisPt and carnosine with and without mechanical stress to examine one possible mechanism employed by mechanical stress to enhance CisPt effects. Carnosine is a dipeptide that reportedly sequesters platinum-based drugs away from their pharmacological target-site. Mechanical stress was achieved using an orbital shaker that produced 300 rpm with a horizontal circular motion. Our results demonstrated that mechanical stress promoted CisPt-induced death of HepG2 cells (~35% more cell death). Moreover, results showed that CisPt-induced death was compromised when CisPt was left to mix with carnosine 24 hours preceding treatment. Mechanical stress, however, ameliorated cell death (20% more cell death). PMID:25685789

  19. Mechanical Stress Promotes Cisplatin-Induced Hepatocellular Carcinoma Cell Death

    Directory of Open Access Journals (Sweden)

    Laila Ziko

    2015-01-01

    Full Text Available Cisplatin (CisPt is a commonly used platinum-based chemotherapeutic agent. Its efficacy is limited due to drug resistance and multiple side effects, thereby warranting a new approach to improving the pharmacological effect of CisPt. A newly developed mathematical hypothesis suggested that mechanical loading, when coupled with a chemotherapeutic drug such as CisPt and immune cells, would boost tumor cell death. The current study investigated the aforementioned mathematical hypothesis by exposing human hepatocellular liver carcinoma (HepG2 cells to CisPt, peripheral blood mononuclear cells, and mechanical stress individually and in combination. HepG2 cells were also treated with a mixture of CisPt and carnosine with and without mechanical stress to examine one possible mechanism employed by mechanical stress to enhance CisPt effects. Carnosine is a dipeptide that reportedly sequesters platinum-based drugs away from their pharmacological target-site. Mechanical stress was achieved using an orbital shaker that produced 300 rpm with a horizontal circular motion. Our results demonstrated that mechanical stress promoted CisPt-induced death of HepG2 cells (~35% more cell death. Moreover, results showed that CisPt-induced death was compromised when CisPt was left to mix with carnosine 24 hours preceding treatment. Mechanical stress, however, ameliorated cell death (20% more cell death.

  20. Cisplatin-induced CCL5 secretion from CAFs promotes cisplatin-resistance in ovarian cancer via regulation of the STAT3 and PI3K/Akt signaling pathways.

    Science.gov (United States)

    Zhou, Bo; Sun, Chaoyang; Li, Na; Shan, Wanying; Lu, Hao; Guo, Lili; Guo, Ensong; Xia, Meng; Weng, Danhui; Meng, Li; Hu, Junbo; Ma, Ding; Chen, Gang

    2016-05-01

    Currently, acquired resistance to cisplatin (DDP) is a substantial obstacle to reducing the morbidity and mortality due to ovarian malignant tumors. Nevertheless, cisplatin plays a vital role in killing the tumor cells while it may also be a 'primer' involved in chemotherapy resistance. We found that the cisplatin-induced chemokine (C-C motif) ligand 5 (CCL5) secretion derived from cancer-associated fibroblasts (CAFs) promoted ovarian cancer cell resistance to cisplatin. Via a cytokine chip assay, we identified a spectrum of secreted proteins that were derived from the CAFs through cisplatin-induced treatment. Among these, CCL5 significantly attenuated the cytotoxic effect of cisplatin chemotherapy in vitro and in vivo. Additionally, CCL5 expression was also detected in 62 serous ovarian cancer patient tissue specimens using IHC, and the results demonstrated that chemotherapy resistant patients displayed higher expression of CCL5 than the chemo-sensitive patients (Povarian cancer cells. These results indicated that cisplatin- induced CCL5 secretion derived from the CAFs may promote cisplatin resistance, which was mediated by regulation of the STAT3 and PI3K/Akt signal pathways.

  1. Sip-jeon-dea-bo-tang, a traditional herbal medicine, ameliorates cisplatin-induced anorexia via the activation of JAK1/STAT3-mediated leptin and IL-6 production in the fat tissue of mice.

    Science.gov (United States)

    Woo, Sang-Mi; Choi, Youn Kyung; Kim, Ah-Jeong; Yun, Yee Jin; Shin, Yong Cheol; Cho, Sung-Gook; Ko, Seong Gyu

    2016-04-01

    Despite its therapeutic advantages, chemotherapy can also cause adverse effects, including anorexia and loss of appetite. Although numerous patients with cancer have been reported to suffer from anorexia during or following chemotherapy, treatment options for anorexia remain to be determined. In Asian countries, traditional medicines are widely used to treat problems with appetite; sip-jeon-dea-bo-tang (SJDBT) is one of those medicines used for the treatment of anorexia. The present study demonstrated that SJDBT ameliorated cisplatin-induced anorexia. In a mouse model of chemotherapy-induced anorexia, oral administration of SJDBT prevented the cisplatin-induced reduction of food intake, inhibiting weight loss. The results of multiplex assays showed that SJDBT only altered the levels of interleukin (IL)-6 and leptin in the serum and fat tissue. In addition, SJDBT maintained the serum leptin level and increased the serum IL-6 level, whereas cisplatin reduced the levels of both serum leptin and IL‑6. Furthermore, SJDBT was revealed to increase the levels of leptin and IL-6 in the fat tissue by activating the JAK1/STAT3 signaling pathway. In conclusion, the present results revealed that SJDBT ameliorated cisplatin-induced anorexia, suggesting its usefulness in the prevention of anorexia during chemotherapy.

  2. Azadirachta indica attenuates cisplatin-induced neurotoxicity in rats.

    Science.gov (United States)

    Abdel Moneim, Ahmed Esmat

    2014-01-01

    The objective of this study is to investigate the neuroprotective effects of Azadirachta indica leaves against cisplatin (CP)-induced neurotoxicity. Female Wistar rats were treated with vehicle (control); a single intraperitoneal 5 mg/kg CP (CP group); neem leaves (orally 500 mg/kg) for 5 and 10 days, N5 and N10 groups, respectively; neem leaves (500 mg/kg) for 5 days after CP injection, collagenous protein nitrogen (CPN) group; neem leaves (500 mg/kg) for 5 days before CP injection, noncollagenous protein group and neem leaves in a dose of 500 mg/kg for 5 days before and after CP injection, noncollagenous protein nitrogen group. Rats were sacrificed 5 days after CP injection to determine neural lipid peroxidation (LPO), nitric oxide (NO), and glutathione (GSH) levels. The neuronal antioxidant enzymes were evaluated in brain homogenates. CP injection increased LPO, NO levels and decreased GSH level, whereas neem reversed these effects. Morphological brain damage and apoptosis induction were apparent in the CP group. In the CPN group, the histological damage and apoptosis induction caused by CP was improved, whereas morphological findings of neem before and after CP injection implied a well preserved brain tissue. No changes, in biochemical parameters were observed with neem treated groups. This study suggests that methanolic extract of neem leaves may be of therapeutic benefit when used with CP.

  3. Azadirachta indica attenuates cisplatin-induced nephrotoxicity and oxidative stress.

    Science.gov (United States)

    Abdel Moneim, Ahmed E; Othman, Mohamed S; Aref, Ahmed M

    2014-01-01

    We investigated the effects of methanolic leaves extract of Azadirachta indica (MLEN, 500 mg/kg bwt) on cisplatin- (CP-) induced nephrotoxicity and oxidative stress in rats. CP (5 mg/kg bwt) was injected intraperitoneally and MLEN was given by gastric gavage for 5 days before or after CP injection. After 5 days of CP injection, CP-induced injury of the renal tissue was evidenced (i) as histopathological damage of the renal tissue, (ii) as increases in serum uric acid, urea, and creatinine, (iii) as increases in malondialdehyde (MDA) and nitric oxide (NO), (iv) as decreases in the level of glutathione and activities of superoxide dismutase, catalase, glutathione reductase, glutathione-S-transferase, and glutathione peroxidase, and (v) as increase in the expression of nuclear factor kappa B and apoptosis in kidney tissues. However, the oral administration of MLEN to CP-intoxicated rats for 5 days brought back MDA, NO production, and enzymatic and nonenzymatic antioxidants to near normalcy. Moreover, the histological observations evidenced that neem extract effectively rescues the kidney from CP-mediated oxidative damage. Furthermore, PCR results for caspase-3 and caspase-9 and Bax genes showed downregulation in MLEN treated groups. Therefore, Azadirachta indica can be considered a potential candidate for protection of nephrotoxicity induced by cisplatin.

  4. Azadirachta indica Attenuates Cisplatin-Induced Nephrotoxicity and Oxidative Stress

    Directory of Open Access Journals (Sweden)

    Ahmed E. Abdel Moneim

    2014-01-01

    Full Text Available We investigated the effects of methanolic leaves extract of Azadirachta indica (MLEN, 500 mg/kg bwt on cisplatin- (CP- induced nephrotoxicity and oxidative stress in rats. CP (5 mg/kg bwt was injected intraperitoneally and MLEN was given by gastric gavage for 5 days before or after CP injection. After 5 days of CP injection, CP-induced injury of the renal tissue was evidenced (i as histopathological damage of the renal tissue, (ii as increases in serum uric acid, urea, and creatinine, (iii as increases in malondialdehyde (MDA and nitric oxide (NO, (iv as decreases in the level of glutathione and activities of superoxide dismutase, catalase, glutathione reductase, glutathione-S-transferase, and glutathione peroxidase, and (v as increase in the expression of nuclear factor kappa B and apoptosis in kidney tissues. However, the oral administration of MLEN to CP-intoxicated rats for 5 days brought back MDA, NO production, and enzymatic and nonenzymatic antioxidants to near normalcy. Moreover, the histological observations evidenced that neem extract effectively rescues the kidney from CP-mediated oxidative damage. Furthermore, PCR results for caspase-3 and caspase-9 and Bax genes showed downregulation in MLEN treated groups. Therefore, Azadirachta indica can be considered a potential candidate for protection of nephrotoxicity induced by cisplatin.

  5. Cisplatin-induced Casepase-3 activation in different tumor cells

    Science.gov (United States)

    Shi, Hua; Li, Xiao; Su, Ting; Zhang, Yu-Hai

    2008-12-01

    Apoptosis plays an essential role in normal organism development which is one of the main types of programmed cell death to help tissues maintain homeostasis. Defective apoptosis can result in cell accumulation and therefore effects on tumor pathogenesis, progression and therapy resistance. A family of proteins, known as caspases, is typically activated in the early stages of apoptosis. Therefore, studying the kinetics of activation of caspases induced by antitumor drugs can contribute to antitumor drug discovery and explanation of the molecular mechanisms. This paper detected the Caspase-3 activity induced by cisplatin in human adenoid cystic carcinoma cell line (ACC-M), human hepatocellular liver carcinoma cell line (HepG2) and human epithelial carcinoma cell line (Hela) with stably expressing ECFP-DEVDDsRed (CD3) probe, a fluorescent probe consisting of Enhanced Cyan Fluorescent Protein (ECFP), red fluorescent protein (DsRed) and a linker with a recognition site of Caspase-3, by using the capillary electrophoresis (CE) and fluorescence resonance energy transfer (FRET) imaging system. Under the same concentration of cisplatin, ACC-M cells responded the most rapidly, and then HepG2 cells and Hela cells, respectively, in the early 30 hours. Later, HepG2 cells represented acceleration in the Caspase-3 activation speed and reached full activation the earliest comparing to other two cell types. The results demonstrated that ACC-M cell is more sensitive than the other two cell types under the treatment of cisplatin.

  6. The Potential Role of Azadirachta indica Treatment on Cisplatin-Induced Hepatotoxicity and Oxidative Stress in Female Rats

    Science.gov (United States)

    Dkhil, Mohamed A.; Al-Quraishy, Saleh; Aref, Ahmed M.; Othman, Mohamed S.; El-Deib, Kamal M.; Abdel Moneim, Ahmed E.

    2013-01-01

    Azadirachta indica A. Juss. (neem, family: Meliaceae) is perhaps the most commonly used traditional medicinal plant of India. In this study we investigated the protective effect of methanolic neem leaves extract (MNLE; 500 mg/Kg bwt) on rats treated with cisplatin (CDDP)-induced hepatotoxicity. Adult rats were randomly divided into four groups. CDDP was given to rats by intraperitoneal injection, while MNLE was given by oral gavage for 5 days after the CDDP injection. The injury and oxidative stress caused by CDDP on the liver and the effect of MNLE were evaluated by measuring (a) histological changes, (b) tissue biochemical oxidant and antioxidant parameters, and (c) investigating apoptosis markers immunohistochemically and by real time PCR. After treatment with MNLE, the histological damage and apoptosis induction caused by cisplatin were improved. Malondialdehyde and nitric oxide were significantly decreased; the antioxidant system, namely, glutathione content, glutathione-S-transferase, glutathione peroxidase, catalase, and superoxide dismutase activities were significantly elevated. In conclusion, MNLE may have a potential role when combined with cisplatin in chemotherapy to alleviate cisplatin-induced damage and oxidative stress in liver. PMID:24369490

  7. The Potential Role of Azadirachta indica Treatment on Cisplatin-Induced Hepatotoxicity and Oxidative Stress in Female Rats

    Directory of Open Access Journals (Sweden)

    Mohamed A. Dkhil

    2013-01-01

    Full Text Available Azadirachta indica A. Juss. (neem, family: Meliaceae is perhaps the most commonly used traditional medicinal plant of India. In this study we investigated the protective effect of methanolic neem leaves extract (MNLE; 500 mg/Kg bwt on rats treated with cisplatin (CDDP-induced hepatotoxicity. Adult rats were randomly divided into four groups. CDDP was given to rats by intraperitoneal injection, while MNLE was given by oral gavage for 5 days after the CDDP injection. The injury and oxidative stress caused by CDDP on the liver and the effect of MNLE were evaluated by measuring (a histological changes, (b tissue biochemical oxidant and antioxidant parameters, and (c investigating apoptosis markers immunohistochemically and by real time PCR. After treatment with MNLE, the histological damage and apoptosis induction caused by cisplatin were improved. Malondialdehyde and nitric oxide were significantly decreased; the antioxidant system, namely, glutathione content, glutathione-S-transferase, glutathione peroxidase, catalase, and superoxide dismutase activities were significantly elevated. In conclusion, MNLE may have a potential role when combined with cisplatin in chemotherapy to alleviate cisplatin-induced damage and oxidative stress in liver.

  8. Simultaneous imaging of two initiator caspases during cisplatin-induced HeLa apoptosis

    Science.gov (United States)

    Chu, Jun; Wang, Liang; Luo, Qingming; Zhang, Zhihong

    2008-02-01

    Caspase-2 is an initiating caspase required for stress-induced apoptosis in various human cancer cells. Activation of caspase-9, a key event in stress-mediated apoptosis, also has been shown to be an initiator caspase. However, the timing or activation sequence of these initiator caspases, which trigger apoptotic pathway, is unclear. Here we report caspase-2 and caspase-9 dynamics during cisplatin-induced HeLa apoptosis using Double Fluorescence Resonance Energy Transfer (FRET) technique. Two FRET probes were constructed that each encoded a CRS (caspase-2 or caspase-9 recognition Site) fused with a cyan/yellow fluorescent protein (CFP/YFP) and a red fluorescent protein (DsRed) (CFP/YFP-CRS-DsRed). By using two probes, CFP-C2-DsRed and YFP-C9-DsRed, we carried out simultaneous double-FRET analysis and revealed that activation of caspase-2 had the same time course with caspase-9. These data suggest parallel activation of initiator caspase-2 and caspase-9 in cisplatin-induced cell death.

  9. Prevention of Cisplatin-Induced Hearing Loss by Intratympanic Dexamethasone: A Randomized Controlled Study.

    Science.gov (United States)

    Marshak, Tal; Steiner, Mariana; Kaminer, Margalith; Levy, Levana; Shupak, Avi

    2014-06-01

    To examine the role of intratympanic Dexamethasone (ITD) in the prevention of Cisplatin-induced hearing loss. Prospective randomized controlled clinical trial. Tertiary referral center. Twenty-six patients suffering from a neoplastic disease for which the treatment protocol included Cisplatin were recruited. Prior to each Cisplatin treatment session ITD was injected to the baseline randomly assigned ear while the other ear of the same patient served as the control. Audiometry and Distortion Product Otoacoustic Emissions (DPOAEs) test results of the baseline and follow-up examinations were compared within and between the study and control ears. The cumulative dose of Cisplatin was greater than 400 mg for the 15 subjects who completed the study. The pure tone threshold at 8000 Hz and pure tone average threshold at 4000 to 8000 Hz significantly increased in both the study (P control ears (P control (P control (P < .04) but not in the study ears. ITD significantly attenuated hearing loss at 6000 Hz and decreased the outer hair dysfunction in the DPOAE f2 range of 4000 to 8000 Hz. ITD might have potential in the reduction of Cisplatin-induced hearing loss. © American Academy of Otolaryngology—Head and Neck Surgery Foundation 2014.

  10. Does the kidney injury molecule-1 predict cisplatin-induced kidney injury in early stage?

    Science.gov (United States)

    Tekce, Buket Kin; Uyeturk, Ummugul; Tekce, Hikmet; Uyeturk, Ugur; Aktas, Gulali; Akkaya, Akcan

    2015-01-01

    It is not possible to diagnose acute kidney injury (AKI) in early stages with traditional biomarkers. Kidney injury molecule-1 (KIM-1) is a novel biomarker promising the diagnosis of AKI in early stages. We studied whether urinary and serum KIM-1 (KIM-1 U and KIM-1 S ) concentrations were useful in predicting cisplatin-induced AKI in early stages. We prospectively analysed 22 patients on cisplatin treatment. KIM-1 S and KIM-1 U concentrations were assessed in the samples of the patients on four different time periods (before treatment [BT], first [AT1], third [AT3] and fifth [AT5] day after treatment). KIM-1 U concentrations on the first day after cisplatin treatment in patients with AKI were significantly increased compared to both KIM-1 U concentrations of the same patients BT (P=0.009) and to AT1-KIM-1 U concentrations of the patients without AKI (P=0.008). A receiver operating characteristic analysis revealed that AT1-KIM-1 U concentrations may predict AKI with an 87.5% sensitivity and 93.3% specificity (area under the curve=0.94). KIM-1 S concentrations were not significantly changed between BT and AT periods. KIM-1 U concentrations may predict cisplatin-induced AKI in early stages with high sensitivity and specificity. © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

  11. Proanthocyanidin and fish oil potent activity against cisplatin-induced renal cell cycle arrest and apoptosis in rats.

    Science.gov (United States)

    Hassan, Hanaa A; Edrees, Gamal M; El-Gamel, Ezz M; El-Sayed, Elsamra A

    2015-01-01

    Cisplatin is an effective chemotherapeutic agent that displays dose-limiting nephrotoxicity. In the present study, the efficacy of grape seed proanthocyanidin extract (GSPE: 100 mg/kg/day) and fish oil (FO: 5 mL/kg/day) against cisplatin-induced nephrotoxicity was evaluated in terms of DNA damage, histopathological changes and expression levels of molecular markers of apoptosis. The administration of cisplatin (CP) (7 mg/kg) results in an increasing percentage of S-phase, G2/M and apoptosis. Furthermore, CP induces apoptosis as indicated by an elevation of renal caspase-3 and reduction in the expression of BCL-2. In addition to occurred renal histopathological changes as manifested by tubular degeneration, degenerative glomerulus, necrotic tubular cells, and cell debris. On the other hand, the administration of GSPE or FO pre-cisplatin treatment can be ameliorated the current DNA cell cycle alterations by the restoration of expression of proteins related to apoptosis and reduced the undesirable renal histopathological changes. So, it can be concluded that the consumption of GSPE or FO might be useful for minimizing nephrotoxicity caused by cisplatin chemotherapy through their anti-apoptotic and antioxidant properties.

  12. EZH2-mediated Puma gene repression regulates non-small cell lung cancer cell proliferation and cisplatin-induced apoptosis.

    Science.gov (United States)

    Liu, Haidan; Li, Wei; Yu, Xinfang; Gao, Feng; Duan, Zhi; Ma, Xiaolong; Tan, Shiming; Yuan, Yunchang; Liu, Lijun; Wang, Jian; Zhou, Xinmin; Yang, Yifeng

    2016-08-30

    Polycomb group (PcG) proteins are highly conserved epigenetic effectors that maintain the silenced state of genes. EZH2 is the catalytic core and one of the most important components of the polycomb repressive complex 2 (PRC2). In non-small cell lung cancer (NSCLC) cells and primary lung tumors, we found that PRC2 components, including EZH2, are overexpressed. High levels of EZH2 protein were associated with worse overall survival rate in NSCLC patients. RNA interference mediated attenuation of EZH2 expression blunted the malignant phenotype in this setting, exerting inhibitory effects on cell proliferation, anchorage-independent growth, and tumor development in a xenograft mouse model. Unexpectedly, we discovered that, in the suppression of EZH2, p53 upregulated modulator of apoptosis (PUMA) expression was concomitantly induced. This is achieved through EZH2 directly binds to the Puma promoter thus epigenetic repression of PUMA expression. Furthermore, cisplatin-induced apoptosis of EZH2-knocking down NSCLC cells was elevated as a consequence of increased PUMA expression. Our work reveals a novel epigenetic regulatory mechanism controlling PUMA expression and suggests that EZH2 offers a candidate molecular target for NSCLC therapy and EZH2-regulated PUMA induction would synergistically increase the sensitivity to platinum agents in non-small cell lung cancers.

  13. A prospective study of gentamicin ototoxicity

    DEFF Research Database (Denmark)

    Winkel, O; Hansen, M M; Kaaber-Bühler, Søren

    2010-01-01

    Twenty patients were included in a prospective otoneurological study performed to assess the ototoxicity in gentamicin therapy. Gentamicin was administered intravenously, and the serum level was currently determined. Audiographic and electronystagmographic studies were carried out at the institut......Twenty patients were included in a prospective otoneurological study performed to assess the ototoxicity in gentamicin therapy. Gentamicin was administered intravenously, and the serum level was currently determined. Audiographic and electronystagmographic studies were carried out...... of gentamicin did not rule out the possiblity of ototoxicity. These results urge the continuing of prospective studies and indicate that gentamicin should be used only as a link in the primary treatment of severe infection or in cases in which other, less toxic agents have failed....

  14. TNF-α, IL-6 and IL-10 expressions, responsible for disparity in action of curcumin against cisplatin-induced nephrotoxicity in rats.

    Science.gov (United States)

    Kumar, Parveen; Sulakhiya, Kunjbihari; Barua, Chandana C; Mundhe, Nitin

    2017-07-01

    Cisplatin is a regularly employed effective chemotherapeutic agent for the treatment of many types of cancer. The main drawback of cisplatin treatment is kidney toxicity which affects 25-35% of treated patients. Many mechanisms are believed to be involved in this kidney damage, but inflammation plays a significant role in this event. Curcumin is a polyphenol and has antioxidant and anti-inflammatory effects. The purpose of this study was to determine the protective effects of curcumin on cisplatin-induced nephrotoxicity. Female rats were randomly divided into 5 groups: control, curcumin, cisplatin, curcumin plus cisplatin (pre-treatment group) and cisplatin plus curcumin (post-treatment group). Rats were given cisplatin (7.5 mg/kg body weight) with or without curcumin treatment (120 mg/kg body weight). Blood urea nitrogen (BUN), creatinine, albumin, tumour necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, IL-8, IL-10 expressions and histological changes were determined on the 5th day after cisplatin injection. Acute kidney damage was evident by increased BUN and creatinine levels. In addition, cisplatin showed a marked pro-inflammatory response as revealed by a significant increase in the tissue levels of TNF-α, IL-6, IL-8 and decrease in the IL-10 level. Pre-treatment of curcumin reduced cisplatin-induced nephrotoxicity which was clearly evident from the reduced BUN, creatinine, TNF-α, IL-6 and IL-8 levels and increased albumin and IL-10 levels. Additionally, these findings were also supported by histopathology of the kidneys. In contrast, post-treatment of curcumin failed to cut down the expression of inflammatory markers substantially and also neglected to increase the expression of IL-10. The disparity in the action of curcumin after pre- and post-treatment with cisplatin-induced nephrotoxicity was due to the inability of post-treatment to reduce TNF-α & IL-6, besides to show a concurrent rise in IL-10 expression in renal tissues.

  15. Knockdown of TKTL1 additively complements cisplatin-induced cytotoxicity in nasopharyngeal carcinoma cells by regulating the levels of NADPH and ribose-5-phosphate.

    Science.gov (United States)

    Dong, Yuke; Wang, Ming

    2017-01-01

    Transketolase-like 1 (TKTL1) plays an important role in pentose phosphate pathway (PPP) branch, the main pathway generating nicotinamide adenine dinucleotide phosphate (NADPH) and nucleotides for DNA synthesis. TKTL1 is closely related to DNA damage and has a close relationship with incidence and progression of cancers. Cisplatin is the main chemotherapeutic drug by inducing DNA damage. Whether TKTL1 knockdown additively complements cisplatin-induced cytotoxicity in nasopharyngeal carcinoma cells, however, remains largely undefined. Lipofectamine 2000 was used to transfect si-TKTL1s with different sequences into the CNE2 and HONE1 cells. The mRNA and protein levels of TKTL1 were determined by qRT-PCR and western blot, respectively. MTT assay and flow cytometry were used to access the viability and apoptosis of CNE2 and HONE1 cells. The NADPH and ribose-5-phosphate levels in both CNE2 and HONE1 cells were determined by NADPH examination kit and HPCE analysis, respectively. The effect of TKTL1 knockdown and NADPH/ribose-5-phosphate supplement on DNA damage was assessed by using Comet assay. TKTL1 knockdown significantly decreased TKTL1 level in CNE2 and HONE1 cells. A significant decrease in cell viability and an obvious increase in cell apoptosis rate were found in si-TKTL1+cisplatin group compared with si-TKTL1 group or si-control+cisplatin group. The levels of NADPH and ribose-5-phosphate in CNE1 and HONE1 cells were dramatically decreased in si-TKTL1 group compared with si-control group. TKTL1 knockdown additively complemented cisplatin-induced cytotoxicity, which was partly reversed by the supplements of NADPH and ribose-5-phosphate, including the increased survival rate, decreased apoptosis and DNA damage. Knockdown of TKTL1 additively complements cisplatin-induced cytotoxicity in the nasopharyngeal carcinoma cells by inhibiting the levels of NADPH and ribose-5-phosphate, indicating that TKTL1 may be a promising target to improve the therapeutic effect

  16. Physiological and Molecular Pathology of Aminoglycoside Ototoxicity

    Science.gov (United States)

    Sha, Su-Hua

    2005-01-01

    The problem of aminoglycoside-induced ototoxicity, which was recognized within a year of the discovery of streptomycin to combat tuberculosis in 1944, is still of great concern due to the widespread use of these powerful antibacterial agents. These drugs can damage to varying degrees the cochlea and vestibular system. Their primary targets are the…

  17. Aminoglycoside induced ototoxicity associated with mitochondrial ...

    African Journals Online (AJOL)

    Joseph Foster II

    2016-06-16

    Jun 16, 2016 ... tein synthesis caused by the 1555A>G mutation may be suffi- cient to cause the hearing loss phenotype, ... tein synthesis is eventual cell death either through caspase- mediated or non-caspase-mediated ..... Although other mitigating agents such as Aspirin have been successful in reducing the ototoxicity, ...

  18. Aminoglycoside induced ototoxicity associated with mitochondrial ...

    African Journals Online (AJOL)

    Efforts to alter the molecular structure of aminoglycosides have shown a potential path to reducing ototoxicity while preserving antibacterial properties, but these drugs are not clinically available. On the other hand, application of preemptive audiometry provides the most readily available method to both monitor and reduce ...

  19. Two cases of cisplatin-induced permanent renal failure following neoadjuvant chemotherapy for esophageal cancer.

    Science.gov (United States)

    Sasaki, Tomohiko; Motoyama, Satoru; Komatsuda, Atsushi; Shibata, Hiroyuki; Sato, Yusuke; Yoshino, Kei; Wakita, Akiyuki; Saito, Hajime; Anbai, Akira; Jin, Mario; Minamiya, Yoshihiro

    2016-01-01

    We experienced two esophageal cancer patients who developed severe acute renal failure after neoadjuvant chemotherapy with cisplatin and 5-fluorourasil. After administration of cisplatin, their serum creatinine increased gradually until they required hemodialysis and their renal failure was permanent. In both cases, renal biopsy examination indicated partial recovery of the proximal tubule, but renal function did not recover. After these events, one patient underwent definitive radiotherapy and the other underwent esophagectomy for their esophageal cancers, while continuing dialysis. Both patients are alive without cancer recurrence. In these two cases of cisplatin-induced renal failure, renal biopsy examination showed only slight disorder of proximal tubules and tendency to recover. Although cisplatin-related nephrotoxicity is a well-recognized complication, there have been few reports of renal failure requiring hemodialysis in cancer patients. In this report, we present their clinical courses and the pathological findings of cisplatin-related renal failure. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

  20. Neural regulation of the kidney function in rats with cisplatin induced renal failure

    Science.gov (United States)

    Goulding, Niamh E.; Johns, Edward J.

    2015-01-01

    Aim: Chronic kidney disease (CKD) is often associated with a disturbed cardiovascular homeostasis. This investigation explored the role of the renal innervation in mediating deranged baroreflex control of renal sympathetic nerve activity (RSNA) and renal excretory function in cisplatin-induced renal failure. Methods: Rats were either intact or bilaterally renally denervated 4 days prior to receiving cisplatin (5 mg/kg i.p.) and entered a chronic metabolic study for 8 days. At day 8, other groups of rats were prepared for acute measurement of RSNA or renal function with either intact or denervated kidneys. Results: Following the cisplatin challenge, creatinine clearance was 50% lower while fractional sodium excretion and renal cortical and medullary TGF-β1 concentrations were 3–4 fold higher in both intact and renally denervated rats compared to control rats. In cisplatin-treated rats, the maximal gain of the high-pressure baroreflex curve was only 20% that of control rats, but following renal denervation not different from that of renally denervated control rats. Volume expansion reduced RSNA by 50% in control and in cisplatin-treated rats but only following bilateral renal denervation. The volume expansion mediated natriuresis/diuresis was absent in the cisplatin-treated rats but was normalized following renal denervation. Conclusions: Cisplatin-induced renal injury impaired renal function and caused a sympatho-excitation with blunting of high and low pressure baroreflex regulation of RSNA, which was dependent on the renal innervation. It is suggested that in man with CKD there is a dysregulation of the neural control of the kidney mediated by its sensory innervation. PMID:26175693

  1. Cisplatin Induces Bmi-1 and Enhances the Stem Cell Fraction in Head and Neck Cancer

    Directory of Open Access Journals (Sweden)

    Carolina Nör

    2014-02-01

    Full Text Available Recent evidence has unveiled a subpopulation of highly tumorigenic, multipotent cells capable of self-renewal in head and neck squamous cell carcinomas (HNSCCs. These unique cells, named here cancer stem cells (CSCs, proliferate slowly and might be involved in resistance to conventional chemotherapy. We have shown that CSCs are found in perivascular niches and rely on endothelial cell-secreted factors [particularly interleukin-6 (IL-6] for their survival and self-renewal in HNSCC. Here, we hypothesized that cisplatin enhances the stem cell fraction in HNSCC. To address this hypothesis, we generated xenograft HNSCC tumors with University of Michigan-squamous cell carcinoma 22B (UM-SCC-22B cells and observed that cisplatin treatment increased (P = .0013 the fraction of CSCs [i.e., aldehyde dehydrogenase activity high and cluster of differentiation 44 high (ALDHhighCD44high]. Cisplatin promoted self-renewal and survival of CSCs in vitro, as seen by an increase in the number of orospheres in ultralow attachment plates and induction in B lymphoma Mo-MLV insertion region 1 homolog (Bmi-1 and octamer-binding transcription factor 4 expression. Cisplatin-resistant cells expressed more Bmi-1 than cisplatinsensitive cells. IL-6 potentiated cisplatin-induced orosphere formation generated when primary human HNSCC cells were sorted for ALDHhighCD44high immediately after surgery and plated onto ultralow attachment plates. IL-6-induced signal transducer and activator of transcription 3 (STAT3 phosphorylation (indicative of stemness was unaffected by treatment with cisplatin in UM-SCC-22B cells, whereas IL-6-induced extracellular signal-regulated kinase (ERK phosphorylation (indicative of differentiation processes was partially inhibited by cisplatin. Notably, cisplatin-induced Bmi-1 was inhibited by interleukin-6 receptor blockade in parental and cisplatin-resistant cells. Taken together, these results demonstrate that cisplatin enhances the fraction of CSCs

  2. Far infrared radiation promotes rabbit renal proximal tubule cell proliferation and functional characteristics, and protects against cisplatin-induced nephrotoxicity.

    Science.gov (United States)

    Chiang, I-Ni; Pu, Yeong-Shiau; Huang, Chao-Yuan; Young, Tai-Horng

    2017-01-01

    Far infrared radiation, a subdivision of the electromagnetic spectrum, is beneficial for long-term tissue healing, anti-inflammatory effects, growth promotion, sleep modulation, acceleration of microcirculation, and pain relief. We investigated if far infrared radiation is beneficial for renal proximal tubule cell cultivation and renal tissue engineering. We observed the effects of far infrared radiation on renal proximal tubules cells, including its effects on cell proliferation, gene and protein expression, and viability. We also examined the protective effects of far infrared radiation against cisplatin, a nephrotoxic agent, using the human proximal tubule cell line HK-2. We found that daily exposure to far infrared radiation for 30 min significantly increased rabbit renal proximal tubule cell proliferation in vitro, as assessed by MTT assay. Far infrared radiation was not only beneficial to renal proximal tubule cell proliferation, it also increased the expression of ATPase Na+/K+ subunit alpha 1 and glucose transporter 1, as determined by western blotting. Using quantitative polymerase chain reaction, we found that far infrared radiation enhanced CDK5R1, GNAS, NPPB, and TEK expression. In the proximal tubule cell line HK-2, far infrared radiation protected against cisplatin-mediated nephrotoxicity by reducing apoptosis. Renal proximal tubule cell cultivation with far infrared radiation exposure resulted in better cell proliferation, significantly higher ATPase Na+/K+ subunit alpha 1 and glucose transporter 1 expression, and significantly enhanced expression of CDK5R1, GNAS, NPPB, and TEK. These results suggest that far infrared radiation improves cell proliferation and differentiation. In HK-2 cells, far infrared radiation mediated protective effects against cisplatin-induced nephrotoxicity by reducing apoptosis, as indicated by flow cytometry and caspase-3 assay.

  3. Cisplatin Induces Overactivation of the Dormant Primordial Follicle through PTEN/AKT/FOXO3a Pathway which Leads to Loss of Ovarian Reserve in Mice.

    Directory of Open Access Journals (Sweden)

    Eun Mi Chang

    Full Text Available Cisplatin is a first-line chemotherapeutic agent for ovarian cancer that acts by promoting DNA cross links and adduct. However drug resistance and considerable side effects including reproductive toxicity remain a significant challenge. PTEN is well known as a tumor suppressor function which plays a fundamental role in the regulation of the cell cycle, apoptosis and development of cancer. At the same time PTEN has been revealed to be critically important for the maintenance of the primordial follicle pool. In this study, we investigated the role of PTEN/Akt/FOXO3 pathway in cisplatin-induced primordial follicle depletion. Cisplatin induced ovarian failure mouse model was used to evaluate how this pathway involves. In vitro maturation was used for oocyte rescue after cisplatin damage. We found that cisplatin treatment decreased PTEN levels, leading to a subsequent increase in the phosphorylation of key molecules in the pathway. The activation of the PTEN/Akt/FOXO3 pathway cascade increased cytoplasmic translocation of FOXO3a in cisplatin-treated follicles, which in turn increased the pool size of growing follicles, and rapidly depleted the number of dormant follicles. Once activated, the follicles were more prone to apoptosis, and their cumulus cells showed a loss of luteinizing hormone (LH receptor expression, which leads to failure during final maturation and ovulation. In vitro maturation to rescue oocytes in a cisplatin-treated mouse model resulted in successful maturation and fertilization. This study is the first to show the involvement of the PTEN/Akt/FOXO3 pathway in premature ovarian failure after cisplatin treatment and the possibility of rescue through in vitro maturation.

  4. Bradykinin receptor blockade restores the baroreflex control of renal sympathetic nerve activity in cisplatin-induced renal failure rats.

    Science.gov (United States)

    Abdulla, M H; Duff, M; Swanton, H; Johns, E J

    2016-11-01

    This study investigated the effect of renal bradykinin B1 and B2 receptor blockade on the high- and low-pressure baroreceptor reflex regulation of renal sympathetic nerve activity (RSNA) in rats with cisplatin-induced renal failure. Cisplatin (5 mg/kg) or saline was given intraperitoneally 4 days prior to study. Following chloralose/urethane anaesthesia, rats were prepared for measurement of mean arterial pressure (MAP), heart rate and RSNA and received intrarenal infusions of either Lys-[des-Arg9 , Leu8 ]-bradykinin (LBK), a bradykinin B1 receptor blocker, or bradyzide (BZ), a bradykinin B2 receptor blocker. RSNA baroreflex gain curves and renal sympatho-inhibitory responses to volume expansion (VE) were obtained. In the control and renal failure groups, basal MAP (89 ± 3 vs. 80 ± 8 mmHg) and RSNA (2.0 ± 0.3 vs. 1.7 ± 0.6 μV.s) were similar but HR was lower in the latter group (331 ± 8 vs. 396 ± 9 beats/min). The baroreflex gain for RSNA in the renal failure rats was 39% (P renal failure rats. Intrarenal LBK infusion in the renal failure rats normalized the VE induced renal sympatho-inhibition whereas BZ only partially restored the response. These findings suggest that pro-inflammatory bradykinin acting at different receptors within the kidney generates afferent neural signals which impact differentially within the central nervous system on high- and low-pressure regulation of RSNA. © 2016 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.

  5. Role of high-frequency audiometry in the early detection of ototoxicity. II. Clinical Aspects

    NARCIS (Netherlands)

    Dreschler, W. A.; van der Hulst, R. J.; Tange, R. A.; Urbanus, N. A.

    1989-01-01

    As a supplement to a previous paper [Dreschler et al.: Audiology 1985; 24:387-395] high-frequency (HF) audiometry was applied to compare the ototoxic effects of two different drug administration protocols for cis-platinum (CDDP). In both subgroups, HF audiometry considerably enhanced the early

  6. Drug-related nephrotoxic and ototoxic reactions : a link through a predictive mechanistic commonality

    NARCIS (Netherlands)

    Verdel, Bertha Maria; van Puijenbroek, Eugène P; Souverein, Patrick C; Leufkens, Hubert G M; Egberts, Antoine C G

    2008-01-01

    BACKGROUND: Drug-induced ototoxicity is a subject of interest because many diseases are treated with drugs that have potential toxic effects on the ear. There is evidence that both inner ear and kidney tissue are immunologically, biochemically and functionally related. It has been suggested that

  7. Potentiation of Chemical Ototoxicity by Noise

    OpenAIRE

    Steyger, Peter S.

    2009-01-01

    High-intensity and/or prolonged exposure to noise causes temporary or permanent threshold shifts in auditory perception. Occupational exposure to solvents or administration of clinically important drugs, such as aminoglycoside antibiotics and cisplatin, also can induce permanent hearing loss. The mechanisms by which these ototoxic insults cause auditory dysfunction are still being unraveled, yet they share common sequelae, particularly generation of reactive oxygen species, that ultimately le...

  8. Chemical Ototoxicity of the Fish Inner Ear and Lateral Line.

    Science.gov (United States)

    Coffin, Allison B; Ramcharitar, John

    2016-01-01

    Hair cell-driven mechanosensory systems are crucial for successful execution of a number of behaviors in fishes, and have emerged as good models for exploring questions relevant to human hearing. This review focuses on ototoxic effects in the inner ear and lateral line system of fishes. We specifically examine studies where chemical ototoxins such as aminoglycoside antibiotics have been employed as tools to disable the lateral line. Lateral line ablation results in alterations to feeding behavior and orientation to water current in a variety of species. However, neither behavior is abolished in the presence of additional sensory cues, supporting the hypothesis that many fish behaviors are driven by multisensory integration. Within biomedical research, the larval zebrafish lateral line has become an important model system for understanding signaling mechanisms that contribute to hair cell death and for developing novel pharmacological therapies that protect hair cells from ototoxic damage. Furthermore, given that fishes robustly regenerate damaged hair cells, ototoxin studies in fishes have broadened our understanding of the molecular and genetic events in an innately regenerative system, offering potential targets for mammalian hair cell regeneration. Collectively, studies of fish mechanosensory systems have yielded insight into fish behavior and in mechanisms of hair cell death, protection, and regeneration.

  9. Dynamic Editome of Zebrafish under Aminoglycosides Treatment and Its Potential Involvement in Ototoxicity

    Directory of Open Access Journals (Sweden)

    Sijia Yan

    2017-11-01

    Full Text Available RNA editing is an important co- and post-transcriptional event that generates RNA and protein diversity. Aminoglycosides are a group of bactericidal antibiotics and a mainstay of antimicrobial therapy for several life-threatening infections. However, aminoglycosides can induce ototoxicity, resulting in damage to the organs responsible for hearing and balance. At low concentrations, aminoglycosides can bind to many RNA sequences and critically influence RNA editing. We used a bioinformatics approach to investigate the effect of aminoglycosides on global mRNA editing events to gain insight into the interactions between mRNA editing and aminoglycoside ototoxicity. We identified 6,850 mRNA editing sites in protein coding genes in embryonic zebrafish, and in about 10% of these, the degree of RNA editing changed more than 15% under aminoglycosides treatment. Twelve ear-development or ototoxicity related genes, including plekhm1, fgfr1a, sox9a, and calrl2, exhibited remarkable changes in mRNA editing levels in zebrafish treated with aminoglycosides. Our results indicate that aminoglycosides may have a widespread and complicated influence on the progress of mRNA editing and expression. Furthermore, these results highlight the potential importance of mRNA editing in the pathogenesis and etiology of aminoglycoside-induced ototoxicity.

  10. In-depth Identification of Pathways Related to Cisplatin-induced Hepatotoxicity through an Integrative Method Based on an Informatics-assisted Label-free Protein Quantitation and Microarray Gene Expression Approach*

    Science.gov (United States)

    Cho, Young-Eun; Singh, Thoudam S. K.; Lee, Hyun-Chul; Moon, Pyong-Gon; Lee, Jeong-Eun; Lee, Myung-Hoon; Choi, Eung-Chil; Chen, Yu-Ju; Kim, Sang-Hyun; Baek, Moon-Chang

    2012-01-01

    Cisplatin is used widely for treatment of a variety of cancer diseases. Recently, however, the use of cisplatin is restricted because of its adverse effects such as hepatotoxicity. There is no study with current proteomics technology to evaluate cisplatin-induced hepatotoxicity, even if some studies have reported on the hepatotoxicity. In this study, proteomic as well as genomic analyses have been used for identification of proteins and genes that respond to cisplatin treatment in rat primary hepatocytes. To investigate the hepatotoxic effects of cisplatin, rat primary hepatocytes were treated with an IC20 concentration for 24 h. From proteomic analysis based on label-free quantitation strategy, cisplatin induced 76 up-regulated and 19 down-regulated proteins among 325 distinct proteins. In the mRNA level, genomic analysis revealed 72 up-regulated and 385 down-regulated genes in the cisplatin-treated group. Based on these two analyses, 19 pathways were commonly altered, whereas seven pathways were identified only by proteomic analysis, and 19 pathways were identified only by genomic analysis. Overall, this study explained the mechanism of cisplatin-induced hepatotoxicity with two points of view: well known pathways including drug metabolism, fatty acid metabolism, and glycolysis/TCA cycle and little known pathways including urea cycle and inflammation metabolism, for hepatotoxicity of other toxic agents. Up-regulated proteins detected by proteomic analysis in the cisplatin-treated group: FBP1 (fructose 1,6-bisphosphatase 1), FASN (fatty acid synthase), CAT (catalase), PRDX1 (peroxiredoxin-1), HSPD1 (60-kDa heat shock protein), MDH2 (malate dehydrogenase 2), and ARG1 (arginase 1), and also down-regulated proteins in the cisplatin-treated group: TPM1 (tropomyosin 1), TPM3 (tropomyosin 3), and CTSB (cathepsin B), were confirmed by Western blot analysis. In addition, up-regulated mRNAs detected by microarray analysis in the cisplatin-treated group: GSTA2, GSTT2, YC2

  11. Repair capacity for platinum-DNA adducts determines the severity of cisplatin-induced peripheral neuropathy.

    Science.gov (United States)

    Dzagnidze, Anna; Katsarava, Zaza; Makhalova, Julia; Liedert, Bernd; Yoon, Min-Suk; Kaube, Holger; Limmroth, Volker; Thomale, Juergen

    2007-08-29

    The pronounced neurotoxicity of the potent antitumor drug cisplatin frequently results in the onset of peripheral polyneuropathy (PNP), which is assumed to be initially triggered by platination products in the nuclear DNA of affected tissues. To further elucidate the molecular mechanisms, we analyzed in a mouse model the formation and processing of the main cisplatin-induced DNA adduct (guanine-guanine intrastrand cross-link) in distinct neuronal cell types by adduct-specific monoclonal antibodies. Comparison of the adduct kinetics in cisplatin-injected mice either proficient or deficient for nucleotide excision repair (NER) functions revealed the essential role of this DNA repair pathway in protecting differentiated cells of the nervous system from excessive formation of such lesions. Hence, chronic exposure to cisplatin resulted in an accelerated accumulation of unrepaired intrastrand cross-links in neuronal cells of mice with dysfunctional NER. The augmented adduct levels in dorsal root ganglion (DRG) cells of those animals coincided with an earlier onset of PNP-like functional disturbance of their sensory nervous system. Independently from the respective repair phenotype, the amount of persisting DNA cross-links in DRG neurons at a given cumulative dose was significantly correlated to the degree of sensory impairment as measured by electroneurography. Collectively, these findings suggest a new model for the processing of cisplatin adducts in primary neuronal cells and accentuate the crucial role of effectual DNA repair capacity in the target cells for the individual risk of therapy-induced PNP.

  12. Potential chemoprotective role of resveratrol against cisplatin induced testicular damage in mice.

    Science.gov (United States)

    Singh, Inderjeet; Goyal, Yasmeen; Ranawat, Pavitra

    2017-08-01

    Semen banking is often advised to male patients undergoing chemotherapy as the damage induced is profound and often irreversible. However, low success rates of assisted reproductive techniques (ART) using banked semen have led to the quest for alternative methods to treat chemotherapy-induced infertility. The present study therefore aimed to study the role of resveratrol against cisplatin induced testicular damage. Male albino mice were divided into five groups (n = 6 each), viz. normal control, resveratrol vehicle (4% ethanol), Cisplatin (7.5 mg/kg b.wt/week for 4 weeks), Resveratrol (1 mg/kg b.wt./orally for 28 days) and Resveratrol and Cisplatin combination group. Cisplatin treatment led to an increase in the activity of lactate dehydrogenase and an increase in the levels of lipid peroxidation. Glutathione levels were found to decrease with a concomitant increase in the levels of oxidized glutathione and altered status of antioxidant enzymes. Increased DNA fragmentation was also evident which was further confirmed by histopathological and FT-IR analysis. Resveratrol treatment in combination with cisplatin showed great promise in bringing down the damage statistics to near normal values in most of the parameters studied. Further studies in this direction are however needed to develop an alternative to current procedures adopted to treat chemotherapy-induced male infertility. Copyright © 2017 Elsevier B.V. All rights reserved.

  13. Systemic ototoxicity: a review | Shine | East African Medical Journal

    African Journals Online (AJOL)

    Objectives: To review the literature pertaining to the ototoxic potential of three frequently prescribed systemic medications in the sub-Saharan setting; quinine, furosemide and aminoglycoside antibiotics. The pathophysiology, clinical manifestations and risk factors and risk minimisation strategies regarding the ototoxicity ...

  14. Prevalence of ototoxicity in University of Benin Teaching Hospital ...

    African Journals Online (AJOL)

    Background: Ototoxicity refers to damage of the cochlea and/or vestibular apparatus from exposure to chemical substances, resulting in hearing impairment and or disequilibrium. An earlier study carried out at University of Benin Teaching Hospital (UBTH) in 2000 implicated chloramphenicol as the commonest ototoxic drug ...

  15. The importance of high-tone audiometry in monitoring for ototoxicity

    NARCIS (Netherlands)

    Tange, R. A.; Dreschler, W. A.; van der Hulst, R. J.

    1985-01-01

    Early detection of ototoxicity is of vital importance in cases in which ototoxic drugs are administered. Ototoxicity as a result of cis-platinum administration is well documented. Auditory damage may be reduced by changes in dose, drugs or methods of treatment. As ototoxicity appears to be most

  16. Ototoxicity of boric acid powder in a rat animal model.

    Science.gov (United States)

    Salihoglu, Murat; Dogru, Salim; Cesmeci, Enver; Caliskan, Halil; Kurt, Onuralp; Kuçukodaci, Zafer; Gungor, Atila

    2017-04-22

    Boric acid, which has antiseptic and acidic properties, is used to treat external and middle ear infections. However, we have not found any literature about the effect of boric acid powder on middle ear mucosa and inner ear. The purpose of this study is to investigate possible ototoxic effects of boric acid powder (BAP) on cochlear outer hair cell function and histological changes in middle ear mucosa in a rat animal model. Twenty healthy, mature Wistar albino rats were used in this study. The rats were divided into two groups, Group A and Group B, each of which consisted of 10 rats. Initially, the animals in each group underwent distortion product otoacoustic emissions (DPOAE) testing of their right and left ears. After the first DPOAE test, a surgical microscope was used to make a small perforation in both ears of the rats in each group, and a second DPOAE test was used to measure both ears in all of the rats. BAP was applied to the right middle ear of the rats using tympanic membrane perforation, and the DPOAEs were measured immediately after the BAP application. The histological changes and DPOAEs were evaluated three days later in Group A and 40 days later in Group B. No significant differences were found at all of the DPOAE frequencies. In Group A, mild inflammation of the middle ear mucosa was found on the third day after BAP application. In Group B, BAP caused mild inflammatory changes on the 40th day, which declined over time. Those changes did not lead to significant fibrosis within the mucosa. In rats, BAP causes mild inflammation in middle ear mucosa and it has no ototoxic effects on cochlear outer hair cell function in the inner ear of rats. Copyright © 2017 Associação Brasileira de Otorrinolaringologia e Cirurgia Cérvico-Facial. Published by Elsevier Editora Ltda. All rights reserved.

  17. Galangin ameliorates cisplatin induced nephrotoxicity in vivo by modulation of oxidative stress, apoptosis and inflammation through interplay of MAPK signaling cascade.

    Science.gov (United States)

    Tomar, Ameesha; Vasisth, Swati; Khan, Sana Irfan; Malik, Salma; Nag, Tapas Chandra; Arya, Dharamveer Singh; Bhatia, Jagriti

    2017-10-15

    Cisplatin is a widely used chemotherapeutic agent but now-a-days its usage is limited in clinical chemotherapy because of its severe nephrotoxic effect on renal tissues. Galangin, a flavonoid obtained from ginger family has been demonstrated to have antioxidant, anti-apoptotic and anti-inflammatory properties. This study is aimed to investigate the possible ameliorative effect of galangin in a rodent model of cisplatin-induced nephrotoxicity. Adult male albino wistar rats were divided into six groups (n=6) viz normal, cisplatin-control, galangin (25, 50 and 100mg/kg p.o.) and per se (100mg/kg galangin, p.o.). Galangin was administrated orally to the rats for a period of 10 days. On the 7th day of the treatment, nephrotoxicity was induced in all the groups by a single dose of cisplatin (8mg/kg, i.p.) (except normal and per se group). On the 11th day, the rats were anaesthetized and blood was withdrawn via direct heart puncture for biochemical estimation. Rats were sacrificed and kidneys were isolated and preserved for evaluation of histopathological, ultra structural immunohistochemical studies and western blot analysis. Cisplatin significantly impaired renal function and increased oxidative stress and inflammation. It also increased expression of pro-apoptotic proteins Bax and caspase-3 and decreased the expression of the anti-apoptotic protein Bcl-2. Histological and ultrastructural findings were also supportive of renal tubular damage. Pretreatment with galangin (100mg/kg p.o.) preserved renal function, morphology, suppressed oxidative stress, inflammation and the activation of apoptotic pathways. TUNEL assay showed decreased DNA fragmentation on galangin pre-treatment. Furthermore, galangin (100mg/kg) pre-treatment also reduced the expression of NFκB along with proteins MAPK pathway i.e. p38, JNK and ERK1/2. In conclusion, Galangin (100mg/kg, p.o.) significantly ameliorated cisplatin induced nephrotoxicity by suppressing MAPK induced inflammation and apoptosis

  18. Cisplatin-induced haemolytic uraemic syndrome associated with a novel intronic mutation of CD46 treated with eculizumab.

    Science.gov (United States)

    Gilbert, Rodney D; Stanley, Louise K; Fowler, Darren J; Angus, Elizabeth M; Hardy, Steven A; Goodship, Timothy H

    2013-08-01

    A 2-year-old patient with a neuroblastoma developed haemolytic uraemic syndrome (HUS) following treatment with cisplatin and carboplatin. Following treatment with eculizumab, there was a substantial improvement in renal function with the recovery of the platelet count and the cessation of haemolysis. Subsequent investigations showed a novel, heterozygous CD46 splice site mutation with reduced peripheral blood neutrophil CD46 expression. Withdrawal of eculizumab was followed by the recurrence of disease activity, which resolved with re-introduction of therapy. Abnormal regulation of complement may be associated with other cases of cisplatin-induced HUS and treatment with eculizumab may be appropriate for other affected individuals.

  19. Study of Methylene Blue Ototoxicity in the Guinea Pig.

    Science.gov (United States)

    Belhassen, Sarah; Alzahrani, Musaed; Nader, Marc-Elie; Gaboury, Louis; Saliba, Issam

    2017-11-01

    Methylene blue is widely used in the medical field, especially as a blue dye for staining. It is also used as a photosensitizing agent in antimicrobial photodynamic therapy, which once photoactivated is effective for the eradication of several multi-resistant bacteria. The objective of this study was to investigate the ototoxic potential of methylene blue and precise its use in otology. It was a prospective animal study performed on guinea pigs in our tertiary medical center. We divided the animals into two groups: an experimental group and a control group, who underwent a series of three intratympanic (IT) injections. In the control group (n = 10), they received injections of gentamicin in one ear (positive control) and normal saline in the contralateral ear (negative control). The experimental group (n = 10) received injections of methylene blue in one ear, compared to injections of normal saline in the contralateral ear. We conducted auditory-evoked brainstem response (ABR) before and 1 week after the injection series. Once this is completed, the cochlea was dissected and caspase-3 was analyzed by immunohistochemistry. The mean difference of hearing loss in the methylene blue group compared to normal saline was 1.50 dB, and it was not shown to be statistically significant (P = 0.688). For the positive control group, which received IT injections of gentamicin, the mean threshold of hearing loss difference for all the frequencies combined was 66.25 dB (P methylene blue. In light of our results, IT injections of methylene blue did not demonstrate an ototoxic potential. We recommend further studies to precise its use in the otologic field.

  20. Growth hormone secretagogues hexarelin and JMV2894 protect skeletal muscle from mitochondrial damages in a rat model of cisplatin-induced cachexia.

    Science.gov (United States)

    Sirago, Giuseppe; Conte, Elena; Fracasso, Flavio; Cormio, Antonella; Fehrentz, Jean-Alain; Martinez, Jean; Musicco, Clara; Camerino, Giulia Maria; Fonzino, Adriano; Rizzi, Laura; Torsello, Antonio; Lezza, Angela Maria Serena; Liantonio, Antonella; Cantatore, Palmiro; Pesce, Vito

    2017-10-12

    Chemotherapy can cause cachexia, which consists of weight loss associated with muscle atrophy. The exact mechanisms underlying this skeletal muscle toxicity are largely unknown and co-therapies to attenuate chemotherapy-induced side effects are lacking. By using a rat model of cisplatin-induced cachexia, we here characterized the mitochondrial homeostasis in tibialis anterior cachectic muscle and evaluated the potential beneficial effects of the growth hormone secretagogues (GHS) hexarelin and JMV2894 in this setting. We found that cisplatin treatment caused a decrease in mitochondrial biogenesis (PGC-1α, NRF-1, TFAM, mtDNA, ND1), mitochondrial mass (Porin and Citrate synthase activity) and fusion index (MFN2, Drp1), together with changes in the expression of autophagy-related genes (AKT/FoxO pathway, Atg1, Beclin1, LC3AII, p62) and enhanced ROS production (PRX III, MnSOD). Importantly, JMV2894 and hexarelin are capable to antagonize this chemotherapy-induced mitochondrial dysfunction. Thus, our findings reveal a key-role played by mitochondria in the mechanism responsible for GHS beneficial effects in skeletal muscle, strongly indicating that targeting mitochondrial dysfunction might be a promising area of research in developing therapeutic strategies to prevent or limit muscle wasting in cachexia.

  1. FIRST REPORT ON OTOTOXICITY OF MEGLUMINE ANTIMONIATE

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    Cláudia Maria Valete-Rosalino

    2014-09-01

    Full Text Available Introduction: Pentavalent antimonials are the first drug of choice in the treatment of tegumentary leishmaniasis. Data on ototoxicity related with such drugs is scarcely available in literature, leading us to develop a study on cochleovestibular functions. Case Report: A case of a tegumentary leishmaniasis patient, a 78-year-old man who presented a substantial increase in auditory threshold with tinnitus and severe rotatory dizziness during the treatment with meglumine antimoniate, is reported. These symptoms worsened in two weeks after treatment was interrupted. Conclusion: Dizziness and tinnitus had already been related to meglumine antimoniate. However, this is the first well documented case of cochlear-vestibular toxicity related to meglumine antimoniate.

  2. Pre-stimulation of the kallikrein system in cisplatin-induced acute renal injury: An approach to renoprotection

    Energy Technology Data Exchange (ETDEWEB)

    Aburto, Andrés [Program of M.Sc., Faculty of Medicine, Universidad Austral de Chile, Valdivia (Chile); Barría, Agustín [School of Biochemistry, Faculty of Sciences, Universidad Austral de Chile, Valdivia (Chile); Cárdenas, Areli [Ph.D. Program, Faculty of Sciences, Universidad Austral de Chile, Valdivia (Chile); Carpio, Daniel; Figueroa, Carlos D. [Department of Anatomy, Histology and Pathology, Universidad Austral de Chile, Valdivia (Chile); Burgos, Maria E. [Department of Nephrology, Faculty of Medicine, Universidad Austral de Chile, Valdivia (Chile); Ardiles, Leopoldo, E-mail: leopoldoardiles@gmail.com [Department of Nephrology, Faculty of Medicine, Universidad Austral de Chile, Valdivia (Chile)

    2014-10-15

    Antineoplastic treatment with cisplatin is frequently complicated by nephrotoxicity. Although oxidative stress may be involved, the pathogenic mechanisms responsible for renal damage have not been completely clarified. In order to investigate the role of the renal kinin system in this condition, a group of rats was submitted to high potassium diet to stimulate the synthesis and excretion of tissue kallikrein 1 (rKLK1) previous to an intraperitoneal injection of 7 mg/kg cisplatin. A significant reduction in lipoperoxidation, evidenced by urinary excretion of malondialdehyde and renal immunostaining of hidroxy-nonenal, was accompanied by a decline in apoptosis. Coincident with these findings we observed a reduction in the expression of renal KIM-1 suggesting that renoprotection may be occurring. Stimulation or indemnity of the renal kinin system deserves to be evaluated as a complementary pharmacological measure to diminish cisplatin nephrotoxicity. - Highlights: • Mechanisms of cisplatin-induced-renal damage have not been completely clarified. • Cisplatin induces oxidative stress and apoptosis. • The renal kallikrein-kinin system is protective in experimental acute renal damage. • Kallikrein stimulation reduces oxidative stress and apoptosis induced by cisplatin. • Protection of the kallikrein-kinin system may reduce cisplatin toxicity.

  3. N-Acetylcysteine in the prevention of ototoxicity

    DEFF Research Database (Denmark)

    Tepel, Martin

    2007-01-01

    Prevention of ototoxicity after the administration of aminoglycoside antibiotics has been notably difficult, in particular in patients with chronic kidney disease. Feldman et al. report that oral administration of 600 mg N-acetylcysteine twice daily significantly ameliorates gentamicin-induced ot......-induced ototoxicity in hemodialysis patients. That approach may help to prevent aminoglycoside-induced hearing loss in these high-risk patients in daily practice....

  4. Preventing Ototoxic Synergy of Prior Noise Trauma During Aminoglycoside Therapy

    Science.gov (United States)

    2015-12-01

    Johns Hopkins University. 212 p (2007). 9. Liao S, et al. Noise Exposure in the Neonatal Intensive Care Unit : A Prospective Study. American Academy...AD_________________ Award Number: W81XWH-14-1-0006 TITLE: Preventing Ototoxic Synergy Of Prior Noise Trauma During Aminoglycoside Therapy ...Dec 2014 - 30 Nov 2015 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Preventing Ototoxic Synergy Of Prior Noise Trauma During Aminoglycoside Therapy

  5. Amelioration of cisplatin-induced nephrotoxicity by grape seed extract and fish oil is mediated by lowering oxidative stress and DNA damage.

    Science.gov (United States)

    Hassan, Hanaa A; Edrees, Gamal M; El-Gamel, Ezz M; El-Sayed, Elsamra A

    2014-05-01

    Cisplatin (CP) is a chemotherapeutic drug used in treatment of malignancies. However, its clinical utility is limited by nephrotoxicity. The purpose of the present study was to investigate the protective role of grape seed proanthocyanidin extract (GSPE) (100 mg/kg/day) or fish oil (FO) (5 ml/kg/day) against cisplatin induced nephrotoxicity in terms of biochemical parameters, oxidative stress and DNA damage. CP nephrotoxiciy is manifested by increased levels of serum creatinine, urea and uric acid, accompanied by their decrease in urine. Na, K and Ca levels were altered in both serum and urine. In addition, cisplatin caused a decrease in renal GSH, SH-group, SOD, GST, and Na-K-ATPase levels. However the levels of MDA, H2O2 and NO were increased. Also, we assessed the renal genotoxic potential of cisplatin as manifested by an increase in the tail length of DNA, tail intensity (DNA %) and tail moment. On the other hand, administration of GSPE or FO pre-cisplatin treatment ameliorated the current changes in most of the above tested parameters, particularly oxidative stress, endogenous antioxidant defense system and DNA damage indicating their curative effect. Thus, it can be concluded that the consumption of GSPE or FO might be useful for preventing nephrotoxicity caused by cisplatin treatment.

  6. Coenzyme Q10 plus Multivitamin Treatment Prevents Cisplatin Ototoxicity in Rats.

    Directory of Open Access Journals (Sweden)

    Laura Astolfi

    Full Text Available Cisplatin (Cpt is known to induce a high level of oxidative stress, resulting in an increase of reactive oxygen species damaging the inner ear and causing hearing loss at high frequencies. Studies on animal models show that antioxidants may lower Cpt-induced ototoxicity. The aim of this study is to evaluate the ototoxic effects of two different protocols of Cpt administration in a Sprague-Dawley rat model, and to test in the same model the synergic protective effects of a solution of coenzyme Q10 terclatrate and Acuval 400®, a multivitamin supplement containing antioxidant agents and minerals (Acu-Qter. The Cpt was administered intraperitoneally in a single dose (14 mg/kg or in three daily doses (4.6 mg/kg/day to rats orally treated or untreated with Acu-Qter for 5 days. The auditory function was assessed by measuring auditory brainstem responses from 2 to 32 kHz at day 0 and 5 days after treatment. Similar hearing threshold and body weight alterations were observed in both Cpt administration protocols, but mortality reduced to zero when Cpt was administered in three daily doses. The Acu-Qter treatment was able to prevent and completely neutralize ototoxicity in rats treated with three daily Cpt doses, supporting the synergic protective effects of coenzyme Q terclatrate and Acuval 400® against Cpt-induced oxidative stress. The administration protocol involving three Cpt doses is more similar to common human chemotherapy protocols, therefore it appears more useful for long-term preclinical studies on ototoxicity prevention.

  7. Antioxidant treatment with coenzyme Q-ter in prevention of gentamycin ototoxicity in an animal model.

    Science.gov (United States)

    Fetoni, A R; Eramo, S L M; Rolesi, R; Troiani, D; Paludetti, G

    2012-04-01

    Aminoglycosides, such as gentamycin, are well known ototoxic agents. Toxicity occurs via an activation process involving the formation of an iron-gentamycin complex with free radical production. Antioxidants like Q-ter (a soluble formulation of coenzyme Q(10), CoQ(10)), can limit or prevent cellular ototoxic damage. The present study was designed to investigate the possible protective effects of Q-ter on gentamycin ototoxicity in albino guinea pigs (250-300 g). Animals were divided into five experimental groups: I, a sham control group given an intra-peritoneal (I.P.) injection of 0.5 ml saline (SHAM); II, gentamycin group (GM), treated with an injection of gentamycin (100 mg/ kg); III, gentamycin + Q-ter group (GM+Q-ter), treated with gentamycin (same dose as group II) and an I.P. injection of coenzyme Q(10) terclatrate (Q-ter) at 100 mg/kg body weight; IV, injected with gentamycin (100 mg/kg) plus saline; V, treated with Q-ter alone (100 mg/ kg). All animals were treated for 14 consecutive days. Auditory function was evaluated by recording auditory brainstem responses (ABR) at 15 and 30 days from the beginning of treatment. Morphological changes were analyzed by rhodamine-phalloidine staining. Gentamycin-induced progressive high-frequency hearing loss of 45-55 dB SPL. Q-ter therapy slowed and attenuated the progression of hearing loss, yielding a threshold shift of 20 dB. The significant loss of outer hair cells (OHCs) in the cochlear medio-basal turn in gentamycin-treated animals was not observed in the cochleae of animals protected with Q-ter. This study supports the hypothesis that Q-ter interferes with gentamycin-induced free radical formation, and suggests that it may be useful in protecting OHC function from aminoglycoside ototoxicity, thus reducing hearing loss.

  8. FGF22 protects hearing function from gentamycin ototoxicity by maintaining ribbon synapse number.

    Science.gov (United States)

    Li, Shuna; Hang, Lihua; Ma, Yongming

    2016-02-01

    Inner hair cell (IHC) ribbon synapses of cochlea play important role in transmitting sound signal into auditory nerve and are sensitive to ototoxicity. However, ototoxic damage of ribbon synapses is not understood clearly. Roles of fibroblast growth factor 22 (FGF22) on synapse formation were explored under gentamycin ototoxicity. 6-week-old mice were injected intraperitoneally once daily with 50-150 mg/kg gentamicin for 10 days. Immunostaining with anti- GluR2&3/CtBP2 was used to estimate the number of ribbon synapses in the cochlea. Expression of FGF22 and myocyte enhancer factor 2D (MEF2D) was assayed with RT-PCR. Expression and localization of FGF22 protein were visualized with anti-FGF22 immunostaining. Hearing thresholds were assessed using auditory brainstem responses. Gentamicin administration caused reduction in ribbon synapse number and hearing impairment without effect on hair cells in CBA/J mouse model. Immunohistochemistry showed that FGF22 protein was expressed in IHCs, but not OHCs of cochlea. Gentamycin attenuated expression of FGF22 but enhanced expression of MEF2D. Cochlear infusion of recombinant FGF22 inhibited expression of MEF2D, preserved ribbon synapses, and restored hearing function impaired by gentamycin. FGF22 restores hearing loss through maintaining ribbon synapse number, likely via inhibition of MEF2D. Activating FGF22 might provide the conceptual basis for the therapeutic strategies. Copyright © 2015 Elsevier B.V. All rights reserved.

  9. The synthesis, structure-toxicity relationship of cisplatin derivatives for the mechanism research of cisplatin-induced nephrotoxicity.

    Science.gov (United States)

    Hu, Jing; Wu, Tian-Ming; Li, Hong-Ze; Zuo, Ze-Ping; Zhao, Ying-Lan; Yang, Li

    2017-08-01

    Cisplatin is a widely used antineoplastic drug, while its nephrotoxicity limits the clinical application. Although several mechanisms contributing to nephrotoxicity have been reported, the direct protein targets are unclear. Herein we reported the synthesis of 29 cisplatin derivatives and the structure-toxicity relationship (STR) of these compounds with MTT assay in human renal proximal tubule cells (HK-2) and pig kidney epithelial cells (LLC-PK1). To the best of our knowledge, this study represented the first report regarding the structure-toxicity relationship (STR) of cisplatin derivatives. The potency of biotin-pyridine conjugated derivative 3 met the requirement for target identification, and the preliminary chemical proteomics results suggested that it is a promising tool for further target identification of cisplatin-induced nephrotoxicity. Copyright © 2017. Published by Elsevier Ltd.

  10. Short hydration regimen with magnesium supplementation prevents cisplatin-induced nephrotoxicity in lung cancer: a retrospective analysis.

    Science.gov (United States)

    Yamaguchi, Teppei; Uozu, Sakurako; Isogai, Sumito; Hayashi, Masamichi; Goto, Yasuhiro; Nakanishi, Toru; Imaizumi, Kazuyoshi

    2017-04-01

    The purpose of this study was to evaluate renal function in lung cancer patients who were administered cisplatin with continuous higher-volume hydration (CH) or a short hydration (SH) regimen. We retrospectively evaluated patients with lung cancer who were treated with chemotherapy regimens including >50 mg/m2 of cisplatin between August 2007 and March 2015. Between August 2007 and December 2012, patients received a continuous higher-volume hydration regimen without magnesium (Mg) supplementation (CH group), and after May 2013, patients received a short hydration regimen with Mg supplementation (SH group). To evaluate the factors influencing serum creatinine (SCr) increase during the first course of cisplatin chemotherapy, univariate and multivariate logistic regression analyses were conducted. A total of 122 patients were evaluated, 62 patients in the CH group and 60 patients in the SH group. Grade 1 (National Cancer Institute Common Toxicity Criteria for Adverse Events; version 4.0) or higher SCr increases were more frequently observed in the CH group than in the SH group after the first cycle (P = 0.01, Fisher's exact test) and for all cycles (P = 0.03). Multivariate analysis revealed that short hydration (odds ratio (OR), 0.30; 95% confidence internal (CI) (0.11-0.75), P = 0.01) and estimated creatinine clearance (eCcr) of ≥70 mL/min (OR, 0.25; 95% CI (0.088-0.69), P = 0.008) were associated with a significantly reduced risk for cisplatin-induced grade 1 or higher SCr increase. Our study suggested that a short hydration method with Mg supplementation and eCcr of ≥70 mL/min reduced the risk of cisplatin-induced nephrotoxicity.

  11. Protective efficacy of antioxidants on cisplatin-induced tissue damage caused in Leishmania donovani infected BALB/c mice against murine visceral leishmaniasis

    Directory of Open Access Journals (Sweden)

    Meenakshi Sharma

    2013-06-01

    Full Text Available Objective: Therapeutic interventions against visceral leishmaniasis (VL are limited and facing serious concerns of toxicity, high cost and emerging resistance, there is a greater interest in new drug developments which are cost effective, efficient and easily available to people suffering from leishmaniasis. Cisplatin (cis-diamminedichloroplatinum II; CDDP has been found to have antileishmanial activity in vitro and in vivo which lead towards an apoptosis like cell death of both promastigotes and amastigotes and a significant reduction in parasite load and enhanced DTH responses which suggested the generation of protective cell-mediated immune responses. But, at higher doses it causes nephrotoxicity-a major side effect. The present study was designed to evaluate the protective efficacy of antioxidants on cisplatin induced tissue damage in Leishmania donovani infected BALB/c mice. Materials and methods: L. donovani infected and uninfected animals were treated with higher doses (5 and 2.5 mg/kg body weight of cisplatin alone and in combination with antioxidants (vitamin C, vitamin E and silibinin for 5 days. Mice were examined for the protective effects of antioxidants on cisplatin indiced tissue damage by DNA fragmentation and histological studies of kidneys, liver and spleen. Results: The damage caused by cisplatin was ameliorated after the supplementation of antioxidants showing a marked reduction in the extent of tubular damage, the focal reaction changes in liver were reversed and no signs of toxicity in the spleen were reported. Moreover, no DNA damage was observed in animals treated with cisplatin along with various antioxidants. Conclusion: The present results showed that antioxidants helped in the amelioration of drug induced toxic effects against murine visceral leishmaniasis, making the combination a potential anti-leishmanial therapy. [J Interdiscipl Histopathol 2013; 1(3.000: 121-136

  12. Cisplatin-induced neuropathic pain is mediated by upregulation of N-type voltage-gated calcium channels in dorsal root ganglion neurons.

    Science.gov (United States)

    Leo, Markus; Schmitt, Linda-Isabell; Erkel, Martin; Melnikova, Margarita; Thomale, Jürgen; Hagenacker, Tim

    2017-02-01

    Cisplatin is important in the treatment of various types of cancer. Although it is highly effective, it also has severe side effects, with neurotoxicity in dorsal root ganglion (DRG) neurons being one of the most common. The key mechanisms of neurotoxicity are still controversially discussed; however, disturbances of the calcium homeostasis in DRG neurons have been suggested to mediate cisplatin neurotoxicity. By using the whole-cell patch-clamp technique, immunostaining and behavioral experiments with Sprague-Dawley rats, we examined the influence of short- and long-term exposure to cisplatin on voltage-gated calcium channel (VGCC) currents (ICa(V)) in small DRG neurons. In vitro exposure to cisplatin reduced ICa(V) in a concentration-dependent manner (0.01-50μM; 13.8-77.3%; IC50 5.07μM). Subtype-specific measurements of VGCCs showed differential effects on ICa(V). While the ICa(V) of P/Q-, L- and T-type VGCCs were reduced, ICa(V) of N-type VGCCs were increased by 30.3% during depolarization to 0mV. Exposure of DRG neurons to cisplatin (0.5 or 5μM) for 24-48h in vitro significantly increased a CaMK II-mediated ICa(V) current density. Immunostaining and western blot analysis revealed an increase of N-type VGCC protein level in DRG neurons 24h after cisplatin exposure. Cisplatin-mediated activation of caspase-3 was prevented by inhibition of N-type VGCCs using Ɯ-conotoxin MVIIA. Behavioral experiments showed that Ɯ-conotoxin MVIIA treatment prevented neuropathic syndromes in vivo by inhibiting upregulation of the N-type protein level. Here we show evidence for the first time for a crucial role of N-type VGCC in the genesis of cisplatin-induced polyneuropathy. Copyright © 2016 Elsevier Inc. All rights reserved.

  13. Short-term exposure to 50 Hz ELF-EMF alters the cisplatin-induced oxidative response in AT478 murine squamous cell carcinoma cells.

    Science.gov (United States)

    Bułdak, Rafał Jakub; Polaniak, Renata; Bułdak, Lukasz; Zwirska-Korczala, Krystyna; Skonieczna, Magdalena; Monsiol, Aleksandra; Kukla, Michał; Duława-Bułdak, Anna; Birkner, Ewa

    2012-12-01

    The aim of this study was to assess the influence of cisplatin and an extremely low frequency electromagnetic field (ELF-EMF) on antioxidant enzyme activity and the lipid peroxidation ratio, as well as the level of DNA damage and reactive oxygen species (ROS) production in AT478 carcinoma cells. Cells were cultured for 24 and 72 h in culture medium with cisplatin. Additionally, the cells were irradiated with 50 Hz/1 mT ELF-EMF for 16 min using a solenoid as a source of the ELF-EMF. The amount of ROS, superoxide dismutase (SOD) isoenzyme activity, glutathione peroxidase (GSH-Px) activity, DNA damage, and malondialdehyde (MDA) levels were assessed. Cells that were exposed to cisplatin exhibited a significant increase in ROS and antioxidant enzyme activity. The addition of ELF-EMF exposure to cisplatin treatment resulted in decreased ROS levels and antioxidant enzyme activity. A significant reduction in MDA concentrations was observed in all of the study groups, with the greatest decrease associated with treatment by both cisplatin and ELF-EMF. Cisplatin induced the most severe DNA damage; however, when cells were also irradiated with ELF-EMF, less DNA damage occurred. Exposure to ELF-EMF alone resulted in an increase in DNA damage compared to control cells. ELF-EMF lessened the effects of oxidative stress and DNA damage that were induced by cisplatin; however, ELF-EMF alone was a mild oxidative stressor and DNA damage inducer. We speculate that ELF-EMF exerts differential effects depending on the exogenous conditions. This information may be of value for appraising the pathophysiologic consequences of exposure to ELF-EMF. Copyright © 2012 Wiley Periodicals, Inc.

  14. Changes in expression of renal Oat1, Oat3 and Mrp2 in cisplatin-induced acute renal failure after treatment of JBP485 in rats

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Tao, E-mail: liutaomedical@qq.com [Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, 9 West Section, Lvshun South Road, Lvshunkou District, Dalian 116044 (China); Meng, Qiang, E-mail: mengq531@yahoo.cn [Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, 9 West Section, Lvshun South Road, Lvshunkou District, Dalian 116044 (China); Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning, Dalian Medical University (China); Wang, Changyuan, E-mail: wangcyuan@163.com [Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, 9 West Section, Lvshun South Road, Lvshunkou District, Dalian 116044 (China); Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning, Dalian Medical University (China); Liu, Qi, E-mail: llaqii@yahoo.com.cn [Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, 9 West Section, Lvshun South Road, Lvshunkou District, Dalian 116044 (China); Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning, Dalian Medical University (China); Guo, Xinjin, E-mail: guo.xinjin@163.com [Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, 9 West Section, Lvshun South Road, Lvshunkou District, Dalian 116044 (China); Sun, Huijun, E-mail: sunhuijun@hotmail.com [Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, 9 West Section, Lvshun South Road, Lvshunkou District, Dalian 116044 (China); Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning, Dalian Medical University (China); Peng, Jinyong, E-mail: jinyongpeng2005@163.com [Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, 9 West Section, Lvshun South Road, Lvshunkou District, Dalian 116044 (China); Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning, Dalian Medical University (China); and others

    2012-11-01

    The purpose of this study is to investigate whether the effect of cyclo-trans-4-L-hydroxyprolyl-L-serine (JBP485) on acute renal failure (ARF) induced by cisplatin is related to change in expression of renal Oat1, Oat3 and Mrp2 in rats. JBP485 reduced creatinine, blood urea nitrogen (BUN) and indoxyl sulfate (IS) in plasma and malondialdehyde (MDA) in kidney, and recovered the glomerular filtration rate (GFR) and the activity of superoxide dismutase (SOD) in cisplatin-treated rats. The plasma concentration of PAH (para-aminohippurate) determined by LC–MS/MS was increased markedly after intravenous administration of cisplatin, whereas cumulative urinary excretion of PAH and the uptake of PAH in kidney slices were significantly decreased. qRT-PCR and Western-blot showed a decrease in mRNA and protein of Oat1 and Oat3, an increase in mRNA and protein of Mrp2 in cisplatin-treated rats, and an increase in IS (a uremic toxin) after co-treatment with JBP485. It indicated that JBP485 promoted urinary excretion of toxins by upregulating renal Mrp2. This therefore gives in part the explanation about the mechanism by which JBP485 improves ARF induced by cisplatin in rats. -- Highlights: ► Cisplatin induces acute renal failure (ARF). ► The expression of Oat1, Oat3 and Mrp2 were changed during ARF. ► The regulated expression of Oat1, Oat3 and Mrp2 is an adaptive protected response. ► JBP485 could facilitate the adaptive protective action.

  15. Effect of enalapril in cisplatin-induced nephrotoxicity in rats; gender-related difference

    Directory of Open Access Journals (Sweden)

    Zohreh Zamani

    2016-01-01

    Conclusion: Enalapril as an ACE inhibitor failed to ameliorate nephrotoxicity induced by CP in both male and female rats. In addition, enalapril aggravated CP-induced nephrotoxicity in female possibly due to gender-dependent RAS response.

  16. The effect of Hibiscus sabdariffa calyx extract on cisplatin-induced ...

    African Journals Online (AJOL)

    JTEkanem

    2008-12-14

    Dec 14, 2008 ... controls. Tissue damage was later assessed in sera by measuring the levels of alanine aminotransferase, aspartate aminotransferase, urea, and creatinine. Thiobarbituric acid reactive species, catalase, and reduced glutathione levels were also measured in the livers and kidneys. The results reveal that the ...

  17. Ototoxicity in the South African mining industry: a position paper

    CSIR Research Space (South Africa)

    Edwards, AL

    2013-02-01

    Full Text Available This position paper asserts that exposure to chemicals in certain occupations and work activities in the mining industry can lead to ototoxicity which accentuates the problem of noise-induced hearing loss (NIHL). Increased awareness of all factors...

  18. Prevalence of ototoxicity in University of Benin Teaching Hospital ...

    African Journals Online (AJOL)

    2012-01-23

    Jan 23, 2012 ... Background: Ototoxicity refers to damage of the cochlea and/or vestibular apparatus from exposure to chemical substances, resulting in hearing impairment and or disequilibrium. An earlier study carried out at University of Benin Teaching. Hospital (UBTH) in 2000 implicated chloramphenicol as the ...

  19. CCR9 interactions support ovarian cancer cell survival and resistance to cisplatin-induced apoptosis in a PI3K-dependent and FAK-independent fashion

    Directory of Open Access Journals (Sweden)

    Johnson Erica L

    2010-06-01

    Full Text Available Abstract Background Cisplatin is more often used to treat ovarian cancer (OvCa, which provides modest survival advantage primarily due to chemo-resistance and up regulated anti-apoptotic machineries in OvCa cells. Therefore, targeting the mechanisms responsible for cisplatin resistance in OvCa cell may improve therapeutic outcomes. We have shown that ovarian cancer cells express CC chemokine receptor-9 (CCR9. Others have also shown that CCL25, the only natural ligand for CCR9, up regulates anti-apoptotic proteins in immature T lymphocytes. Hence, it is plausible that CCR9-mediated cell signals might be involved in OvCa cell survival and inhibition of cisplatin-induced apoptosis. In this study, we investigated the potential role and molecular mechanisms of CCR9-mediated inhibition of cisplatin-induced apoptosis in OvCa cells. Methods Cell proliferation, vibrant apoptosis, and TUNEL assays were performed with or without cisplatin treatment in presence or absence of CCL25 to determine the role of the CCR9-CCL25 axis in cisplatin resistance. In situ Fast Activated cell-based ELISA (FACE assays were performed to determine anti-apoptotic signaling molecules responsible for CCL25-CCR9 mediated survival. Results Our results show interactions between CCR9 and CCL25 increased anti-apoptotic signaling cascades in OvCa cells, which rescued cells from cisplatin-induced cell death. Specifically, CCL25-CCR9 interactions mediated Akt, activation as well as GSK-3β and FKHR phosphorylation in a PI3K-dependent and FAK-independent fashion. Conclusions Our results suggest the CCR9-CCL25 axis plays an important role in reducing cisplatin-induced apoptosis of OvCa cells.

  20. CCR9 interactions support ovarian cancer cell survival and resistance to cisplatin-induced apoptosis in a PI3K-dependent and FAK-independent fashion.

    Science.gov (United States)

    Johnson, Erica L; Singh, Rajesh; Johnson-Holiday, Crystal M; Grizzle, William E; Partridge, Edward E; Lillard, James W; Singh, Shailesh

    2010-06-17

    Cisplatin is more often used to treat ovarian cancer (OvCa), which provides modest survival advantage primarily due to chemo-resistance and up regulated anti-apoptotic machineries in OvCa cells. Therefore, targeting the mechanisms responsible for cisplatin resistance in OvCa cell may improve therapeutic outcomes. We have shown that ovarian cancer cells express CC chemokine receptor-9 (CCR9). Others have also shown that CCL25, the only natural ligand for CCR9, up regulates anti-apoptotic proteins in immature T lymphocytes. Hence, it is plausible that CCR9-mediated cell signals might be involved in OvCa cell survival and inhibition of cisplatin-induced apoptosis. In this study, we investigated the potential role and molecular mechanisms of CCR9-mediated inhibition of cisplatin-induced apoptosis in OvCa cells. Cell proliferation, vibrant apoptosis, and TUNEL assays were performed with or without cisplatin treatment in presence or absence of CCL25 to determine the role of the CCR9-CCL25 axis in cisplatin resistance. In situ Fast Activated cell-based ELISA (FACE) assays were performed to determine anti-apoptotic signaling molecules responsible for CCL25-CCR9 mediated survival. Our results show interactions between CCR9 and CCL25 increased anti-apoptotic signaling cascades in OvCa cells, which rescued cells from cisplatin-induced cell death. Specifically, CCL25-CCR9 interactions mediated Akt, activation as well as GSK-3beta and FKHR phosphorylation in a PI3K-dependent and FAK-independent fashion. Our results suggest the CCR9-CCL25 axis plays an important role in reducing cisplatin-induced apoptosis of OvCa cells.

  1. Inhibition of Src family kinases overcomes anoikis resistance induced by spheroid formation and facilitates cisplatin-induced apoptosis in human mesothelioma cells.

    Science.gov (United States)

    Eguchi, Ryoji; Fujita, Yumiko; Tabata, Chiharu; Ogawa, Hiroyasu; Wakabayashi, Ichiro; Nakano, Takashi; Fujimori, Yoshihiro

    2015-11-01

    Malignant mesothelioma is an aggressive tumor arising from mesothelial cells of serous membranes, and forms spheroid-like cell aggregates in pleural and peritoneal effusions. We examined the levels of anoikis, apoptosis induced by the detachment of cells from the extracellur matrix, in suspension culture in the human mesothelioma cell line NCI-H2052. NCI-H2052 cells were adherent in conventional monolayer cultures, but were found to form spheroids in suspension cultures using dishes with ultra-low cell binding capacity. NCI-H2052 cells proliferated in both cultures, but the proliferation rate was markedly lower in suspension cultures than in monolayer cultures. In addition, NCI-H2052 cells in suspension cultures showed little apoptosis, suggesting that the suspension culture induces anoikis resistance. Western blot analysis revealed that suspension cultures induced activation of Src family kinases (SFK) after spheroid formation. Dasatinib, an inhibitor of multi-tyrosine kinases including SFK, abolished anoikis resistance in suspension cultures, indicating that SFK activated by spheroid formation are responsible for anoikis resistance. Cisplatin induced apoptosis in NCI-H2052 cells, but the apoptotic rate was significantly lower in suspension cultures than in monolayer cultures, suggesting that spheroid formation is involved in cisplatin resistance. Furthermore, a combination of dasatinib and cisplatin induced apoptosis more significantly than either alone in suspension cultures. These results suggest that spheroid formation induces resistance to anoikis and to cisplatin through SFK activation and that dasatinib facilitates cisplatin-induced apoptosis in human mesothelioma cells.

  2. Monitoring carboplatin ototoxicity with distortion-product otoacoustic emissions in children with retinoblastoma

    Science.gov (United States)

    Bhagat, Shaum P.; Bass, Johnnie K.; White, Stephanie T.; Qaddoumi, Ibrahim; Wilson, Matthew W.; Wu, Jianrong; Rodriguez-Galindo, Carlos

    2016-01-01

    Objective Carboplatin is a common chemotherapy agent with potential ototoxic side effects that is used to treat a variety of pediatric cancers, including retinoblastoma. Retinoblastoma is a malignant tumor of the retina that is usually diagnosed in young children. Distortion-product otoacoustic emission tests offer an effective method of monitoring for ototoxicity in young children. This study was designed to compare measurements of distortion-product otoacoustic emissions obtained before and after several courses of carboplatin chemotherapy in order to examine if (a) mean distortion-product otoacoustic emission levels were significantly different; and (b) if criterion reductions in distortion-product otoacoustic emission levels were observed in individual children. Methods A prospective repeated measures study. Ten children with a median age of 7.6 months (range, 3–72 months) diagnosed with unilateral or bilateral retinoblastoma were examined. Distortion-product otoacoustic emissions were acquired from both ears of the children with 65/55 dB SPL primary tones (f2= 793–7996 Hz) and a frequency resolution of 3 points/octave. Distortion-product otoacoustic emission levels in dB SPL were measured before chemotherapy treatment (baseline measurement) and after 3–4 courses of chemotherapy (interim measurement). Comparisons were made between baseline and interim distortion-product otoacoustic emission levels (collapsed across ears). Evidence of ototoxicity was based on criterion reductions (≥ 6 dB) in distortion-product otoacoustic emission levels. Results Significant differences between baseline and interim mean distortion-product otoacoustic emission levels were only observed at f2=7996 Hz. Four children exhibited criterion reductions in distortion-product otoacoustic emission levels. Conclusions Mean distortion-product otoacoustic emission levels at most frequencies were not changed following 3–4 courses of carboplatin chemotherapy in children with

  3. Lack of protection against gentamicin ototoxicity by auditory conditioning with noise

    Directory of Open Access Journals (Sweden)

    Alex Strose

    2014-10-01

    Full Text Available INTRODUCTION: Auditory conditioning consists of the pre-exposure to low levels of a potential harmful agent to protect against a subsequent harmful presentation. OBJECTIVE: To confirm if conditioning with an agent different from the used to cause the trauma can also be effective. METHOD: Experimental study with 17 guinea pigs divided as follows: group Som: exposed to 85 dB broadband noise centered at 4 kHz, 30 minutes a day for 10 consecutive days; group Cont: intramuscular administration of gentamicin 160 mg/kg a day for 10 consecutive days; group Expt: conditioned with noise similarly to group Som and, after each noise presentation, received gentamicin similarly to group Cont. The animals were evaluated by distortion product otoacoustic emissions (DPOAEs, brainstem auditory evoked potentials (BAEPs and scanning electron microscopy. RESULTS: The animals that were conditioned with noise did not show any protective effect compared to the ones that received only the ototoxic gentamicin administration. This lack of protection was observed functionally and morphologically. CONCLUSION: Conditioning with 85 dB broadband noise, 30 min a day for 10 consecutive days does not protect against an ototoxic gentamicin administration of 160 mg/kg a day for 10 consecutive days in the guinea pig.

  4. Preventing Ototoxic Synergy of Prior Noise Trauma during Aminoglycoside Therapy

    Science.gov (United States)

    2017-06-01

    Otolaryngology . Page 10 of 11 “Ototoxicity under bacterial infection and inflammation”, 2nd Hearing Science Symposium: from Hair Cells to Cortex, Shandong...for Research in Otolaryngology , Baltimore MD, as attached in the Appendix. 9. OTHER ACHIEVEMENTS a) Other general lab activities included personal...REFERENCES Not applicable. 11. APPENDICES Poster presentation at 2017 Midwinter meeting of Association for Research in Otolaryngology , Baltimore MD

  5. The terminal basal mitosis of chicken retinal Lim1 horizontal cells is not sensitive to cisplatin-induced cell cycle arrest.

    Science.gov (United States)

    Shirazi Fard, Shahrzad; Thyselius, Malin; All-Ericsson, Charlotta; Hallböök, Finn

    2014-01-01

    For proper development, cells need to coordinate proliferation and cell cycle-exit. This is mediated by a cascade of proteins making sure that each phase of the cell cycle is controlled before the initiation of the next. Retinal progenitor cells divide during the process of interkinetic nuclear migration, where they undergo S-phase on the basal side, followed by mitoses on the apical side of the neuroepithelium. The final cell cycle of chicken retinal horizontal cells (HCs) is an exception to this general cell cycle behavior. Lim1 expressing (+) horizontal progenitor cells (HPCs) have a heterogenic final cell cycle, with some cells undergoing a terminal mitosis on the basal side of the retina. The results in this study show that this terminal basal mitosis of Lim1+ HPCs is not dependent on Chk1/2 for its regulation compared to retinal cells undergoing interkinetic nuclear migration. Neither activating nor blocking Chk1 had an effect on the basal mitosis of Lim1+ HPCs. Furthermore, the Lim1+ HPCs were not sensitive to cisplatin-induced DNA damage and were able to continue into mitosis in the presence of γ-H2AX without activation of caspase-3. However, Nutlin3a-induced expression of p21 did reduce the mitoses, suggesting the presence of a functional p53/p21 response in HPCs. In contrast, the apical mitoses were blocked upon activation of either Chk1/2 or p21, indicating the importance of these proteins during the process of interkinetic nuclear migration. Inhibiting Cdk1 blocked M-phase transition both for apical and basal mitoses. This confirmed that the cyclin B1-Cdk1 complex was active and functional during the basal mitosis of Lim1+ HPCs. The regulation of the final cell cycle of Lim1+ HPCs is of particular interest since it has been shown that the HCs are able to sustain persistent DNA damage, remain in the cell cycle for an extended period of time and, consequently, survive for months.

  6. Cellular glutathione content in the organ of Corti and its role during ototoxicity

    Directory of Open Access Journals (Sweden)

    Paromita eMajumder

    2015-04-01

    Full Text Available Glutathione (GSH is the major scavenger of reactive oxygen (ROS inside cells. We used live confocal imaging in order to clarify the role of GSH in the biology of the organ of Corti, the sensory epithelium of the cochlea, before, during and after the onset of hearing and in ~1 year old mice. GSH content was measured using monochlorobimane (MCB, a non-fluorescent cell permeant bimane that reacts with GSH, forming a fluorescent adduct through a reaction catalysed by glutathione-S-transferase. GSH content increased significantly in inner hair cells during maturation in young adult animals, whereas there was no significant change in the outer hair cells. However, the GSH content in inner hair cells was significantly reduced in ~1 year old mice. The GSH content of supporting cells was comparatively stable over these ages. To test whether the GSH content played a significant protective role during ototoxicity, GSH synthesis was inhibited by buthionine sulfoximine (BSO in organotypic cochlear explant cultures from immature mice. BSO treatment alone, which reduced [GSH] by 65% and 85% in inner hair cells and outer hair cells respectively, did not cause any significant cell death. Surprisingly, GSH depletion had no significant effect on hair cell survival even during exposure to the ototoxic aminoglycoside neomycin. These data suggest that the involvement of ROS during aminoglycoside-induced hair cell death is less clear than previously thought and requires further investigation.

  7. Long Term Study of Protective Mechanisms of Human Adipose Derived Mesenchymal Stem Cells on Cisplatin Induced Kidney injury in Sprague-Daweley Rats

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    Elhusseini FM

    2016-05-01

    Full Text Available Background/Aims: Long-term evaluation of cisplatin induced nephrotoxicity and the probable renal protective activities of stem cells are lacking up until now. We evaluated the early and long-term role of human adipose derived mesenchymal stem cells (ADMSCs in prevention or amelioration of cisplatin induced acute kidney injury (AKI in Sprague-Dawley rats. For this, we determined the kidney tissue level of oxidative stress markers in conjugation with a renal histopathological scoring system of both acute and chronic renal changes. Methods: This study used eighty Sprague-Dawley (SD rats weighing 250-300g. They were assigned into four equal groups (each group n=20: (I Negative control group, rats injected with single dose of 1 ml normal saline. (II Positive control cisplatin, rats injected with a single dose of 5 mg/kg I.P in 1 ml saline. (III Cisplatin and culture media group, rats injected with 0.5 ml of culture media single dose into the tail vein and (IV Cisplatin and ADMSCs group, rats injected with a single dose of 0.5 ml of culture media containing 5 x106ADMSCs into the tail vein one day after cisplatin administration. Each main group was further divided according to the timing of sacrifice into four subgroups (each subgroup n=5. Rats in the subgroup A were sacrificed after 4 days; subgroup B were sacrificed after 7 days; subgroup C were sacrificed after 11 days; and subgroup D were sacrificed after 30 days. Before sacrifice, 24 hrs.-urine was collected using a metabolic cage. Renal function was evaluated through blood urea nitrogen (BUN, serum creatinine and creatinine clearance. Kidney tissue homogenate oxidative stress parameters, Malondialdehyde (MDA, Superoxide dismutase (SOD and Glutathione (GSH were determined. In addition, histopathological analysis for active injury, regenerative and chronic changes was performed. Results: ADMSCs were characterized and their capability of differentiation was proved. Cisplatin induced a significant

  8. Cisplatin Induces Up-Regulation of KAI1, a Metastasis Suppressor ...

    African Journals Online (AJOL)

    HP

    Purpose: To investigate the effect of cisplatin on cell toxicity and metastasis through modulation of KAI1 gene expression. Methods: MCF-7cells were incubated with different concentrations of cisplatin for 24 h. RNA was extracted by trizol and cDNA synthesized. KAI1 and TBP were chosen as target and internal control.

  9. Hydrogen sulfide : A novel nephroprotectant against cisplatin-induced renal toxicity

    NARCIS (Netherlands)

    Dugbartey, George J.; Bouma, Hjalmar R.; Lobb, Ian; Sener, Alp

    2016-01-01

    Cisplatin is a potent chemotherapeutic agent for the treatment of various solid-organ cancers. However, a plethora of evidence indicates that nephrotoxicity is a major side effect of cisplatin therapy. While the antineoplastic action of cisplatin is due to formation of cisplatin-DNA cross-links,

  10. Hemin Attenuates Cisplatin-Induced Acute Renal Injury in Male Rats

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    Mohamed A. Al-Kahtani

    2014-01-01

    Full Text Available Background. The aim of this study is to investigate the protective effects of hemin (the heme oxygenase-1 [OH-1] inducer against nephrotoxic effects induced by cisplatin [cis-diamminedichloroplatinum II (CP] in male rats. Methods. The evaluation was performed through monitoring renal redox parameters: lipid peroxidation (LPO, glutathione peroxidase (GPx, superoxide dismutase (SOD, glutathione reductase (GR, and reduced glutathione (GSH. The work also examined renal function tests (urea and creatinine, tissue proinflammatory mediator like nitric oxide (NO, and kidney cytopathology. Results. A single intraperitoneal dose of CP (10 mg/kg b.w. caused significant elevation of blood urea, serum creatinine, and renal LPO and NO, along with significant decline of the activities of GPx and GR, but renal SOD activity and GSH level were statistically insignificant as compared to control group. Subcutaneous injection of hemin (40 µmol/kg b.w. partially ameliorated CP-induced renal damage, based on suppression of blood urea, serum creatinine, the renal MDA and NO levels, and increased antioxidant capacity in CP-treated rats. The results of histopathological and ultrastructural investigations supported the renoprotective effect of hemin against CP-induced acute toxicity. Conclusion. The induction of HO-1 by hemin is a promising approach in the treatment of CP-induced nephrotoxicity. However, further preclinical studies are warranted to test effectiveness of CP/hemin on the outcome of tumor chemotherapy.

  11. Cisplatin Induces Up-Regulation of KAI1, a Metastasis Suppressor ...

    African Journals Online (AJOL)

    Purpose: To investigate the effect of cisplatin on cell toxicity and metastasis through modulation of KAI1 gene expression. Methods: MCF-7cells were incubated with different concentrations of cisplatin for 24 h. RNA was extracted by trizol and cDNA synthesized. KAI1 and TBP were chosen as target and internal control ...

  12. Ototoxicity monitoring with ultra-high frequency audiometry in peritoneal dialysis patients treated with vancomycin or gentamicin

    NARCIS (Netherlands)

    van der Hulst, R. J.; Boeschoten, E. W.; Nielsen, F. W.; Struijk, D. G.; Dreschler, W. D.; Tange, R. A.

    1991-01-01

    Ototoxicity affects the higher frequencies first and extends to the lower frequencies during continuation of the ototoxic treatment. Peritonitis due to continuous ambulatory peritoneal dialysis (CAPD) regularly demands ototoxic antibiotic treatment, e.g. with gentamicin and vancomycin. In this study

  13. Doxorubicin and cisplatin induce apoptosis in ovarian stromal cells obtained from cryopreserved human ovarian tissue.

    Science.gov (United States)

    Fabbri, Raffaella; Macciocca, Maria; Vicenti, Rossella; Paradisi, Roberto; Klinger, Francesca Gioia; Pasquinelli, Gianandrea; Spisni, Enzo; Seracchioli, Renato; Papi, Alessio

    2016-07-01

    To investigate mechanisms by which doxorubicin (DOX) and cisplatin (CIS) cause human ovarian stroma injury. Stromal cells from human cryopreserved ovarian tissue were cultured in the presence of 1 µM DOX and 10 µM CIS. Ovarian damage induced by treatments was evaluated by 'Live/Dead' and sulforhodamine-B assays, the expression of different apoptosis markers. Stromal cell growth was inhibited by DOX and CIS, and this effect was accompanied by apoptosis through mitochondrial pathway activation: Bax, cleaved-caspase 9, cleaved-PARP1 induction and Akt1, Bcl2, phospho-44/42-MAPK/ERK1/2 reduction were observed. DOX and CIS induced apoptosis in human ovarian stromal cells. Knowledge of mechanisms by which the drugs act is important to identify possible ways to counteract side effects of chemotherapy on ovaries.

  14. Voluntary Exercise Prevents Cisplatin-Induced Muscle Wasting during Chemotherapy in Mice

    DEFF Research Database (Denmark)

    Hojman, Pernille; Fjelbye, Jonas; Zerahn, Bo

    2014-01-01

    Loss of muscle mass related to anti-cancer therapy is a major concern in cancer patients, being associated with important clinical endpoints including survival, treatment toxicity and patient-related outcomes. We investigated effects of voluntary exercise during cisplatin treatment on body weight...... loss by 50% (P Exercise...... training may preserve muscle mass in cancer patients receiving cisplatin treatment, potentially improving physical capacity, quality of life and overall survival....

  15. Voluntary exercise prevents cisplatin-induced muscle wasting during chemotherapy in mice

    DEFF Research Database (Denmark)

    Hojman, Pernille; Fjelbye, Jonas; Zerahn, Bo

    2014-01-01

    Loss of muscle mass related to anti-cancer therapy is a major concern in cancer patients, being associated with important clinical endpoints including survival, treatment toxicity and patient-related outcomes. We investigated effects of voluntary exercise during cisplatin treatment on body weight......% (PExercise training may...... preserve muscle mass in cancer patients receiving cisplatin treatment, potentially improving physical capacity, quality of life and overall survival....

  16. LH prevents cisplatin-induced apoptosis in oocytes and preserves female fertility in mouse

    Science.gov (United States)

    Rossi, Valerio; Lispi, Monica; Longobardi, Salvatore; Mattei, Maurizio; Rella, Francesca Di; Salustri, Antonietta; De Felici, Massimo; Klinger, Francesca G

    2017-01-01

    Premature ovarian failure and female infertility are frequent side effects of anticancer therapies, owing to the extreme sensitivity of the ovarian reserve oocytes to the damaging effects of irradiation and chemotherapy on DNA. We report here a robust protective effect of luteinizing hormone (LH) on the primordial follicle pool of prepubertal ovaries against the cisplatin (Cs)-induced apoptosis. In vitro LH treatment of prepubertal ovarian fragments generated anti-apoptotic signals by a subset of ovarian somatic cells expressing LH receptor (LHR) through cAMP/PKA and Akt pathways. Such signals, reducing the oocyte level of pro-apoptotic TAp63 protein and favoring the repair of the Cs-damaged DNA in the oocytes, prevented their apoptosis. Noteworthy, in vivo administration to prepubertal female mice of a single dose of LH together with Cs inhibited the depletion of the primordial follicle reserve caused by the drug and preserved their fertility in reproductive age, preventing significant alteration in the number of pregnancy and of delivered pups. In conclusion, these findings establish a novel ovoprotective role for LH and further support the very attracting prospective to use physiological 'fertoprotective' approaches for preventing premature infertility and risks linked to precocious menopause in young patients who survived cancer after chemotherapy. PMID:27689876

  17. Efeito de fármacos ototóxicos na audição de recém-nascidos de alto risco Effects of ototoxic drugs in the hearing of high risk newborns

    Directory of Open Access Journals (Sweden)

    Marília Fontenele e Silva Câmara

    2010-01-01

    Full Text Available OBJETIVOS: Calcular a incidência da perda auditiva sensorioneural (PASN em recém-nascidos de alto risco, verificar se existe associação causal entre o uso de fármacos ototóxicos em neonatos de alto risco e a PASN e estabelecer a frequência das mutações genéticas relacionadas à PASN em neonatos de alto risco. MÉTODOS: A pesquisa foi uma coorte retrospectiva e prospectiva realizada em 250 crianças. Foi realizada coleta de dados em prontuários e com os responsáveis, triagem auditiva por emissões otoacústicas-produto de distorção, timpanometria, audiometria com reforço visual, potencial evocado auditivo de tronco encefálico e emissões otoacústicas transientes. A pesquisa das mutações genéticas 35delG e mitocondriais A1555G e A7445G, foi fundamental para avaliar a possibilidade da PASN ser de origem genética não-sindrômica. RESULTADOS: A incidência da PASN foi de 11,6%, as associações causais entre a PASN e os fármacos administrados foram: amicacina e cefotaxima (OR 5,35, cefotaxima e furosemida (OR 7,02, ceftazidima e vancomicina (OR 9,12. A frequência da mutação 35delG foi de 0,8% e para as mutações mitocondriais A1555G e A7445G foi 0%. CONCLUSÃO: A incidência de PASN em recém-nascidos de alto risco foi alta, apresentando importante relação causal com o uso de medicamentos e pequena relação com mutações genéticas.PURPOSE: To calculate the incidence of sensorineural hearing loss (SNHL, to verify if there is a causal association between the use of ototoxic drugs and SNHL, and to establish the frequency of genetic mutations related to SNHL in high risk newborns. METHODS: The study was a retrospective and prospective cohort research with 250 children. Data was gathered from subjects' charts and with their caregivers. Moreover, subjects were submitted to auditory evaluation with distortion product otoacoustic emissions, timpanometry, visual reinforcement audiometry, auditory brainstem response and

  18. Saponin and non-saponin fractions of red ginseng ameliorate cisplatin-induced pica in rats.

    Science.gov (United States)

    Sathyanath, Rekha; Hanumantha Rao, Balaji Raghavendran; Kim, Hyeong-Geug; Cho, Jung-Hyo; Son, Chang-Gue

    2013-08-01

    Nausea and vomiting are considered as the foremost unpleasant side effects of chemotherapy experienced by 20-90% of cancer patients. In the present study, the effects of Korean Panax ginseng C.A. Meyer (Araliaceae) (RG), ginseng saponin (GS) and non-saponin (GNS) on cisplatin (CP)-induced pica and gastric damage in rats were investigated. Rats were treated with RG (25, 50, 100 mg/kg b.wt.), GS (5 and 10 mg/kg 100 mg/kg b.wt.) and GNS (50 and 100 mg/kg b.wt.) before or after a single intraperitoneal injection of CP (6 mg/kg b.wt.). Kaolin together with normal food intake, normal food alone, body weight, histological examination of stomach and small intestine were used as indices of CP-induced pica in rats. Pre-treatment with RG (50 and 100 mg/kg b.wt.) attenuated CP-induced kaolin intake at 24 h. CP-induced kaolin intake decreased upon post-treatment of rats with RG (50 and 100 mg/kg b.wt.) at 48 h. The incidence of body weight reduction at 48 and 72 h diminished in rats post-treated with RG (50 mg/kg b.wt.). Pre-treatment with GS (5 and 10 mg/kg b.wt.) and GNS (50 and 100 mg/kg b.wt.) attenuated CP-induced kaolin intake while normal food intake was not improved in 24 and 48 h. The gastro-protective effects of RG, GS and GNS were further confirmed by histopathological (damage in glandular portion and villi with dilated appearance) findings. The study indicates that both the red GS and GNS improve feeding behavior against CP-induced pica in rats.

  19. Protection of cisplatin-induced spermatotoxicity, DNA damage and chromatin abnormality by selenium nano-particles

    Energy Technology Data Exchange (ETDEWEB)

    Rezvanfar, Mohammad Amin; Rezvanfar, Mohammad Ali [Department of Toxicology and Pharmacology, Faculty of Pharmacy, and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences (TUMS), Tehran (Iran, Islamic Republic of); Shahverdi, Ahmad Reza [Department of Pharmaceutical Biotechnology and Biotechnology Research Centre, Faculty of Pharmacy, TUMS, Tehran (Iran, Islamic Republic of); Ahmadi, Abbas [Department of Histology and Embryology, Faculty of Veterinary Medicine, Urmia University, Urmia (Iran, Islamic Republic of); Baeeri, Maryam; Mohammadirad, Azadeh [Department of Toxicology and Pharmacology, Faculty of Pharmacy, and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences (TUMS), Tehran (Iran, Islamic Republic of); Abdollahi, Mohammad, E-mail: mohammad.abdollahi@utoronto.ca [Department of Toxicology and Pharmacology, Faculty of Pharmacy, and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences (TUMS), Tehran (Iran, Islamic Republic of)

    2013-02-01

    Cisplatin (CIS), an anticancer alkylating agent, induces DNA adducts and effectively cross links the DNA strands and so affects spermatozoa as a male reproductive toxicant. The present study investigated the cellular/biochemical mechanisms underlying possible protective effect of selenium nano-particles (Nano-Se) as an established strong antioxidant with more bioavailability and less toxicity, on reproductive toxicity of CIS by assessment of sperm characteristics, sperm DNA integrity, chromatin quality and spermatogenic disorders. To determine the role of oxidative stress (OS) in the pathogenesis of CIS gonadotoxicity, the level of lipid peroxidation (LPO), antioxidant enzymes including superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) and peroxynitrite (ONOO) as a marker of nitrosative stress (NS) and testosterone (T) concentration as a biomarker of testicular function were measured in the blood and testes. Thirty-two male Wistar rats were equally divided into four groups. A single IP dose of CIS (7 mg/kg) and protective dose of Nano-Se (2 mg/kg/day) were administered alone or in combination. The CIS-exposed rats showed a significant increase in testicular and serum LPO and ONOO level, along with a significant decrease in enzymatic antioxidants levels, diminished serum T concentration and abnormal histologic findings with impaired sperm quality associated with increased DNA damage and decreased chromatin quality. Coadministration of Nano-Se significantly improved the serum T, sperm quality, and spermatogenesis and reduced CIS-induced free radical toxic stress and spermatic DNA damage. In conclusion, the current study demonstrated that Nano-Se may be useful to prevent CIS-induced gonadotoxicity through its antioxidant potential. Highlights: ► Cisplatin (CIS) affects spermatozoa as a male reproductive toxicant. ► Effect of Nano-Se on CIS-induced spermatotoxicity was investigated. ► CIS-exposure induces oxidative sperm DNA damage

  20. C-phycocyanin prevents cisplatin-induced nephrotoxicity through inhibition of oxidative stress.

    Science.gov (United States)

    Fernández-Rojas, Berenice; Medina-Campos, Omar Noel; Hernández-Pando, Rogelio; Negrette-Guzmán, Mario; Huerta-Yepez, Sara; Pedraza-Chaverri, José

    2014-03-01

    The aim of this study was to evaluate whether the antioxidant C-phycocyanin (C-PC, 5-30 mg kg(-1) i.p.) was able to prevent cisplatin (CP, 18 mg kg(-1) i.p.) induced nephrotoxicity by reducing oxidative stress in CD-1 mice. Nephrotoxicity was assessed by measuring blood urea nitrogen, plasma glutathione peroxidase, plasma creatinine, the renal activity of N-acetyl-β-d-glucosaminidase, apoptosis and histopathological changes. Oxidative stress was evaluated by measuring the content of glutathione, malondialdehyde, 4-hydroxynonenal and oxidized proteins in renal tissue. C-PC prevented CP-induced renal damage and oxidative stress in a dose-dependent manner. Moreover, C-PC prevented the decrease in the renal activity of the antioxidant enzymes glutathione peroxidase, glutathione reductase, glutathione-S-transferase and catalase induced by cisplatin. In vitro assays showed that C-PC was an effective scavenger of the following reactive species: hypochlorous acid, peroxynitrite anions, peroxyl radicals, diphenyl-1-picrylhydrazyl, hydroxyl radicals, superoxide anions, singlet oxygen and hydrogen peroxide. It is concluded that the protective effect of the nutraceutical C-PC against CP-induced nephrotoxicity was associated with the attenuation of oxidative stress and the preservation of the activity of antioxidant enzymes.

  1. Fasting boosts sensitivity of human skin melanoma to cisplatin-induced cell death.

    Science.gov (United States)

    Antunes, Fernanda; Corazzari, Marco; Pereira, Gustavo; Fimia, Gian Maria; Piacentini, Mauro; Smaili, Soraya

    2017-03-25

    Melanoma is one of leading cause of tumor death worldwide. Anti-cancer strategy includes combination of different chemo-therapeutic agents as well as radiation; however these treatments have limited efficacy and induce significant toxic effects on healthy cells. One of most promising novel therapeutic approach to cancer therapy is the combination of anti-cancer drugs with calorie restriction. Here we investigated the effect Cisplatin (CDDP), one of the most potent chemotherapeutic agent used to treat tumors, in association with fasting in wild type and mutated BRAF(V600E) melanoma cell lines. Here we show that nutrient deprivation can consistently enhance the sensitivity of tumor cells to cell death induction by CDDP, also of those malignancies particularly resistant to any treatment, such as oncogenic BRAF melanomas. Mechanistic studies revealed that the combined therapy induced cell death is characterized by ROS accumulation and ATF4 in the absence of ER-stress. In addition, we show that autophagy is not involved in the enhanced sensitivity of melanoma cells to combined CDDP/EBSS-induced apoptosis. While, the exposure to 2-DG further enhanced the apoptotic rate observed in SK Mel 28 cells upon treatment with both CDDP and EBSS. Copyright © 2016. Published by Elsevier Inc.

  2. Taurine Rescues Cisplatin-Induced Muscle Atrophy In Vitro: A Morphological Study

    Directory of Open Access Journals (Sweden)

    Alessandra Stacchiotti

    2014-01-01

    Full Text Available Cisplatin (CisPt is a widely used chemotherapeutic drug whose side effects include muscle weakness and cachexia. Here we analysed CisPt-induced atrophy in C2C12 myotubes by a multidisciplinary morphological approach, focusing on the onset and progression of autophagy, a protective cellular process that, when excessively activated, may trigger protein hypercatabolism and atrophy in skeletal muscle. To visualize autophagy we used confocal and transmission electron microscopy at different times of treatment and doses of CisPt. Moreover we evaluated the effects of taurine, a cytoprotective beta-amino acid able to counteract oxidative stress, apoptosis, and endoplasmic reticulum stress in different tissues and organs. Our microscopic results indicate that autophagy occurs very early in 50 μM CisPt challenged myotubes (4 h–8 h before overt atrophy but it persists even at 24 h, when several autophagic vesicles, damaged mitochondria, and sarcoplasmic blebbings engulf the sarcoplasm. Differently, 25 mM taurine pretreatment rescues the majority of myotubes size upon 50 μM CisPt at 24 h. Taurine appears to counteract atrophy by restoring regular microtubular apparatus and mitochondria and reducing the overload and the localization of autophagolysosomes. Such a promising taurine action in preventing atrophy needs further molecular and biochemical studies to best define its impact on muscle homeostasis and the maintenance of an adequate skeletal mass in vivo.

  3. Asparagus racemosus ameliorates cisplatin induced toxicities and augments its antileishmanial activity by immunomodulation in vivo.

    Science.gov (United States)

    Sachdeva, Heena; Sehgal, Rakesh; Kaur, Sukhbir

    2014-02-01

    Current drugs for the treatment of visceral leishmaniasis are inadequate and their efficacies are also compromised due to suppression of immune function associated during the course of infection. To overcome this problem, efforts are needed to develop therapies with effective immunomodulatory agents where decrease of parasitic burden and simultaneous enhancement of adaptive immunity can be achieved. In this study we have evaluated a new therapeutic approach based on combination of Asparagus racemosus, an immunomodulatory drug, in combination with cisplatin against Leishmania donovani infected BALB/c mice. We demonstrate that A. racemosus (650 mg/kg b.wt./day for 15 days, orally) in combination with cisplatin (5 mg/kg b.wt./day for 5 days, intraperitoneally) enhanced the clearance of parasites as determined by Giemsa-stained liver impression smears. Besides having better killing activity, this combination group achieved increased production of disease resolving Th-1 response (IFN-gamma, IL-2), heightened DTH (delayed type hypersensitivity) response and augmented levels of IgG2a. Moreover, A. racemosus in combination with cisplatin not only provided enhanced protective immune response but also resulted in remarkable improved kidney and liver function tests as manifested by normal levels of SGOT, SGPT, alkaline phosphatase, creatinine and urea in blood plasma with normal histological observations as compared to only cisplatin treated L. donovani infected BALB/c mice. Through this study we have ascertained that A. racemosus in combination with cisplatin in L. donovani infected BALB/c mice boosted as well as restored both cellular and humoral immunity. Thus in view of severe immunosuppression in visceral leishmaniasis, a better and effective strategy for optimum efficacy of future antileishmanial drugs would direct not only killing of parasite by the drug, but also simultaneous generation of immunity against the disease. © 2013.

  4. C-phycocyanin prevents cisplatin-induced mitochondrial dysfunction and oxidative stress.

    Science.gov (United States)

    Fernández-Rojas, Berenice; Rodríguez-Rangel, Daniela Sarai; Granados-Castro, Luis Fernando; Negrette-Guzmán, Mario; León-Contreras, Juan Carlos; Hernández-Pando, Rogelio; Molina-Jijón, Eduardo; Reyes, José L; Zazueta, Cecilia; Pedraza-Chaverri, José

    2015-08-01

    The potential of C-phycocyanin (C-PC) to prevent cisplatin (CP)-induced kidney mitochondrial dysfunction was determined in CD-1 male mice. The CP-induced mitochondrial dysfunction was characterized by ultrastructural abnormalities and by decrease in the following parameters in isolated kidney mitochondria: adenosine diphosphate (ADP)-induced oxygen consumption (state 3), respiratory control ratio, ADP/oxygen (ADP/O) ratio, adenosine triphosphate synthesis, membrane potential, calcium retention, glutathione (GSH) content, and activity of respiratory complex I, aconitase, catalase, and GSH peroxidase. These mitochondria also showed increase in hydrogen peroxide production, malondialdehyde, and 3-nitrotyrosine protein adducts content. The above-described changes, as well as CP-induced nephrotoxicity, were attenuated in mice pretreated with a single injection of C-PC. Our data suggest that the attenuation of mitochondrial abnormalities is involved in the protective effect of C-PC against CP-induced nephrotoxicity. This is the first demonstration that C-PC pretreatment prevents CP-induced mitochondrial dysfunction in mice.

  5. Protective Role of Selenium and High Dose Vitamin E against Cisplatin - Induced Nephrotoxicty in Rats.

    Science.gov (United States)

    Aksoy, Asude; Karaoglu, Aziz; Akpolat, Nusret; Naziroglu, Mustafa; Ozturk, Turkan; Karagoz, Zuhal Karaca

    2015-01-01

    Cisplatin (CDDP) is one of the most active cytotoxic agents in the treatment of cancer. We investigated the effect of selenium (Se) with high dose vitamin E (VE) administration to prevent CDDP-induced nephrotoxicity in rats. In this study, 40 female Wistar rats were randomly divided into five equal groups. The first group, which served as the control, was administered physiological saline (2.5 cc/day, 5 days) intraperitoneally (IP), while group A was administered cisplatin (6 mg/kg BW/ single dose) plus physiological saline IP. Groups B, C, D received IP five doses of Se (1.5 mg/kg BW), and a high dose of VE (1000 mg/kg BW) (Se-VE) in combination before, simultaneously, and after CDDP, respectively. The rats were sacrificed five days after CDDP administration. Plasma malondialdehide (MDA), glutathione peroxidase (GSH-Px), reduced glutathione (GSH), catalase, urea, creatinine levels, renal histopathological changes were measured. The histopathological injury score, plasma levels of MDA, urea, creatinine were found to increase in group A compared to the control (p<0.05), while plasma levels of GSH-Px, GSH and catalase decreased (p<0.05). In contrast, plasma levels of MDA decreased (p<0.05) in groups B, C, D, which were treated with Se- VE, whereas levels of GSH-Px, GSH were found to increase only for group D (p<0.05). Plasma urea, creatinine levels improved in the treatment groups compared to group A (p<0.001). Histopathological changes caused by CDDP were also significantly improved after Se-VE treatment (p<0.05). Oxidative stress increases with CDDP-induced nephrotoxicity in rats. Se-VE supplementation might thus play a role in the prevention of CDDP-induced nephrotoxicity in patients.

  6. Assessment of cisplatin-induced kidney injury using an integrated rodent platform

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Yafei [Global Safety Assessment, AstraZeneca R and D Waltham, MA 02451 (United States); Brott, David [Patient Safety, AstraZeneca R and D Wilmington, DE 19850 (United States); Luo, Wenli [Discovery Statistics, AstraZeneca R and D Waltham, MA 02451 (United States); Gangl, Eric [DMPK, AstraZeneca R and D Waltham, MA 02451 (United States); Kamendi, Harriet; Barthlow, Herbert; Lengel, David; Fikes, James; Kinter, Lewis [Global Safety Assessment, AstraZeneca R and D Waltham, MA 02451 (United States); Valentin, Jean-Pierre [Global Safety Assessment, AstraZeneca R and D Alderley Park, Macclesfield, SK10 4TG (United Kingdom); Bialecki, Russell, E-mail: russell.bialecki@astrazeneca.com [Global Safety Assessment, AstraZeneca R and D Waltham, MA 02451 (United States)

    2013-05-01

    Current diagnosis of drug-induced kidney injury (DIKI) primarily relies on detection of elevated plasma creatinine (Cr) or blood urea nitrogen (BUN) levels; however, both are indices of overall kidney function and changes are delayed with respect to onset of nephron injury. Our aim was to investigate whether early changes in new urinary DIKI biomarkers predict plasma Cr, BUN, renal hemodynamic and kidney morphological changes associated with kidney injury following a single dose of cisplatin (CDDP) using an integrated platform in rodent. Conscious surgically prepared male Han Wistar rats were given a single intraperitoneal dose of CDDP (15 mg/kg). Glomerular filtration rate (GFR), effective renal plasma flow (ERPF), urinalysis, DIKI biomarkers, CDDP pharmacokinetics, blood pressures, heart rate, body temperature and electroencephalogram (EEG) were measured in the same vehicle- or CDDP-treated animals over 72 h. Plasma chemistry (including Cr and BUN) and renal tissues were examined at study termination. Cisplatin caused progressive reductions of GFR, ERPF, heart rate and body temperature from day 1 (0–24 h). DIKI biomarkers including alpha-glutathione S-transferase (α-GST) significantly increased as early as 6 h post-dose, which preceded significant declines of GFR and ERPF (24 h), increased plasma Cr and BUN (72 h), and associated with renal acute tubular necrosis at 72 h post-dose. The present study adds to the current understanding of CDDP action by demonstrating that early increases in urinary excretion of α-GST predict DIKI risk following acute exposure to CDDP in rats, before changes in traditional DIKI markers are evident. - Highlights: ► CDDP causes direct damage to kidneys without affecting EEG or CVS function. ► α-GST and albumin detect DIKI earlier when compared with traditional indices. ► Integrated “cardiovascular-EEG-renal” model to better understand DIKI mechanisms ► Promotes 3R's principles in drug discovery and development.

  7. Salinomycin enhances cisplatin-induced cytotoxicity in human lung cancer cells via down-regulation of AKT-dependent thymidylate synthase expression.

    Science.gov (United States)

    Ko, Jen-Chung; Zheng, Hao-Yu; Chen, Wen-Ching; Peng, Yi-Shuan; Wu, Chia-Hung; Wei, Chia-Li; Chen, Jyh-Cheng; Lin, Yun-Wei

    2016-12-15

    Salinomycin, a polyether antibiotic, acts as a highly selective potassium ionophore and has anticancer activity on various cancer cell lines. Cisplatin has been proved as chemotherapy drug for advanced human non-small cell lung cancer (NSCLC). Thymidylate synthase (TS) is a key enzyme in the pyrimidine salvage pathway, and increased expression of TS is thought to be associated with resistance to cisplatin. In this study, we showed that salinomycin (0.5-2μg/mL) treatment down-regulating of TS expression in an AKT inactivation manner in two NSCLC cell lines, human lung adenocarcinoma A549 and squamous cell carcinoma H1703 cells. Knockdown of TS using small interfering RNA (siRNA) or inhibiting AKT activity with PI3K inhibitor LY294002 enhanced the cytotoxicity and cell growth inhibition of salinomycin. A combination of cisplatin and salinomycin resulted in synergistic enhancement of cytotoxicity and cell growth inhibition in NSCLC cells, accompanied with reduced activation of phospho-AKT, and TS expression. Overexpression of a constitutive active AKT (AKT-CA) expression vector reversed the salinomycin and cisplatin-induced synergistic cytotoxicity. In contrast, pretreatment with LY294002 further decreased the cell viability in salinomycin and cisplatin cotreated cells. Our findings suggested that the down-regulation of AKT-mediated TS expression by salinomycin enhanced the cisplatin-induced cytotoxicity in NSCLC cells. These results may provide a rationale to combine salinomycin with cisplatin for lung cancer treatment. Copyright © 2016 Elsevier Inc. All rights reserved.

  8. Urinary neutrophil gelatinase-associated lipocalin levels predict cisplatin-induced acute kidney injury better than albuminuria or urinary cystatin C levels

    Directory of Open Access Journals (Sweden)

    Hugo You-Hsien Lin

    2013-06-01

    Full Text Available Cisplatin-induced acute kidney injury (AKI is a major concern among clinicians in prescribing cisplatin-based chemotherapy. This study evaluated and compared the ability of urinary biomarkers, including urinary neutrophil gelatinase-associated lipocalin (NGAL, cystatin C, and the urinary albumin to creatinine ratio (ACR to predict cisplatin-induced AKI. Thirty-three cancer patients receiving cisplatin-based chemotherapy were prospectively studied, including 10 (30% who developed AKI (the study group. Changes of urinary biomarkers were compared at 4 hours, 8 hours, and 12 hours, and 1 day, 2 days, 3 days, and 4 days after cisplatin intravenous infusions (75 mg/m2 versus the baseline. There was a significant increase in urinary NGAL levels from 12 hours to 4 days (p<0.05 compared to baseline after cisplatin infusion in the AKI group. The magnitude of these changes over time differed significantly by group (p<0.001. The area under the receiver operating curve describing the relationship between urinary NGAL levels and AKI within 12 hours was 0.865 (95% confidence interval=0.691–1.000. Urinary NGAL levels independently predicted AKI 12 hours after cisplatin (p=0.045 after adjustments for age, gender, body mass index, baseline serum creatinine, and urinary total protein. Urinary NGAL levels may be an early biomarker of AKI in patients receiving cisplatin-based treatment.

  9. Pharmacological drugs inducing ototoxicity, vestibular symptoms and tinnitus: a reasoned and updated guide.

    Science.gov (United States)

    Cianfrone, G; Pentangelo, D; Cianfrone, F; Mazzei, F; Turchetta, R; Orlando, M P; Altissimi, G

    2011-06-01

    The present work on drug-induced ototoxicity, tinnitus and vertigo represents the update and revision of a previous guide to adverse drug reactions for italian physicians (2005). The panorama of drug-induced side effects causing ototoxicity or symptoms such as tinnitus or dizziness and vertigo has enlarged in recent years, thanks to a better knowledge and a more specific attention of pharmaceutical firms and drug-control institutions. In daily clinical practice, there is a need for the family physician and the ENT specialist or audiologist (also in consideration of the possible medico-legal implications) to focus the attention on the possible risk of otological side effects. This would allow a clinical risk-benefit evaluation, weighing the possible clinical advantage in their field of competence against possible otological side-effects. The list of active ingredients and drugs is subdivided in categories based on their audiological and otoneurological side-effects, that have been signaled by the drug companies and/or ministerial notes. Drugs have also been subcategorized with regards to the field in which they are applied, the therapeutic indications and the clinical behaviour. They have also been organized in alphabetical order, for an easier consultation. The guide above, even if initially conceived for being used in Italy, also presents a more general and international interest, expecially as for as the concepts of pharmacology and the features of the active ingredients are concerned. The guide is, therefore, useful as for as we are concerned to any physician, regardless of the country he/she operates in.

  10. Comparison of local and systemic ciprofloxacin ototoxicity in the treatment of chronic media otitis.

    Science.gov (United States)

    Samarei, R

    2014-09-18

    Chronic media otitis is a common cause of reference to ear, nose and throat clinics and the treatment is one of the health problems among ENT specialists. Ciprofloxacin drop that is of fluoroquinolone drug class due to good treatment effect is now widely used in the treatment of chronic media otitis. Due to the widespread use, it seems proper research on the human population has not been taken to ensure its non-toxicity in the inner ear, therefore comparison of local ciprofloxacin ototoxicity with systemic in chronic media otitis is investigated in this study. This study was conducted as a randomized clinical trial. Prospective methods were considered and the number of samples in the study group was 40 patients that were treated with ciprofloxacin drops. And in the control group 32 patients with chronic media otitis who were treated with ciprofloxacin tablets. The collected data was analyzed using SPSS software. Statistical indicators of different frequencies in air conduction (AC) in both groups showed, there was significant improvement in hearing thresholds at frequencies of 250, 8000, 1000 in air conduction for the group receiving drops compared to the group receiving tablet. Based on statistical indicators in different frequencies of bone conduction in the two treated groups, there was significant difference in the two groups receiving tablets and drops only at a frequency of 4000 Hz that drop impact improves hearing threshold and in contrast in the group receiving tablet hearing loss was seen in the frequency of 4000. Topical ciprofloxacin is a safe and uncomplicated ototoxic drug that is an effective antibiotic used in the treatment of refractory chronic otitis those dregs such as pseudomonas aerogenusa and staphylococci resistant to methicillin are responsible for it, which in the usual doses has not harmful effects on hearing hairy cells.

  11. A Fully Automated High-Throughput Zebrafish Behavioral Ototoxicity Assay.

    Science.gov (United States)

    Todd, Douglas W; Philip, Rohit C; Niihori, Maki; Ringle, Ryan A; Coyle, Kelsey R; Zehri, Sobia F; Zabala, Leanne; Mudery, Jordan A; Francis, Ross H; Rodriguez, Jeffrey J; Jacob, Abraham

    2017-08-01

    Zebrafish animal models lend themselves to behavioral assays that can facilitate rapid screening of ototoxic, otoprotective, and otoregenerative drugs. Structurally similar to human inner ear hair cells, the mechanosensory hair cells on their lateral line allow the zebrafish to sense water flow and orient head-to-current in a behavior called rheotaxis. This rheotaxis behavior deteriorates in a dose-dependent manner with increased exposure to the ototoxin cisplatin, thereby establishing itself as an excellent biomarker for anatomic damage to lateral line hair cells. Building on work by our group and others, we have built a new, fully automated high-throughput behavioral assay system that uses automated image analysis techniques to quantify rheotaxis behavior. This novel system consists of a custom-designed swimming apparatus and imaging system consisting of network-controlled Raspberry Pi microcomputers capturing infrared video. Automated analysis techniques detect individual zebrafish, compute their orientation, and quantify the rheotaxis behavior of a zebrafish test population, producing a powerful, high-throughput behavioral assay. Using our fully automated biological assay to test a standardized ototoxic dose of cisplatin against varying doses of compounds that protect or regenerate hair cells may facilitate rapid translation of candidate drugs into preclinical mammalian models of hearing loss.

  12. Influence of Genetic Variants in TPMT and COMT Associated with Cisplatin Induced Hearing Loss in Patients with Cancer : Two New Cohorts and a Meta-Analysis Reveal Significant Heterogeneity between Cohorts

    NARCIS (Netherlands)

    Hagleitner, Melanie M.; Coenen, Marieke J. H.; Patino-Garcia, Ana; de Bont, Eveline S. J. M.; Gonzalez-Neira, Anna; Vos, Hanneke I.; van Leeuwen, Frank N.; Gelderblom, Hans; Hoogerbrugge, Peter M.; Guchelaar, Henk-Jan; te Loo, Maroeska W. M.

    2014-01-01

    Treatment with cisplatin-containing chemotherapy regimens causes hearing loss in 40-60% of cancer patients. It has been suggested that genetic variants in the genes encoding thiopurine S-methyltransferase (TPMT) and catechol O-methyltransferase (COMT) can predict the development of cisplatin-induced

  13. Ototoxicity of artemether/lumefantrine in the treatment of falciparum malaria: a randomized trial

    Directory of Open Access Journals (Sweden)

    Krause Eike

    2008-09-01

    Full Text Available Abstract Background Due to increasing drug resistance, artemisinin-based combination chemotherapy (ACT has become the first-line treatment of falciparum malaria in many endemic countries. However, irreversible ototoxicity associated with artemether/lumefantrine (AL has been reported recently and suggested to be a serious limitation in the use of ACT. The aim of the study was to compare ototoxicity, tolerability, and efficacy of ACT with that of quinine and atovaquone/proguanil in the treatment of uncomplicated falciparum malaria. Methods Ninety-seven patients in south-west Ethiopia with slide-confirmed malaria were randomly assigned to receive either artemether/lumefantrine or quinine or atovaquone/proguanil and followed-up for 90 days. Comprehensive audiovestibular testing by pure tone audiometry (PTA, transitory evoked (TE and distortion product (DP otoacoustic emissions (OAE and brain stem evoked response audiometry (BERA was done before enrolment and after seven, 28 and 90 days. Results PTA and DP-OAE levels revealed transient significant cochlear hearing loss in patients treated with quinine but not in those treated with artemether/lumefantrine or atovaquone/proguanil. TE-OAE could be elicited in all examinations, except for three patients in the Q group on day 7, who suffered a transient hearing loss greater than 30 dB. There was no evidence of drug-induced brain stem lesions by BERA measurements. Conclusion There was no detrimental effect of a standard oral regimen of artemether/lumefantrine on peripheral hearing or brainstem auditory pathways in patients with uncomplicated falciparum malaria. In contrast, transient hearing loss is common after quinine therapy and due to temporary outer hair cell dysfunction.

  14. Monitoramento auditivo na ototoxidade Auditory monitoring in ototoxicity

    Directory of Open Access Journals (Sweden)

    Lilian Cassia Bornia Jacob

    2006-12-01

    Full Text Available Algumas drogas, denominadas ototóxicas, têm a capacidade de lesar os sistemas auditivo e vestibular. O avanço tecnológico tem disponibilizado inúmeros recursos para realizar o monitoramento da audição, porém, apesar da disponibilização de protocolos de avaliação internacionais, existem controvérsias quanto à escolha do procedimento de maior sensibilidade e especificidade para este fim. OBJETIVO: Analisar os procedimentos audiológicos utilizados no monitoramento auditivo dos indivíduos expostos à medicação ototóxica. METODOLOGIA: Realizou-se busca eletrônica nas bases de dados MEDLINE e LILACS, a partir da combinação entre os descritores que caracterizaram as temáticas monitoramento auditivo, ototoxicidade e câncer. A literatura apontou dois principais procedimentos efetivos no monitoramento: a audiometria de altas freqüências e as emissões otoacústicas. Ambos permitem que a alteração no sistema auditivo seja identificada antes que haja um comprometimento dos limiares tonais na faixa de freqüências convencional, e conseqüentemente na habilidade de compreensão da fala. CONCLUSÃO: O protocolo de monitoramento auditivo foi sugerido considerando a capacidade do paciente em responder aos testes comportamentais e a etapa do monitoramento (primeira avaliação ou subseqüentes. No caso de portadores de câncer, o monitoramento auditivo deve ser disponibilizado no local de tratamento do indivíduo.Some pharmaceutical products are capable of damaging the human auditory system. Technological progress has provided numerous resources to monitor hearing but there still is some controversy regarding the selection of the most sensitive and specific tests. OBJECTIVE: to analyze audiological procedures used in the auditory monitoring of individuals exposed to ototoxic medication. METHODS: we searched the MEDLINE and LILACS literature databases, using terms pertinent to audiological monitoring, ototoxicity and cancer. The

  15. Real-time detection of caspase-2 activation in a single living HeLa cell during cisplatin-induced apoptosis

    Science.gov (United States)

    Lin, Juqiang; Zhang, Zhihong; Yang, Jie; Zeng, Shaoqun; Liu, Bifeng; Luo, Qingming

    2006-03-01

    Caspase-2 is important for the mitochondrial apoptotic pathway, however, the mechanism by which caspase-2 executes apoptosis remains obscure. We carry out the first measurements of the dynamics of caspase-2 activation in a single living cell by a FRET (fluorescence resonance energy transfer) probe. Two FRET probes are constructed that each encoded a CRS (caspase-2 or caspase-3 recognition site) fused with a cyan fluorescent protein (CFP) and a red fluorescent protein (DsRed) (CFP-CRS-DsRed). Using these probes, we found that during cisplatin-induced apoptosis, caspase-2 activation occurred more slowly than did activation of caspase-3; additionally, caspase-2 activation was initiated much earlier than that of caspase-3.

  16. Cisplatin-induced downregulation of miR-199a-5p increases drug resistance by activating autophagy in HCC cell

    Energy Technology Data Exchange (ETDEWEB)

    Xu, Ning; Zhang, Jianjun; Shen, Conghuan; Luo, Yi; Xia, Lei; Xue, Feng [Department of Transplantation and Hepatic Surgery, Renji Hospital, Shanghai Jiaotong University School of Medicine, 1630 Dongfang Road, Shanghai 200127, People' s Republic of China (China); Xia, Qiang, E-mail: xiaqiang1@yahoo.com.cn [Department of Transplantation and Hepatic Surgery, Renji Hospital, Shanghai Jiaotong University School of Medicine, 1630 Dongfang Road, Shanghai 200127, People' s Republic of China (China)

    2012-07-13

    Highlights: Black-Right-Pointing-Pointer miR-199a-5p levels were significantly decreased after cisplatin treatment. Black-Right-Pointing-Pointer Cisplatin treatment induced autophagy activation. Black-Right-Pointing-Pointer Cisplatin-induced downregulation of miR-199a-5p increases drug resistance by activating autophagy in HCC cell. -- Abstract: Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. Systemic chemotherapy plays an important role in the treatment of patients with advanced liver cancer. However, chemoresistance to cisplatin is a major limitation of cisplatin-based chemotherapy in the clinic, and the underlying mechanism of such resistance is not fully understood. In the study, we found that miR-199a-5p levels were significantly reduced in HCC patients treated with cisplatin-based chemotherapy. Cisplatin treatment also resulted in decreased miR-199a-5p levels in human HCC cell lines. Forced expression of miR-199a-5p promoted cisplatin-induced inhibition of cell proliferation. Cisplatin treatment activated autophagy in Huh7 and HepG2 cells, which increased cell proliferation. We further demonstrated that downregulated miR-199a-5p enhanced autophagy activation by targeting autophagy-associated gene 7 (ATG7). More important, autophagy inhibition abrogated miR-199a-5p downregulation-induced cell proliferation. These data demonstrated that miR-199a-5p/autophagy signaling represents a novel pathway regulating chemoresistance, thus offering a new target for chemotherapy of HCC.

  17. Human bladder cancer cells undergo cisplatin-induced apoptosis that is associated with p53-dependent and p53-independent responses.

    Science.gov (United States)

    Konstantakou, Eumorphia G; Voutsinas, Gerassimos E; Karkoulis, Panagiotis K; Aravantinos, Gerasimos; Margaritis, Lukas H; Stravopodis, Dimitrios J

    2009-08-01

    Cisplatin is a first-line chemotherapeutic agent and a powerful component of standard treatment regimens for several human malignancies including bladder cancer. DNA-Pt adducts produced by cisplatin are mainly responsible for cellular toxicity and induction of apoptosis. Identification of the mechanisms that control sensitivity to cisplatin is central to improving its therapeutic index and to successfully encountering the acquired resistance frequently emerging during therapy. In the present study, using MTT-based assays, Western blotting and semi-quantitative RT-PCR, we examined the apoptosis-related cellular responses to cisplatin exposure in two human urinary bladder cancer cell lines characterized by different malignancy grade and p53 genetic status. Both RT4 (grade I; wild-type p53) and T24 (grade III; mutant p53) cell types proved to be vulnerable to cisplatin apoptotic activity, albeit in a grade-dependent and drug dose-specific manner, as demonstrated by the proteolytic processing profiles of Caspase-8, Caspase-9, Caspase-3, and the Caspase repertoire characteristic substrates PARP and Lamin A/C, as well. The differential resistance of RT4 and T24 cells to cisplatin-induced apoptosis was associated with an RT4-specific phosphorylation (Ser15; Ser392) pattern of p53, together with structural amputations of the Akt and XIAP anti-apoptotic regulators. Furthermore, cisplatin administration resulted in a Granzyme B-mediated proteolytic cleavage of Hsp90 molecular chaperone, exclusively occurring in RT4 cells. To generate functional networks, expression analysis of a number of genes, including Bik, Bim, Bcl-2, FAP-1, Fas, FasL, TRAIL, Puma, Caspase-10, ATP7A, ATP7B and MRP1, was performed, strongly supporting the role of p53-dependent and p53-independent transcriptional responses in cisplatin-induced apoptosis of bladder cancer cells.

  18. A Multifaceted Medical Data Information System and One Product: The Index-Handbook of Ototoxic Agents

    Science.gov (United States)

    Heath, Miriam T.; Lunin, Lois F.

    1976-01-01

    Describes the creation and development of a biomedical information system that includes a machine-readable data base containing clinical and research data and a publication entitled the Index-Handbook of Ototoxic Agents. (Author)

  19. High-frequency audiometry reveals high prevalence of aminoglycoside ototoxicity in children with cystic fibrosis.

    Science.gov (United States)

    Al-Malky, Ghada; Dawson, Sally J; Sirimanna, Tony; Bagkeris, Emmanouil; Suri, Ranjan

    2015-03-01

    Intravenous aminoglycoside (IV AG) antibiotics, widely used in patients with cystic fibrosis (CF), are known to have ototoxic complications. Despite this, audiological monitoring is not commonly performed and if performed, uses only standard pure-tone audiometry (PTA). The aim of this study was to investigate ototoxicity in CF children, to determine the most appropriate audiological tests and to identify possible risk factors. Auditory assessment was performed in CF children using standard pure tone audiometry (PTA), extended high-frequency (EHF) audiometry and distortion-product otoacoustic emissions (DPOAE). 70 CF children, mean (SD) age 10.7 (3.5) years, were recruited. Of the 63 children who received IV AG, 15 (24%) children had ototoxicity detected by EHF audiometry and DPOAE. Standard PTA only detected ototoxicity in 13 children. Eleven of these children had received at least 10 courses of IV AG courses. A 25 to 85 dBHL hearing loss (mean±SD: 57.5±25.7 dBHL) across all EHF frequencies and a significant drop in DPOAE amplitudes at frequencies 4 to 8 kHz were detected. However, standard PTA detected a significant hearing loss (>20 dBHL) only at 8 kHz in 5 of these 15 children and none in 2 subjects who had significantly elevated EHF thresholds. The number of courses of IV AG received, age and lower lung function were shown to be risk factors for ototoxicity. CF children who had received at least 10 courses of IV AG had a higher risk of ototoxicity. EHF audiometry identified 2 more children with ototoxicity than standard PTA and depending on facilities available, should be the test of choice for detecting ototoxicity in children with CF receiving IV AG. Copyright © 2014 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

  20. Clinical predictors of aminoglycoside-induced ototoxicity in drug-resistant Tuberculosis patients on intensive therapy.

    Science.gov (United States)

    Sogebi, Olusola Ayodele; Adefuye, Bolanle Olufunlola; Adebola, Stephen Oluwatosin; Oladeji, Susan Modupe; Adedeji, Taiwo Olugbemiga

    2017-08-01

    The study objectives were to determine the incidence of aminoglycoside-induced ototoxicity in institutionalized patients on intensive phase of therapy for drug-resistant Tuberculosis (DR Tb) and also to assess clinical factors which could predict the ototoxicity. The study was a prospective analytical study among consecutive DR Tb patients who were admitted for intensive phase of therapy (of 4 months) at the DR-Tb center over a 12-month period. Patients were diagnosed as DR Tb using the Gene Xpert machine to confirm Rifampicin resistance. All eligible 70 out of 87 consenting patients were consecutively recruited into the study. Patients had baseline (admission) and serial pure tone audiometries (PTAs) performed at 4 weekly intervals until discharge after 4 months of admission. Audiometric confirmation of aminoglycoside-induced ototoxicity was done by comparing serial with baseline PTA. Among the 70 patients the male:female ratio was 1.7:1. Nine patients (12.9%) were retroviral-positive, and 16 patients (22.9%) were confirmed to have ototoxicity by audiometric criteria. The duration of treatment when ototoxicity was detected in the patients ranged 4-17 (Mean±SD; 9.4±3.4) weeks. Ototoxicity was detected in the audiometric low frequency ranges in 7 (43.8%) and at the high frequencies in 4 (25.0%) of the patients. Univariate analyses of clinical parameters found that age, underlying diabetes mellitus, deranged baseline PTAv >25dB HL, BMI on admission and retroviral status were significantly associated, while sex and previous drug regimen failure were not associated with ototoxicity. Multivariate adjusted logistic regression analyses, controlling for sex, revealed age (OR=1.068, p=0.018), BMI on admission (OR=0.673, p=0.012) and retroviral positivity (OR=8.822, p=0.014) of patients could significantly predict aminoglycoside-induced ototoxicity. Incidence of aminoglycoside-induced ototoxicity in DR Tb patients was 22.9%. The clinical predictors for ototoxicity were age

  1. Rosmarinic acid, active component of Dansam-Eum attenuates ototoxicity of cochlear hair cells through blockage of caspase-1 activity.

    Directory of Open Access Journals (Sweden)

    Hyun-Ja Jeong

    Full Text Available Cisplatin causes auditory impairment due to the apoptosis of auditory hair cells. There is no strategy to regulate ototoxicity by cisplatin thus far. Dansam-Eum (DSE has been used for treating the central nerve system injury including hearing loss in Korea. However, disease-related scientific investigation by DSE has not been elucidated. Here, we demonstrated that DSE and its component rosmarinic acid (RA were shown to inhibit apoptosis of the primary organ of Corti explants as well as the auditory cells. Administration of DSE and RA reduced the thresholds of the auditory brainstem response in cisplatin-injected mice. A molecular docking simulation and a kinetic assay show that RA controls the activity of caspase-1 by interaction with the active site of caspase-1. Pretreatment of RA inhibited caspase-1 downstream signal pathway, such as the activation of caspase-3 and 9, release of cytochrome c, translocation of apoptosis-inducing factor, up-regulation of Bax, down-regulation of Bcl-2, generation of reactive oxygen species, and activation of nuclear factor-κB. Anticancer activity by cisplatin was not affected by treatment with RA in SNU668, A549, HCT116, and HeLa cells but not B16F10 cells. These findings show that blocking a critical step by RA in apoptosis may be useful strategy to prevent harmful side effects of ototoxicity in patients with having to undergo chemotherapy.

  2. Mercury Exposure in a Riverside Amazon Population, Brazil: A Study of the Ototoxicity of Methylmercury

    Directory of Open Access Journals (Sweden)

    Hoshino, Ana

    2015-02-01

    Full Text Available Introduction Mercury poisoning causes hearing loss in humans and animals. Acute and long-term exposures produce irreversible peripheral and central auditory system damage, and mercury in its various forms of presentation in the environment is ototoxic. Objective We investigated the otoacoustic emissions responses in a riverside population exposed to environmental mercury by analyzing the inhibitory effect of the medial olivocochlear system (MOCS on transient otoacoustic emissions (TEOAE. Methods The purpose of the research was to evaluate the entire community independently of variables of sex and age. All of the participants were born and lived in a riverside community. After otolaryngologic evaluation, participants were received tympanometry, evaluation of contralateral acoustic reflexes, pure tone audiometry, and recording of TEOAEs with nonlinear click stimulation. Hair samples were collect to measure mercury levels. Results There was no significant correlation between the inhibitory effect of the MOCS, age, and the level of mercury in the hair. Conclusions The pathophysiological effects of chronic exposure may be subtle and nonspecific and can have a long period of latency; therefore, it will be important to monitor the effects of mercury exposure in the central auditory system of the Amazon population over time. Longitudinal studies should be performed to determine whether the inhibitory effect of the MOCS on otoacoustic emissions can be an evaluation method and diagnostic tool in populations exposed to mercury.

  3. The role of magnesium supplementation in cisplatin-induced nephrotoxicity in a rat model: No nephroprotectant effect

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    Farzaneh Ashrafi

    2012-01-01

    Results: All CP-treated animals lost weight, and the percentage of weight loss in Group 1 (low dose Mg sulfate treated was significantly higher compared with the positive control group (Group 4, P < 0.05. The increase in blood urea nitrogen (BUN and creatinine (Cr levels in serum in Group 1 were more than those in other groups ( P < 0.05. No statistical differences were observed in serum magnesium, nitrite, and total protein levels among the groups. The kidney tissue damage in Groups 1-3 was not significantly different when compared with Group 4. Moreover, the kidney and testis weights in Group 1 were significantly greater than those in the positive control group (P < 0.05. Conclusion: Regarding the BUN and Cr levels in the serum, kidneys weight, and the histopathological study, the low dose of Mg supplementation intensifies kidney toxicity and renal dysfunction in CP-induced nephrotoxicity in the rat model. However, the protective role of Mg with moderate and high doses is not certain.

  4. miR-101 Enhances Cisplatin-Induced DNA Damage Through Decreasing Nicotinamide Adenine Dinucleotide Phosphate Levels by Directly Repressing Tp53-Induced Glycolysis and Apoptosis Regulator Expression in Prostate Cancer Cells.

    Science.gov (United States)

    Huang, Shiqiao; Yang, Zhiguo; Ma, Yong; Yang, Yiyong; Wang, Shangren

    2017-04-01

    Tp53-induced glycolysis and apoptosis regulator (TIGAR) enhances the pentose phosphate pathway, thereby contributing directly to DNA repair due to generation of nicotinamide adenine dinucleotide phosphate (NADPH) and ribose-5-phosphate, two key precursors of DNA synthesis and repair. Targetscan database showed that miR-101 was predicted to potentially target TIGAR. Therefore, we speculated that miR-101 could enhance cisplatin-induced DNA damage by directly repressing TIGAR expression in prostate cancer cells. We found that upregulation of miR-101 inhibited viability, induced apoptosis, increased glycolysis rate and fructose-2,6-bisphosphate levels, decreased glucose-6-phosphate dehydrogenase expression and NADPH levels, and enhanced cisplatin-induced DNA damage in prostate cancer cells. We also demonstrated that TIGAR was a direct target of miR-101 by using luciferase activity assay. Furthermore, this study revealed that the roles of knockdown of TIGAR were similar to miR-101 upregulation in prostate cancer cells. Taken together, miR-101 inhibited viability, induced apoptosis, reprogramed glucose metabolism, and enhanced cisplatin-induced DNA damage through decreasing NADPH levels by directly suppressing the expression of TIGAR in prostate cancer cells.

  5. IN0523 (Urs-12-ene-3α,24β-diol) a plant based derivative of boswellic acid protect Cisplatin induced urogenital toxicity.

    Science.gov (United States)

    Singh, Amarinder; Arvinda, S; Singh, Surjeet; Suri, Jyotsna; Koul, Surinder; Mondhe, Dilip M; Singh, Gurdarshan; Vishwakarma, Ram

    2017-03-01

    The limiting factor for the use of Cisplatin in the treatment of different type of cancers is its toxicity and more specifically urogenital toxicity. Oxidative stress is a well-known phenomenon associated with Cisplatin toxicity. However, in Cisplatin treated group, abnormal animal behavior, decreased body weight, cellular and sub-cellular changes in the kidney and sperm abnormality were observed. Our investigation revealed that Cisplatin when administered in combination with a natural product derivative (Urs-12-ene-3α,24β-diol, labeled as IN0523) resulted in significant restoration of body weight and protection against the pathological alteration caused by Cisplatin to kidney and testis. Sperm count and motility were significantly restored near to normal. Cisplatin caused depletion of defense system i.e. glutathione peroxidase, catalase and superoxide dismutase, which were restored close to normal by treatment of IN0523. Reduction in excessive lipid peroxidation induced by Cisplatin was also found by treatment with IN0523. The result suggests that IN0523 is a potential candidate for ameliorating Cisplatin induced toxicity in the kidney and testes at a dose of 100mg/kg p.o. via inhibiting the oxidative stress/redox status imbalance and may be improving the efflux mechanism. Copyright © 2017 Elsevier Inc. All rights reserved.

  6. Ototoxicity of paclitaxel in rat cochlear organotypic cultures

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    Dong, Yang [Shanghai University of Traditional Chinese Medicine, Shanghai 201203 (China); Center for Hearing and Deafness, University at Buffalo, NY 14214 (United States); Ding, Dalian; Jiang, Haiyan [Center for Hearing and Deafness, University at Buffalo, NY 14214 (United States); Shi, Jian-rong [Shanghai University of Traditional Chinese Medicine, Shanghai 201203 (China); Salvi, Richard [Center for Hearing and Deafness, University at Buffalo, NY 14214 (United States); Roth, Jerome A., E-mail: jaroth@buffalo.edu [Department of Pharmacology and Toxicology, University at Buffalo, NY 14214 (United States)

    2014-11-01

    Paclitaxel (taxol) is a widely used antineoplastic drug employed alone or in combination to treat many forms of cancer. Paclitaxel blocks microtubule depolymerization thereby stabilizing microtubules and suppressing cell proliferation and other cellular processes. Previous reports indicate that paclitaxel can cause mild to moderate sensorineural hearing loss and some histopathologic changes in the mouse cochlea; however, damage to the neurons and the underlying cell death mechanisms are poorly understood. To evaluate the ototoxicity of paclitaxel in more detail, cochlear organotypic cultures from postnatal day 3 rats were treated with paclitaxel for 24 or 48 h with doses ranging from 1 to 30 μM. No obvious histopathologies were observed after 24 h treatment with any of the paclitaxel doses employed, but with 48 h treatment, paclitaxel damaged cochlear hair cells in a dose-dependent manner and also damaged auditory nerve fibers and spiral ganglion neurons (SGN) near the base of the cochlea. TUNEL labeling was negative in the organ of Corti, but positive in SGN with karyorrhexis 48 h after 30 μM paclitaxel treatment. In addition, caspase-6, caspase-8 and caspase-9 labeling was present in SGN treated with 30 μM paclitaxel for 48 h. These results suggest that caspase-dependent apoptotic pathways are involved in paclitaxel-induced damage of SGN, but not hair cells in cochlea. - Highlights: • Paclitaxel was toxic to cochlear hair cells and spiral ganglion neurons. • Paclitaxel-induced spiral ganglion degeneration was apoptotic. • Paclitaxel activated caspase-6, -8 and -8 in spiral ganglion neurons.

  7. Cisplatin resistance in non-small cell lung cancer cells is associated with an abrogation of cisplatin-induced G2/M cell cycle arrest.

    Science.gov (United States)

    Sarin, Navin; Engel, Florian; Kalayda, Ganna V; Mannewitz, Mareike; Cinatl, Jindrich; Rothweiler, Florian; Michaelis, Martin; Saafan, Hisham; Ritter, Christoph A; Jaehde, Ulrich; Frötschl, Roland

    2017-01-01

    The efficacy of cisplatin-based chemotherapy in cancer is limited by the occurrence of innate and acquired drug resistance. In order to better understand the mechanisms underlying acquired cisplatin resistance, we have compared the adenocarcinoma-derived non-small cell lung cancer (NSCLC) cell line A549 and its cisplatin-resistant sub-line A549rCDDP2000 with regard to cisplatin resistance mechanisms including cellular platinum accumulation, DNA-adduct formation, cell cycle alterations, apoptosis induction and activation of key players of DNA damage response. In A549rCDDP2000 cells, a cisplatin-induced G2/M cell cycle arrest was lacking and apoptosis was reduced compared to A549 cells, although equitoxic cisplatin concentrations resulted in comparable platinum-DNA adduct levels. These differences were accompanied by changes in the expression of proteins involved in DNA damage response. In A549 cells, cisplatin exposure led to a significantly higher expression of genes coding for proteins mediating G2/M arrest and apoptosis (mouse double minute 2 homolog (MDM2), xeroderma pigmentosum complementation group C (XPC), stress inducible protein (SIP) and p21) compared to resistant cells. This was underlined by significantly higher protein levels of phosphorylated Ataxia telangiectasia mutated (pAtm) and p53 in A549 cells compared to their respective untreated control. The results were compiled in a preliminary model of resistance-associated signaling alterations. In conclusion, these findings suggest that acquired resistance of NSCLC cells against cisplatin is the consequence of altered signaling leading to reduced G2/M cell cycle arrest and apoptosis.

  8. Activation of endoplasmic reticulum stress response by enhanced polyamine catabolism is important in the mediation of cisplatin-induced acute kidney injury.

    Directory of Open Access Journals (Sweden)

    Kamyar Zahedi

    Full Text Available Cisplatin-induced nephrotoxicity limits its use in many cancer patients. The expression of enzymes involved in polyamine catabolism, spermidine/spermine N1-acetyltransferase (SSAT and spermine oxidase (SMOX increase in the kidneys of mice treated with cisplatin. We hypothesized that enhanced polyamine catabolism contributes to tissue damage in cisplatin acute kidney injury (AKI. Using gene knockout and chemical inhibitors, the role of polyamine catabolism in cisplatin AKI was examined. Deficiency of SSAT, SMOX or neutralization of the toxic products of polyamine degradation, H2O2 and aminopropanal, significantly diminished the severity of cisplatin AKI. In vitro studies demonstrated that the induction of SSAT and elevated polyamine catabolism in cells increases the phosphorylation of eukaryotic translation initiation factor 2α (eIF2α and enhances the expression of binding immunoglobulin protein BiP/GRP78 and CCAAT-enhancer-binding protein homologous protein (CHOP/GADD153. The increased expression of these endoplasmic reticulum stress response (ERSR markers was accompanied by the activation of caspase-3. These results suggest that enhanced polyamine degradation in cisplatin AKI may lead to tubular damage through the induction of ERSR and the consequent onset of apoptosis. In support of the above, we show that the ablation of the SSAT or SMOX gene, as well as the neutralization of polyamine catabolism products modulate the onset of ERSR (e.g. lower BiP and CHOP and apoptosis (e.g. reduced activated caspase-3. These studies indicate that enhanced polyamine catabolism and its toxic products are important mediators of ERSR and critical to the pathogenesis of cisplatin AKI.

  9. Cisplatin resistance in non-small cell lung cancer cells is associated with an abrogation of cisplatin-induced G2/M cell cycle arrest.

    Directory of Open Access Journals (Sweden)

    Navin Sarin

    Full Text Available The efficacy of cisplatin-based chemotherapy in cancer is limited by the occurrence of innate and acquired drug resistance. In order to better understand the mechanisms underlying acquired cisplatin resistance, we have compared the adenocarcinoma-derived non-small cell lung cancer (NSCLC cell line A549 and its cisplatin-resistant sub-line A549rCDDP2000 with regard to cisplatin resistance mechanisms including cellular platinum accumulation, DNA-adduct formation, cell cycle alterations, apoptosis induction and activation of key players of DNA damage response. In A549rCDDP2000 cells, a cisplatin-induced G2/M cell cycle arrest was lacking and apoptosis was reduced compared to A549 cells, although equitoxic cisplatin concentrations resulted in comparable platinum-DNA adduct levels. These differences were accompanied by changes in the expression of proteins involved in DNA damage response. In A549 cells, cisplatin exposure led to a significantly higher expression of genes coding for proteins mediating G2/M arrest and apoptosis (mouse double minute 2 homolog (MDM2, xeroderma pigmentosum complementation group C (XPC, stress inducible protein (SIP and p21 compared to resistant cells. This was underlined by significantly higher protein levels of phosphorylated Ataxia telangiectasia mutated (pAtm and p53 in A549 cells compared to their respective untreated control. The results were compiled in a preliminary model of resistance-associated signaling alterations. In conclusion, these findings suggest that acquired resistance of NSCLC cells against cisplatin is the consequence of altered signaling leading to reduced G2/M cell cycle arrest and apoptosis.

  10. Mannitol to prevent cisplatin-induced nephrotoxicity in patients with squamous cell cancer of the head and neck (SCCHN) receiving concurrent therapy.

    Science.gov (United States)

    McKibbin, Trevor; Cheng, Linda L; Kim, Sungjin; Steuer, Conor E; Owonikoko, Taofeek K; Khuri, Fadlo R; Shin, Dong M; Saba, Nabil F

    2016-04-01

    The purpose of this study is to compare the incidence and severity of nephrotoxicity in patients receiving cisplatin with saline hydration vs. saline hydration with mannitol. Retrospective chart review of all patients receiving a starting dose of cisplatin 100 mg/m(2) with concurrent radiation for SCCHN between January 1, 2009 and March 1, 2013. All patients received pre and post hydration each with 1 l of 0.9 % saline. The mannitol group received 12.5 g of mannitol in the prehydration fluid. The primary outcome was to compare the rate of grade 3 or greater serum creatinine (SCr) increase in patients receiving saline hydration vs. the addition of mannitol; additional parameters of interest included creatinine clearance, electrolyte disturbances, dose changes, and discontinuation of cisplatin. Data from 139 patients (80 % male) with a median age of 56 years (range 22 to 75 years) were collected; 88 received mannitol and 51 received saline alone. On multivariable analysis, the mannitol group was less likely to have grade 3 SCr increase than saline only group (OR 0.16; 95 % CI 0.04-0.65; p value = 0.01). There were no grade 4 SCr increase events. Rates of hypomagnesemia and hypokalemia were similar across groups. Grade 3 hyponatremia was more likely to occur in the mannitol group as compared to saline alone group (41 vs 22 %; p = 0.026). The addition of mannitol to saline hydration decreased the incidence of grade 3 increases in SCr in this cohort of patients and may increase rates of hyponatremia. Further investigations of methods to lessen cisplatin-induced nephrotoxicity are needed.

  11. The protective effect of pomegranate extract against cisplatin toxicity in rat liver and kidney tissue.

    Science.gov (United States)

    Bakır, Salih; Yazgan, Ümit Can; İbiloğlu, İbrahim; Elbey, Bilal; Kızıl, Murat; Kelle, Mustafa

    2015-01-01

    The purpose of this study was to perform a histopathological investigation, at the light microscopy level, of the protective effects of pomegranate extract in cisplatin-induced liver and kidney damage in rats. Twenty-eight adult male Wistar albino rats were randomly divided into four groups of seven animals: Group 1: Control; Group 2: Treated for 10 consecutive days by gavage with pomegranate juice (2 ml/kg/day); Group 3: Injected intraperitoneally with cisplatin (8 mg/kg body weight, single dose) onset of the day 5, and Group 4: Treated by gavage with pomegranate juice 10 days before and after a single injection of cisplatin onset of the day 5. After 10 days, the animals were sacrificed and their kidneys and liver tissue samples were removed from each animal after experimental procedures. Cisplatin-induced renal and hepatic toxicity and the effect of pomegranate juice were evaluated by histopatological examinations. In the kidney tissue, pomegranate juice significantly ameliorated cisplatin-induced structural alterations when compared with the cisplatin alone group. But in the liver tissue, although pomegranate juice attenuated the cisplatin-induced toxicity only in two rats, significant improvement was not observed. In conclusion, these results demonstrate that the anti-oxidant pomegranate juice might have a protective effect against cisplatin-induced toxicity in rat kidney, but not in liver. Pomegranate juice could be beneficial as a dietary supplement in patients receiving chemotherapy medications.

  12. Mutations in cockayne syndrome-associated genes (Csa and Csb) predispose to cisplatin-induced hearing loss in mice

    NARCIS (Netherlands)

    R.N. Rainey (Robert N.); S.-Y. Ng (Sum-Yan); J. Llamas (Juan); G.T.J. van der Horst (Gijsbertus); N. Segil (Neil)

    2016-01-01

    textabstractCisplatin is a common and effective chemotherapeutic agent, yet it often causes permanent hearing loss as a result of sensory hair cell death. The causes of sensitivity to DNA-damaging agents in nondividing cell populations, such as cochlear hair and supporting cells, are poorly

  13. Thymol and carvacrol prevent cisplatin-induced nephrotoxicity by abrogation of oxidative stress, inflammation, and apoptosis in rats.

    Science.gov (United States)

    El-Sayed, E M; Abd-Allah, A R; Mansour, A M; El-Arabey, A A

    2015-04-01

    The aim of the present study is to assess the possible protective effects of thymol and carvacrol against cisplatin (CP)-induced nephrotoxicity. A single dose of CP {6 mg/kg, intraperitoneally (i.p.)} injected to male rats revealed significant increases in serum urea, creatinine, and tumor necrosis factor alpha levels. It also increased kidney contents of malondialdehyde and caspase-3 activity with significant reduction in serum albumin, kidney content of reduced glutathione as well as catalase, and superoxide dismutase activity as compared to that of the control group. In contrast, administration of thymol {20 mg/kg, orally (p.o.)} and/or carvacrol (15 mg/kg, p.o.) for 14 days before CP injection and for 7 days after CP administration restored the kidney function and examined oxidative stress parameters. In conclusion, thymol was more effective nephroprotective than carvacrol. Moreover, a combination of thymol and carvacrol had a synergistic nephroprotective effect that might be attributed to antioxidant, anti-inflammatory, and antiapoptotic activities. © 2014 Wiley Periodicals, Inc.

  14. Epigallocatechin-3-gallate protects against cisplatin-induced nephrotoxicity by inhibiting endoplasmic reticulum stress-induced apoptosis.

    Science.gov (United States)

    Chen, Binbin; Liu, Guangyi; Zou, Peimei; Li, Xing; Hao, Qiufa; Jiang, Bei; Yang, Xiangdong; Hu, Zhao

    2015-11-01

    Cisplatin (CP)-induced nephrotoxicity hampers its application in clinic. Green tea, particularly its predominant polyphenolic constituent epigallocatechin-3-gallate (EGCG), possesses anti-inflammatory, antioxidant, and anti-apoptotic properties. The present study was designed to investigate the protective effects of EGCG against CP-induced nephrotoxicity in mice. Male C57/BL6 mice in different groups received single injection of CP (20 mg/kg) and EGCG (100 mg/kg) in various sets and kidney tissues and blood were collected after killing. Then, samples were used for biochemical and immunohistochemical assay. Our results showed EGCG decreased biochemical factors and immunohistochemical damage induced by CP. Besides, expression of phosphorylated-extracellular signal-regulated kinase (p-ERK), glucose-regulated protein 78 (GRP78), caspase-12, and apoptosis of kidney were decreased by EGCG via inhibition of endoplasmic reticulum (ER) stress-induced apoptosis. © 2015 by the Society for Experimental Biology and Medicine.

  15. Precocious obesity predisposes the development of more severe cisplatin-induced acute kidney injury in young adult mice.

    Science.gov (United States)

    Ribeiro, Rosemara S; Passos, Clevia S; Novaes, Antônio S; Maquigussa, Edgar; Glória, Maria A; Visoná, Iria; Ykuta, Olinda; Oyama, Lila M; Boim, Mirian A

    2017-01-01

    Obesity and its consequences can damage the kidney over time. However, less is known about the impact of developing overweight/obesity during childhood on the kidney in adulthood and the renal impact of a superimposed acute kidney injury (AKI). This study evaluated the effect of obesity induced by a high-fat diet initiated soon after weaning on the adult life of mice and their response to superimposed nephrotoxic effects of cisplatin. C57BL/6 post-weaning mice (3 weeks old) were divided into a control group (CT, n = 12) and a high-fat diet group (HF, n = 12). After 9 weeks, animals were further divided into the following groups: CT, CT treated with a single dose of cisplatin (CTCis, 20 mg/kg, i.p.), HF and HF treated with cisplatin (HFCis). The HF group exhibited higher body weight gain compatible with a moderate obesity. Obese mice presented increased visceral adiposity, hyperkalemia, sodium retention, glomerular hyperfiltration and proteinuria, without any significant changes in blood pressure and glycemia. AKI induced by cisplatin was exacerbated in obese animals with a 92% reduction in the GFR versus a 31% decrease in the CTCis group; this sharp decline resulted in severely elevated serum creatinine and urea levels. Acute tubular necrosis induced by cisplatin was worsened in obese mice. The HFCis group exhibited robust systemic and intrarenal inflammation that was significantly higher than that in the CTCis group; the HFCis group also showed a higher degree of renal oxidative stress. In conclusion, the moderate degree of obesity induced shortly after weaning resulted in mild early renal alterations, however, obese young animals were prone to develop a much more severe AKI induced by cisplatin.

  16. Gene transfection mediated by polyethyleneimine-polyethylene glycol nanocarrier prevents cisplatin-induced spiral ganglion cell damage

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    Guan-gui Chen

    2015-01-01

    Full Text Available Polyethyleneimine-polyethylene glycol (PEI-PEG, a novel nanocarrier, has been used for transfection and gene therapy in a variety of cells. In our previous study, we successfully carried out PEI-PEG-mediated gene transfer in spiral ganglion cells. It remains unclear whether PEI-PEG could be used for gene therapy with X-linked inhibitor of apoptosis protein (XIAP in the inner ear. In the present study, we performed PEI-PEG-mediated XIAP gene transfection in the cochlea of Sprague-Dawley rats, via scala tympani fenestration, before daily cisplatin injections. Auditory brainstem reflex tests demonstrated the protective effects of XIAP gene therapy on auditory function. Immunohistochemical staining revealed XIAP protein expression in the cytoplasm of cells in the spiral ganglion, the organ of Corti and the stria vascularis. Reverse transcription-PCR detected high levels of XIAP mRNA expression in the cochlea. The present findings suggest that PEI-PEG nanocarrier-mediated XIAP gene transfection results in XIAP expression in the cochlea, prevents damage to cochlear spiral ganglion cells, and protects hearing.

  17. Prevention of paclitaxel and cisplatin induced ovarian damage in rats by a gonadotropin-releasing hormone agonist.

    Science.gov (United States)

    Ozcelik, Bulent; Turkyilmaz, Cagdas; Ozgun, Mahmut Tuncay; Serin, Ibrahim Serdar; Batukan, Cem; Ozdamar, Saim; Ozturk, Ahmet

    2010-03-15

    To evaluate the protective effect of GnRH agonist for the prevention of ovarian reserve during treatment with paclitaxel and cisplatin. Experimental study. University-based research laboratory. Seventy female Wistar-Albino rats. Each group consisted of 10 rats. Group 1 served as controls. Groups without GnRH agonist (groups 2, 3, and 4) were administered paclitaxel and cisplatin, respectively; the remaining groups (groups 5, 6, and 7) were given the same regimens with GnRH agonist. The GnRH agonist (leuprolide acetate; 2.5 microg/d subcutaneously for 5 weeks) was started four weeks before chemotherapy to achieve anovulation. Paclitaxel (7.5 mg/kg) and cisplatin (5 mg/kg) were administered intraperitoneally on the 28th day as a single dose. One week after the chemotherapy, the animals were euthanized and primordial, primary, secondary, and tertiary follicle counts were evaluated. Primordial, primary, and tertiary follicle counts in group 5 (paclitaxel plus GnRH agonist) and tertiary follicles in groups 2 and 3 had not decreased, but there was a significant decrease in other treatment groups compared with controls (P fertility in the preservation of primordial follicles. Copyright 2010 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

  18. Ototoxicity management: An investigation into doctors’ knowledge and practices, and the roles of audiologists in a tertiary hospital

    Directory of Open Access Journals (Sweden)

    Anna Wium

    2016-02-01

    Full Text Available Background: A significant number of medications that are prescribed by doctors to treat cancers, tuberculosis and infections are ototoxic. Disclosure of ototoxic risks is ethical practice as patients have the right to be properly informed about and involved in decisions about their health care. Often, doctors fail to disclose such information.Aim: This research investigated whether a group of doctors working in a South African academic hospital inform their patients about the ototoxic risks associated with specific medications, and if not, explore the reasons for it. It was determined what the participants’ knowledge levels of ototoxicity were as knowledge is seen as a precursor to disclosing information to their patients. A further aim of the research was to determine whether audiologists should expand their role by sharing information with patients and other professionals in the management of ototoxicity and in the hospital.Method: There were 90 participants included in the study through convenience sampling, which represented interns, medical officers, registrars and consultants in the neonatal intensive care unit, intensive care unit, ear–nose–throat, and internal and family medicine departments. The research made use of a descriptive survey design that collected mainly quantitative data and a limited amount of qualitative data through questionnaires. The data were descriptively analysed, and the qualitative data were listed and quantified.Results: The research firstly determined the participants’ knowledge and understanding of ototoxicity, and it was found that there was room for improvement. With reference to the current practices of doctors in the prescription of ototoxic medicines, it was found that disclosure of ototoxic risks was limited, mostly because of a lack of time and insufficient knowledge. In comparing knowledge and practices between levels of employment, it was found that particular post levels performed better than

  19. Ototoxicity management: An investigation into doctors’ knowledge and practices, and the roles of audiologists in a tertiary hospital

    Directory of Open Access Journals (Sweden)

    Anna Wium

    2016-12-01

    Full Text Available Background: A significant number of medications that are prescribed by doctors to treat cancers, tuberculosis and infections are ototoxic. Disclosure of ototoxic risks is ethical practice as patients have the right to be properly informed about and involved in decisions about their health care. Often, doctors fail to disclose such information. Aim: This research investigated whether a group of doctors working in a South African academic hospital inform their patients about the ototoxic risks associated with specific medications, and if not, explore the reasons for it. It was determined what the participants’ knowledge levels of ototoxicity were as knowledge is seen as a precursor to disclosing information to their patients. A further aim of the research was to determine whether audiologists should expand their role by sharing information with patients and other professionals in the management of ototoxicity and in the hospital. Method: There were 90 participants included in the study through convenience sampling, which represented interns, medical officers, registrars and consultants in the neonatal intensive care unit, intensive care unit, ear–nose–throat, and internal and family medicine departments. The research made use of a descriptive survey design that collected mainly quantitative data and a limited amount of qualitative data through questionnaires. The data were descriptively analysed, and the qualitative data were listed and quantified. Results: The research firstly determined the participants’ knowledge and understanding of ototoxicity, and it was found that there was room for improvement. With reference to the current practices of doctors in the prescription of ototoxic medicines, it was found that disclosure of ototoxic risks was limited, mostly because of a lack of time and insufficient knowledge. In comparing knowledge and practices between levels of employment, it was found that particular post levels performed better

  20. A Simple Model for Inducing Optimal Increase of SDF-1 with Aminoglycoside Ototoxicity

    Directory of Open Access Journals (Sweden)

    Hyun Mi Ju

    2017-01-01

    Full Text Available Objectives. As a homing factor of stem cell, stromal derived factor-1 (SDF-1 is important for the regenerative research in ototoxicity. Mice models with aminoglycoside ototoxicity have been widely used to study the regeneration capacity of MSCs in repair of cochlear injury. We developed a mouse model with maximal increase in SDF-1 levels in the inner ear, according to the “one-shot” doses of kanamycin and furosemide. Methods. C57BL/6 mice had kanamycin (420, 550, and 600 mg/kg dissolved in PBS, followed by an intraperitoneal injection of furosemide (130 mg/kg. The injuries of inner ear were measured with hearing thresholds, histology, and outer hair cell counts at 0, 3, 5, 7, 10, and 14 days before the sacrifice. The levels of SDF-1 in the inner ear were tested by real-time RT-PCR and immunohistochemistry. Results. There were a significant reduction in hearing thresholds and a maximal increase of SDF-1 levels in the furosemide 130 mg/kg + kanamycin 550 mg/kg group, but severe hearing deterioration over time was observed in the furosemide 130 mg/kg + kanamycin 600 mg/kg group and four mice were dead. SDF-1 was detected mostly in the stria vascularis and organ of Corti showing the highest increase in expression. Conclusion. We observed optimal induction of the stem cell homing factor in the newly generated aminoglycoside-induced ototoxicity mouse model using a “one-shot” protocol. This study regarding high SDF-1 levels in our mouse model of ototoxicity would play a major role in the development of therapeutic agents using MSC homing.

  1. Chirp-Evoked Otoacoustic Emissions and Middle Ear Absorbance for Monitoring Ototoxicity in Cystic Fibrosis Patients.

    Science.gov (United States)

    Garinis, Angela C; Keefe, Douglas H; Hunter, Lisa L; Fitzpatrick, Denis F; Putterman, Daniel B; McMillan, Garnett P; Gold, Jeffrey A; Feeney, M Patrick

    2017-07-13

    The goal of this study was to investigate the use of transient-evoked otoacoustic emissions (TEOAEs) and middle ear absorbance measurements to monitor auditory function in patients with cystic fibrosis (CF) receiving ototoxic medications. TEOAEs were elicited with a chirp stimulus using an extended bandwidth (0.71 to 8 kHz) to measure cochlear function at higher frequencies than traditional TEOAEs. Absorbance over a wide bandwidth (0.25 to 8 kHz) provides information on middle ear function. The combination of these time-efficient measurements has the potential to identify early signs of ototoxic hearing loss. A longitudinal study design was used to monitor the hearing of 91 patients with CF (median age = 25 years; age range = 15 to 63 years) who received known ototoxic medications (e.g., tobramycin) to prevent or treat bacterial lung infections. Results were compared to 37 normally hearing young adults (median age = 32.5 years; age range = 18 to 65 years) without a history of CF or similar treatments. Clinical testing included 226-Hz tympanometry, pure-tone air-conduction threshold testing from 0.25 to 16 kHz and bone conduction from 0.25 to 4 kHz. Experimental testing included wideband absorbance at ambient and tympanometric peak pressure and TEOAEs in three stimulus conditions: at ambient pressure and at tympanometric peak pressure using a chirp stimulus with constant incident pressure level across frequency and at ambient pressure using a chirp stimulus with constant absorbed sound power across frequency. At the initial visit, behavioral audiometric results indicated that 76 of the 157 ears (48%) from patients with CF had normal hearing, whereas 81 of these ears (52%) had sensorineural hearing loss for at least one frequency. Seven ears from four patients had a confirmed behavioral change in hearing threshold for ≥3 visits during study participation. Receiver operating characteristic curve analyses demonstrated that all three TEOAE conditions were useful for

  2. Group-Wide, Prospective Study of Ototoxicity Assessment in Children Receiving Cisplatin Chemotherapy (ACCL05C1): A Report From the Children's Oncology Group.

    Science.gov (United States)

    Knight, Kristin R; Chen, Lu; Freyer, David; Aplenc, Richard; Bancroft, Mary; Bliss, Bonnie; Dang, Ha; Gillmeister, Biljana; Hendershot, Eleanor; Kraemer, Dale F; Lindenfeld, Lanie; Meza, Jane; Neuwelt, Edward A; Pollock, Brad H; Sung, Lillian

    2017-02-01

    Purpose Optimal assessment methods and criteria for reporting hearing outcomes in children who receive treatment with cisplatin are uncertain. The objectives of our study were to compare different ototoxicity classification systems, to evaluate the feasibility of including otoacoustic emissions and extended high frequency audiometry, and to evaluate a central review mechanism for audiologic results for cisplatin-treated children in the cooperative group setting. Patients and Methods Eligible participants were 1 to 30 years, with planned cisplatin-containing treatment. Hearing evaluations were conducted at baseline, before each cisplatin cycle, and at the end of therapy. Audiologic results were assessed and graded by the testing audiologist and by two central review audiologists using the American Speech-Language-Hearing Association Ototoxicity Criteria (ASHA), Common Terminology Criteria for Adverse Events, version 3.0 (CTCAE), and Brock Ototoxicity Grades (Brock). One central reviewer also used the Society for Industrial and Organizational Psychology Ototoxicity Scale (SIOP). Results At the end of treatment, the prevalence of any degree of ototoxicity ranged from 40% to 56%, and severe ototoxicity ranged from 7% to 22%. Compared with CTCAE, SIOP detected significantly more ototoxicity ( P = .004), whereas Brock criteria detected significantly fewer patients with any or severe ototoxicity ( P < .001 for both). SIOP detected ototoxicity earlier than did the other scales. Agreement between the central reviewers and the institutional audiologist was almost perfect for ASHA and Brock, whereas the poorest agreement occurred with CTCAE. Conclusion The SIOP scale may be superior to ASHA, Brock, and CTCAE scales for classifying ototoxicity in pediatric patients who were treated with cisplatin. Future studies should evaluate inter-rater reliability of the SIOP scale.

  3. Evaluation of Mitoquinone for Protecting Against Amikacin-Induced Ototoxicity in Guinea Pigs.

    Science.gov (United States)

    Dirain, Carolyn O; Ng, Maria Raye Ann V; Milne-Davies, Bailey; Joseph, Jerin K; Antonelli, Patrick J

    2017-11-29

    Mitoquinone (MitoQ) attenuates amikacin ototoxicity in guinea pigs. MitoQ, a mitochondria-targeted derivative of the antioxidant ubiquinone, has improved bioavailability and demonstrated safety in humans. Thus, MitoQ is a promising therapeutic approach for protecting against amikacin-induced ototoxicity. Both oral and subcutaneous administrations of MitoQ were tested. Amikacin-treated guinea pigs (n = 12-18 per group) received water alone (control) or MitoQ 30 mg/l-supplemented drinking water; or injected subcutaneously with 3 to 5 mg/kg MitoQ or saline (control). Auditory brainstem responses and distortion product otoacoustic emissions were measured before MitoQ or control solution administration and after amikacin injections. Cochlear hair cell damage was assessed using scanning electron microscopy and Western blotting. With oral administration, animals that received 30 mg/l MitoQ had better hearing than controls at only 24 kHz at 3-week (p = 0.017) and 6-week (p = 0.027) post-amikacin. With subcutaneous administration, MitoQ-injected guinea pigs had better hearing than controls at only 24 kHz, 2-week post-amikacin (p = 0.013). Distortion product otoacoustic emission (DPOAE) amplitudes were decreased after amikacin injections, but were not different between treatments (p > 0.05). Electron microscopy showed minor difference in outer hair cell loss between treatments. Western blotting demonstrated limited attenuation of oxidative stress in the cochlea of MitoQ-supplemented guinea pigs. Oral or subcutaneous MitoQ provided limited protection against amikacin-induced hearing loss and cochlear damage in guinea pigs. Other strategies for attenuating aminoglycoside-induced ototoxicity should be explored.

  4. Determination of ototoxicity of common otic drops using isolated cochlear outer hair cells.

    Science.gov (United States)

    Jinn, T H; Kim, P D; Russell, P T; Church, C A; John, E O; Jung, T T

    2001-12-01

    Otic drops are commonly used not only for otitis externa, but also for otorrhea in the presence of tympanostomy tubes or tympanic membrane perforations. Many studies have demonstrated the ototoxicity of common otic preparations such as Cortisporin otic drops (Monarch Pharmaceuticals, Bristol, TN). The purpose of this study was to assess the relative ototoxicity of common otic preparations by direct exposure to isolated cochlear outer hair cells (OHCs). OHCs from adult chinchilla cochlea were exposed to standard bathing solution (control), acetic acid, Acetasol HC (Alpharma USPD Inc., Baltimore, MD), Gentacidin (CIBA Vision Ophthalmics, Atlanta, GA), and Tobradex (Alcon, Fort Worth, TX). The cells were observed using an inverted microscope, and the images were recorded in digital still-frame and video, and analyzed on the Image Pro-Plus 3.0 program (Media Cybernetics, Silver Spring, MD). As measured by time to cell death and change in morphology of OHCs, acetic acid with or without hydrocortisone was most toxic to OHCs. Cortisporin was more cytotoxic than gentamicin and Tobradex.

  5. Functional hair cell mechanotransducer channels are required for aminoglycoside ototoxicity.

    Directory of Open Access Journals (Sweden)

    Abdelrahman Alharazneh

    Full Text Available Aminoglycosides (AG are commonly prescribed antibiotics with potent bactericidal activities. One main side effect is permanent sensorineural hearing loss, induced by selective inner ear sensory hair cell death. Much work has focused on AG's initiating cell death processes, however, fewer studies exist defining mechanisms of AG uptake by hair cells. The current study investigated two proposed mechanisms of AG transport in mammalian hair cells: mechanotransducer (MET channels and endocytosis. To study these two mechanisms, rat cochlear explants were cultured as whole organs in gentamicin-containing media. Two-photon imaging of Texas Red conjugated gentamicin (GTTR uptake into live hair cells was rapid and selective. Hypocalcemia, which increases the open probability of MET channels, increased AG entry into hair cells. Three blockers of MET channels (curare, quinine, and amiloride significantly reduced GTTR uptake, whereas the endocytosis inhibitor concanavalin A did not. Dynosore quenched the fluorescence of GTTR and could not be tested. Pharmacologic blockade of MET channels with curare or quinine, but not concanavalin A or dynosore, prevented hair cell loss when challenged with gentamicin for up to 96 hours. Taken together, data indicate that the patency of MET channels mediated AG entry into hair cells and its toxicity. Results suggest that limiting permeation of AGs through MET channel or preventing their entry into endolymph are potential therapeutic targets for preventing hair cell death and hearing loss.

  6. HDAC6 inhibition effectively reverses chemotherapy-induced peripheral neuropathy.

    Science.gov (United States)

    Krukowski, Karen; Ma, Jiacheng; Golonzhka, Olga; Laumet, Geoffroy O; Gutti, Tanuja; van Duzer, John H; Mazitschek, Ralph; Jarpe, Matthew B; Heijnen, Cobi J; Kavelaars, Annemieke

    2017-06-01

    Chemotherapy-induced peripheral neuropathy is one of the most common dose-limiting side effects of cancer treatment. Currently, there is no Food and Drug Administration-approved treatment available. Histone deacetylase 6 (HDAC6) is a microtubule-associated deacetylase whose function includes regulation of α-tubulin-dependent intracellular mitochondrial transport. Here, we examined the effect of HDAC6 inhibition on established cisplatin-induced peripheral neuropathy. We used a novel HDAC6 inhibitor ACY-1083, which shows 260-fold selectivity towards HDAC6 vs other HDACs. Our results show that HDAC6 inhibition prevented cisplatin-induced mechanical allodynia, and also completely reversed already existing cisplatin-induced mechanical allodynia, spontaneous pain, and numbness. These findings were confirmed using the established HDAC6 inhibitor ACY-1215 (Ricolinostat), which is currently in clinical trials for cancer treatment. Mechanistically, treatment with the HDAC6 inhibitor increased α-tubulin acetylation in the peripheral nerve. In addition, HDAC6 inhibition restored the cisplatin-induced reduction in mitochondrial bioenergetics and mitochondrial content in the tibial nerve, indicating increased mitochondrial transport. At a later time point, dorsal root ganglion mitochondrial bioenergetics also improved. HDAC6 inhibition restored the loss of intraepidermal nerve fiber density in cisplatin-treated mice. Our results demonstrate that pharmacological inhibition of HDAC6 completely reverses all the hallmarks of established cisplatin-induced peripheral neuropathy by normalization of mitochondrial function in dorsal root ganglia and nerve, and restoration of intraepidermal innervation. These results are especially promising because one of the HDAC6 inhibitors tested here is currently in clinical trials as an add-on cancer therapy, highlighting the potential for a fast clinical translation of our findings.

  7. Cisplatin-induced emesis: systematic review and meta-analysis of the ferret model and the effects of 5-HT receptor antagonists

    OpenAIRE

    Percie Du Sert, N.; Rudd, JA; Apfel, CC; Andrews, PL

    2010-01-01

    Abstract Purpose The ferret cisplatin emesis model has been used for ~30 years and enabled identification of clinically used anti-emetics. We provide an objective assessment of this model including efficacy of 5-HT3 receptor antagonists to assess its translational validity. Methods A systematic review identified available evidence and was used to perform meta-analyses. ...

  8. Transient alteration of the vestibular calyceal junction and synapse in response to chronic ototoxic insult in rats

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    Lara Sedó-Cabezón

    2015-10-01

    Full Text Available Ototoxicity is known to cause permanent loss of vestibule function through degeneration of sensory hair cells (HCs. However, functional recovery has been reported during washout after chronic ototoxicity, although the mechanisms underlying this reversible dysfunction are unknown. Here, we study this question in rats chronically exposed to the ototoxic compound 3,3′-iminodipropionitrile (IDPN. Pronounced alterations in vestibular function appeared before significant loss of HCs or stereociliary coalescence became evident by ultrastructural analyses. This early dysfunction was fully reversible if the exposure was terminated promptly. In cristae and utricles, the distinct junctions formed between type I HCs (HCI and calyx endings were completely dismantled at these early stages of reversible dysfunction, and completely rebuilt during washout. Immunohistochemical observations revealed loss and recovery of the junction proteins CASPR1 and tenascin-C and RT-PCR indicated that their loss was not due to decreased gene expression. KCNQ4 was mislocalized during intoxication and recovered control-like localization after washout. At early stages of the intoxication, the calyces could be classified as showing intact or lost junctions, indicating that calyceal junction dismantlement is triggered on a calyx-by-calyx basis. Chronic toxicity also altered the presence of ribeye, PSD-95 and GluA2 puncta in the calyces. These synaptic alterations varied between the two types of calyx endings (formed by calyx-only or dimorphic afferents and some persisted at the end of the washout period. The present data reveal new forms of plasticity of the calyx endings in adult mammals, including a robust capacity for rebuilding the calyceal junction. These findings contribute to a better understanding of the phenomena involved in progressive vestibular dysfunction and its potential recovery during and after ototoxic exposure.

  9. Concordance between the Chang and the International Society of Pediatric Oncology (SIOP) ototoxicity grading scales in patients treated with cisplatin for medulloblastoma

    Science.gov (United States)

    Bass, Johnnie K.; Huang, Jie; Onar-Thomas, Arzu; Chang, Kay W.; Bhagat, Shaum P.; Chintagumpala, Murali; Bartels, Ute; Gururangan, Sridharan; Hassall, Tim; Heath, John A.; McCowage, Geoffrey; Cohn, Richard J.; Fisher, Michael J.; Robinson, Giles; Broniscer, Alberto; Gajjar, Amar; Gurney, James G.

    2015-01-01

    Background Reporting ototoxicity is frequently complicated by use of various ototoxicity criteria. The International Society of Pediatric Oncology (SIOP) ototoxicity grading scale was recently proposed for standardized use in reporting hearing loss outcomes across institutions. The aim of this study was to evaluate the concordance between the Chang and SIOP ototoxicity grading scales. Differences between the two scales were identified and the implications these differences may have in the clinical setting were discussed. Procedure Audiological evaluations were reviewed for 379 patients with newly diagnosed medulloblastoma (ages 3–21 years). Each patient was enrolled on one of two St. Jude clinical protocols that included craniospinal radiation therapy and four courses of 75 mg/m2 cisplatin chemotherapy. The latest audiogram conducted 5.5 – 24.5 months post-protocol treatment initiation was graded using the Chang and SIOP ototoxicity criteria. Clinically significant hearing loss was defined as Chang grade ≥ 2a and SIOP ≥2. Hearing loss was considered serious (requiring a hearing aid) at the level of Chang grade ≥ 2b and SIOP ≥ 3. Results A strong concordance was observed between the Chang and SIOP ototoxicity scales (Stuart’s tau-c statistic = 0.89, 95% CI: 0.86, 0.91). Among those patients diagnosed with serious hearing loss, the two scales were in good agreement. However, the scales deviated from one another in classifying patients with less serious or no hearing loss. Conclusions Although discrepancies between the Chang and SIOP ototoxicity scales exist primarily for patients with no or minimal hearing loss, the scales share a strong concordance overall. PMID:24504791

  10. Caspase Activation of p21-Activated Kinase 2 Occurs during Cisplatin-Induced Apoptosis of SH-SY5Y Neuroblastoma Cells and in SH-SY5Y Cell Culture Models of Alzheimer's and Parkinson's Disease

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    Jerry W. Marlin

    2010-01-01

    Full Text Available p21-activated kinase 2 (PAK-2 appears to have a dual function in the regulation of cell survival and cell death. Activation of full-length PAK-2 by the p21 G-proteins Rac or Cdc42 stimulates cell survival. However, PAK-2 is unique among the PAK family because it is also activated through proteolytic cleavage by caspase 3 or similar caspases to generate the constitutively active PAK-2p34 fragment. Caspase activation of PAK-2 correlates with the induction of apoptosis in response to many stimuli and recombinant expression of PAK-2p34 has been shown to stimulate apoptosis in several human cell lines. Here, we show that caspase activation of PAK-2 also occurs during cisplatin-induced apoptosis of SH-SY5Y neuroblastoma cells as well as in SH-SY5Y cell culture models for Alzheimer's and Parkinson's disease. Inhibition of mitochondrial complex I or of ubiquitin/proteasome-mediated protein degradation, which both appear to be involved in Parkinson's disease, induce apoptosis and caspase activation of PAK-2 in SH-SY5Y cells. Overexpression of the amyloid precursor protein, which results in accumulation and aggregation of β-amyloid peptide, the main component of β-amyloid plaques in Alzheimer's disease, also induces apoptosis and caspase activation of PAK-2 in SH-SY5Y cells. Expression of the PAK-2 regulatory domain inhibits caspase-activated PAK-2p34 and prevents apoptosis in 293T human embryonic kidney cells, indicating that caspase activation of PAK-2 is directly involved in the apoptotic response. This is the first evidence that caspase activation of PAK-2 correlates with apoptosis in cell culture models of Alzheimer's and Parkinson's disease and that selective inhibition of caspase-activated PAK-2p34 could prevent apoptosis.

  11. A systematic review of mercury ototoxicity Uma revisão sistemática da ototoxicidade do mercúrio

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    Ana Cristina Hiromi Hoshino

    2012-07-01

    Full Text Available Mercury is neurotoxic, and numerous studies have confirmed its ototoxic effect. However, the diagnosis and follow-up of mercury exposure require understanding the pathophysiology of the chemical substance. Based on a systematic literature review, this study aimed to demonstrate whether mercury is ototoxic and to analyze its mechanism of action on the peripheral and central auditory system, in order to contribute to the diagnosis and follow-up of exposure. This was a systematic review of studies published on the effects of mercury exposure on the auditory system. The full text of the studies and their methodological quality were analyzed. The review identified 108 studies published on the theme, of which 28 met the inclusion criteria. All the articles in the analysis showed that mercury exposure is ototoxic and produces peripheral and/or central damage. Acute and long-term exposure produces irreversible damage to the central auditory system. Biomarkers were unable to predict the relationship between degree of mercury poisoning and degree of lesion in the auditory system.O mercúrio é neurotóxico e muitas pesquisas confirmam sua ação ototóxica. Porém, para o diagnóstico e acompanhamento da exposição é necessário entender a fisiopatologia da substância química. O objetivo do trabalho, por meio da revisão sistemática, é evidenciar se o mercúrio é ou não ototóxico e, sendo assim, qual seria sua forma de atuação no sistema auditivo periférico e central, de forma a contribuir para o diagnóstico e acompanhamento da exposição. É uma revisão sistemática dos trabalhos publicados sobre os efeitos da exposição ao mercúrio no sistema auditivo. Analisaram-se os estudos contemplados na íntegra e também sua qualidade metodológica. A pesquisa identificou 108 artigos publicados sobre o tema, sendo que 28 se enquadraram nos critérios de inclusão. Todos os artigos analisados evidenciaram que a exposição ao mercúrio é otot

  12. Low early ototoxicity rates for pediatric medulloblastoma patients treated with proton radiotherapy

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    Gidley Paul W

    2011-06-01

    Full Text Available Abstract Background Hearing loss is common following chemoradiotherapy for children with medulloblastoma. Compared to photons, proton radiotherapy reduces radiation dose to the cochlea for these patients. Here we examine whether this dosimetric advantage leads to a clinical benefit in audiometric outcomes. Methods From 2006-2009, 23 children treated with proton radiotherapy for medulloblastoma were enrolled on a prospective observational study, through which they underwent pre- and 1 year post-radiotherapy pure-tone audiometric testing. Ears with moderate to severe hearing loss prior to therapy were censored, leaving 35 ears in 19 patients available for analysis. Results The predicted mean cochlear radiation dose was 30 60Co-Gy Equivalents (range 19-43, and the mean cumulative cisplatin dose was 303 mg/m2 (range 298-330. Hearing sensitivity significantly declined following radiotherapy across all frequencies analyzed (P Conclusions Rates of high-grade early post-radiation ototoxicity following proton radiotherapy for pediatric medulloblastoma are low. Preservation of hearing in the audible speech range, as observed here, may improve both quality of life and cognitive functioning for these patients.

  13. Tumor Necrosis Factor-α-Induced Ototoxicity in Mouse Cochlear Organotypic Culture.

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    Qian Wu

    Full Text Available Tumor necrosis factor (TNF-α is a cytokine involved in acute inflammatory phase reactions, and is the primary upstream mediator in the cochlear inflammatory response. Treatment of the organ of Corti with TNF-α can induce hair cell damage. However, the resulting morphological changes have not been systematically examined. In the present study, cochlear organotypic cultures from neonatal mice were treated with various concentrations and durations of TNF-α to induce inflammatory responses. Confocal microscopy was used to evaluate the condition of hair cells and supporting cells following immunohistochemical staining. In addition, the ultrastructure of the stereocilia bundle, hair cells, and supporting cells were examined by scanning and transmission electron microscopy. TNF-α treatment resulted in a fusion and loss of stereocilia bundles in hair cells, swelling of mitochondria, and vacuolation and degranulation of the endoplasmic reticulum. Disruption of tight junctions between hair cells and supporting cells was also observed at high concentrations. Hair cell loss was preceded by apoptosis of Deiters' and pillar cells. Taken together, these findings detail the morphological changes in the organ of Corti after TNF-α treatment, and provide an in vitro model of inflammatory-induced ototoxicity.

  14. Long-Term Variability of Distortion-Product Otoacoustic Emissions in Infants and Children and Its Relation to Pediatric Ototoxicity Monitoring.

    Science.gov (United States)

    Konrad-Martin, Dawn; Knight, Kristin; McMillan, Garnett P; Dreisbach, Laura E; Nelson, Elsa; Dille, Marilyn

    2017-12-26

    Distortion-product otoacoustic emissions (DPOAEs) provide a rapid, noninvasive measure of outer hair cell damage associated with chemotherapy and are a key component of pediatric ototoxicity monitoring. Serial monitoring of DPOAE levels in reference to baseline measures is one method for detecting ototoxic damage. Interpreting DPOAE findings in this context requires that test-retest differences be considered in relation to normal variability, data which are lacking in children. This study sought to (1) characterize normal test-retest variability in DPOAE level over the long time periods reflective of pediatric chemotherapy regimens for a variety of childhood ages and f2 primary frequencies using common clinical instrumentation and stimulus parameters; (2) develop level-shift reference intervals; and (3) account for any age-related change in DPOAE level or measurement error that may occur as the auditory system undergoes maturational change early in life. Serial DPOAE measurements were obtained in 38 healthy children (25 females and 13 males) with normal hearing and ranging in age from one month to 10 years at the initial (baseline) visit. On average, children were tested 5.2 times over an observation period of 6.5 months. Data were collected in the form of DP grams, in which DPOAE level was measured for f2 ranging from 1.4 to 10 kHz, using a fixed f2/f1 ratio of 1.22 and stimulus level of 65/55 dB SPL for L1/L2. Age effects on DPOAE level and measurement error were estimated using Bayesian regression of the longitudinal data. The raw and model-based distribution of DPOAE test-retest differences were characterized using means and standard error of the measurement for several ages and f2's. DPOAE test-retest differences for the children in this study are at the high end of those previously observed in adults, as reflected in the associated shift reference intervals. Further, although we observe substantial child-specific variation in DPOAE level, the pattern of age

  15. High-dose metoclopramide + lorazepam versus low-dose metoclopramide + lorazepam + dehydrobenzperidol in the treatment of cisplatin-induced nausea and vomiting

    DEFF Research Database (Denmark)

    Herrstedt, Jørn; Hannibal, J; Hallas, Jesper

    1991-01-01

    In a randomized double-blind, cross-over trial of 34 patients receiving cisplatin-based chemotherapy (20-100 mg/m2), the antiemetic effect of high-dose metoclopramide (HDM) (10 mg/kg iv. loading dose + 7 hours continuous infusion) + lorazepam (L) (2.5 mg x 4 po) was compared with low-dose metoclo...

  16. Diallyl Trisulfide Inhibits Growth of NCI-H460in Vitroandin Vivo, and Ameliorates Cisplatin-Induced Oxidative Injury in the Treatment of Lung Carcinoma in Xenograft Mice.

    Science.gov (United States)

    Jiang, Xiaoyan; Zhu, Xiaosong; Liu, Na; Xu, Hongya; Zhao, Zhongxi; Li, Siying; Li, Shanzhong; Cai, Jianhua; Cao, Jimin

    2017-01-01

    Diallyl trisulfide (DATS), an organosulfuric component of garlic oil, exhibits potential anticancer and chemopreventive effects. Cisplatin (DDP), a common chemotherapeutic agent, has provided great therapeutic contributions to treating solid tumors, but with serious side effects. Here, we verified the anti-tumor properties of DATS on lung cancer in vitro and in vivo , and evaluated synergistic effects of DATS combined with DDP on the NCI-H460 xenograft model. Significantly decreased cell viabilities, cell cycle G 1 arrest, and apoptosis induction were observed in DATS treated NCI-H460 cells ( p <0.05). And injection of DATS (30 or 40 mg/kg) to female Balb/c mice significantly inhibited the growth of human NCI-H460 cell tumor xenograft ( p <0.001). Moreover, DATS in combination with DDP exhibited enhanced anti-tumor activity via induction of apoptosis. Apoptosis pathways were confirmed by modulation of p53, Bcl-2 family members; induction of active caspase-3/8/9 and activation of JNK- and p38-MAPK pathways. Interestedly, DATS+DDP administration exerted fewer side effects, such as suppressing the weight loss and ameliorating DDP-induced oxidative injury, especially in renal parenchyma. In addition, increased E-cadherin and decreased MMP-9 expression levels were observed in DATS-treated tumor tissues. These studies provide supports that DATS might be a potential candidate for combination with DDP in cancer treatment.

  17. Acacia hydaspica ethyl acetate extract protects against cisplatin-induced DNA damage, oxidative stress and testicular injuries in adult male rats.

    Science.gov (United States)

    Afsar, Tayyaba; Razak, Suhail; Khan, Muhammad Rashid; Almajwal, Ali

    2017-12-21

    Cisplatin (CP), an effective anticancer agent, carries the risk of impairing testicular function leading to infertility. The present study aimed at evaluating the protective effect of A. hydaspica ethyl acetate extract (AHE) against CP-induced oxidative stress and testicular injuries in rats. Rats were divided into six groups (n = 6). Group I (control), group II (CP single dose on day 16). Group III received AHE for 21 days. Group IV (CP + AHE; post- treatment group). Group V (AHE + CP; pre-treatment group) and group VI (CP + Sily). CP treatment reduced serum testosterone (T), LH and FSH, decreased the activity level of antioxidant enzymes while increased the concentration of oxidative stress markers, i.e. thiobarbituric acid reactive substances (TBARS), H 2 O 2 and nitric oxide (NO) along with corresponding DNA damages. Furthermore, CP induced adverse morphological changes in testis of rats including reduced epithelial height and tubular diameter, increased luminal diameter with impaired spermatogenesis. Pre and post-treatment with AHE reduced the side effects of CP in testis tissues through improvement in the reproductive hormonal secretions, enzymatic activities, histological and DNA damage parameters. Pretreatment seems to be more effective and equivalent to silymarin group in reversing the CP deleterious effects as compared to post-treatment. The results demonstrated that A. hydaspica treatment in CP-induced testicular toxicity augments the antioxidants defense mechanism, reverted the level of fertility hormones, suppressed the histomorphological alterations and DNA damages and thus provides the evidence that it may have a therapeutic role in free radical mediated diseases.

  18. The aqueous extract of cinnamon bark ameliorated cisplatin-induced cytotoxicity in vero cells without compromising the anticancer efficiency of cisplatin.

    Science.gov (United States)

    ElKady, Ayman I; Ramadan, Wafaa S

    2016-09-01

    Cis-diammine dichloroplatinum (CDDP) is one of the most important chemotherapeutic agents for cancer treatment. Nonetheless, its notable side effect, nephrotoxicity, undermines its clinical use. The current study was undertaken to evaluate the protective potential of the aqueous extract (AEC) of Cinnamomum cassia (cinnamon) against the cytotoxic effect of CDDP in vitro and to elaborate the molecular mechanism underlying protection. MTT assay was performed to assess viability of the normal kidney Vero cells treated with CDDP and/or AEC. Cells were stained with Coomassie blue, acridine orange and ethidium bromide to highlight morphological features of apoptosis. Caspase-3 activity, DNA fragmentation and reactive oxygen species (ROS) level were monitored to assess biochemical hallmarks of apoptosis. Quantitative RT-PCR and Western blot analyses were performed to elucidate expression of cellular molecules underlying the protective potential of AEC. CDDP-treated Vero cells exhibited hallmarks of apoptosis; these hallmarks were significantly suppressed in the presence of AEC. AEC did not alter activity of CDDP-induced cytotoxicity of breast and liver cancer cells. AEC treatment of Vero cells prevented CDDP-induced increased expression of mitochondrial Bax protein, release of mitochondrial cytochrome c, caspase-3 activation, DNA fragmentation and generation of ROS. AEC up-regulated expression of the cytoprotective gene (heme oxygenase (HO)-1). These findings suggest AEC has protective effects against CDDP-induced toxicity via preventing the activation of various cellular mechanisms mediating apoptotic cell death, without compromising the anticancer efficiency of CDDP. Thus, cinnamon may represent one of the most feasible ways to reduce the risk of CDDP-induced toxicity.

  19. Vitamin E, Vitamin C, or Losartan Is Not Nephroprotectant against Cisplatin-Induced Nephrotoxicity in Presence of Estrogen in Ovariectomized Rat Model

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    Mehdi Nematbakhsh

    2012-01-01

    Full Text Available Background. The nephroprotective effect of vitamins E and C or losartan against cisplatin (CP- induced nephrotoxicity when they are accompanied by estrogen was investigated. Methods. The ovariectomized rats received estradiol valerate for two weeks. At the end of the first week, a single dose of CP (7 mg/kg, IP was also administered, and they received placebo (group 1, vitamin E (group 2, vitamin C (group 3, or losartan (group 4 every day during the second week, and they were compared with another three control groups. Results. CP alone increased the serum levels of blood urea nitrogen (BUN, creatinine (Cr, and kidney tissue damage score (KTDS, significantly (P<0.05, however at the presence of estradiol and CP, vitamin C, vitamin E, or losartan not only did not decrease these parameters, but also increased them significantly (P<0.05. The serum level of superoxidase dismutase (SOD was reduced by CP (P<0.05, but it was increased when estradiol or estradiol plus vitamin C or losartan were added (P<0.05. Conclusion. The particular pharmacological dose of estrogen used in this study abolish the nephroprotective effects vitamins C and E or losartan against CP-induced nephrotoxicity.

  20. A single dose of dexamethasone encapsulated in polyethylene glycol-coated polylactic acid nanoparticles attenuates cisplatin-induced hearing loss following round window membrane administration

    Science.gov (United States)

    Sun, Changling; Wang, Xueling; Zheng, Zhaozhu; Chen, Dongye; Wang, Xiaoqin; Shi, Fuxin; Yu, Dehong; Wu, Hao

    2015-01-01

    This study aimed to investigate the sustained drug release properties and hearing protection effect of polyethylene glycol-coated polylactic acid (PEG-PLA) stealth nanoparticles loaded with dexamethasone (DEX). DEX was fabricated into PEG-PLA nanoparticles using an emulsion and evaporation technique, as previously reported. The DEX-loaded PEG-PLA nanoparticles (DEX-NPs) had a hydrodynamic diameter of 130±4.78 nm, and a zeta potential of −26.13±3.28 mV. The in vitro release of DEX from DEX-NPs lasted 24 days in phosphate buffered saline (pH 7.4), 5 days in artificial perilymph (pH 7.4), and 1 day in rat plasma. Coumarin 6-labeled NPs placed onto the round window membrane (RWM) of guinea pigs penetrated RWM quickly and accumulated to the organs of Corti, stria vascularis, and spiral ganglion cells after 1 hour of administration. The DEX-NPs locally applied onto the RWM of guinea pigs by a single-dose administration continuously released DEX in 48 hours, which was significantly longer than the free DEX that was cleared out within 12 hours after administration at the same dose. Further functional studies showed that locally administrated single-dose DEX-NPs effectively preserved outer hair cells in guinea pigs after cisplatin insult and thus significantly attenuated hearing loss at 4 kHz and 8 kHz frequencies when compared to the control of free DEX formulation. Histological analyses indicated that the administration of DEX-NPs did not induce local inflammatory responses. Therefore, prolonged delivery of DEX by PEG-PLA nanoparticles through local RWM diffusion (administration) significantly protected the hair cells and auditory function in guinea pigs from cisplatin toxicity, as determined at both histological and functional levels, suggesting the potential therapeutic benefits in clinical applications. PMID:25999718

  1. Recovery of the vestibulocolic reflex after aminoglycoside ototoxicity in domestic chickens.

    Science.gov (United States)

    Goode, C T; Carey, J P; Fuchs, A F; Rubel, E W

    1999-03-01

    Avian auditory and vestibular hair cells regenerate after damage by ototoxic drugs, but until recently there was little evidence that regenerated vestibular hair cells function normally. In an earlier study we showed that the vestibuloocular reflex (VOR) is eliminated with aminoglycoside antibiotic treatment and recovers as hair cells regenerate. The VOR, which stabilizes the eye in the head, is an open-loop system that is thought to depend largely on regularly firing afferents. Recovery of the VOR is highly correlated with the regeneration of type I hair cells. In contrast, the vestibulocolic reflex (VCR), which stabilizes the head in space, is a closed-loop, negative-feedback system that seems to depend more on irregularly firing afferent input and is thought to be subserved by different circuitry than the VOR. We examined whether this different reflex also of vestibular origin would show similar recovery after hair cell regeneration. Lesions of the vestibular hair cells of 10-day-old chicks were created by a 5-day course of streptomycin sulfate. One day after completion of streptomycin treatment there was no measurable VCR gain, and total hair cell density was approximately 35% of that in untreated, age-matched controls. At 2 wk postlesion there was significant recovery of the VCR; at this time two subjects showed VCR gains within the range of control chicks. At 3 wk postlesion all subjects showed VCR gains and phase shifts within the normal range. These data show that the VCR recovers before the VOR. Unlike VOR gain, recovering VCR gain correlates equally well with the density of regenerating type I and type II vestibular hair cells, except at high frequencies. Several factors other than hair cell regeneration, such as length of stereocilia, reafferentation of hair cells, and compensation involving central neural pathways, may be involved in behavioral recovery. Our data suggest that one or more of these factors differentially affect the recovery of these two

  2. A nontoxic concentration of cisplatin induces autophagy in cervical cancer: selective cancer cell death with autophagy inhibition as an adjuvant treatment.

    Science.gov (United States)

    Leisching, Gina; Loos, Benjamin; Botha, Matthys; Engelbrecht, Anna-Mart

    2015-03-01

    Increasing resistance to cisplatin as well as the severity of the adverse effects limit the use of this drug, particularly at high doses. Evidence has implicated the importance of autophagy in cancer resistance as well as the fact that various chemotherapy agents induce autophagy in cancer cells. We therefore aimed to first assess the role of autophagy in cisplatin treatment and second to assess whether a nontoxic concentration of cisplatin, together with autophagy inhibition, is able to maintain its cancer-specific cytotoxic action. Three human cervical cell lines were used: a noncancerous ectocervical epithelial cell line (Ect1/E6E7) and 2 cancerous cervical cell lines (HeLa and CaSki). Autophagy was monitored through the presence of the classical protein markers LC-3 II and p62 under basal and treatment conditions, and inhibited using bafilomycin and autophagy protein 5 (ATG5) siRNA under treatment conditions. Cell death was analyzed through examination of the apoptotic markers PARP and caspase-3 through Western blotting, as well as the Caspase-Glo assay to confirm caspase-3/7 activity. Cervical biopsies were analyzed for the presence of LC-3 using Western blotting and immunofluorescence to determine if a correlation between autophagic levels and the progression of the disease exists. Cervical cancer cells exhibit increased basal autophagic levels in comparison to the noncancerous counterparts. Cisplatin treatment enhanced autophagic activity in all 3 cell lines. Inhibition of this autophagic response together with cisplatin treatment leads to significant increases in cancer cell death. Expression profiles of LC-3 in normal, premalignant (low-grade and high-grade squamous intraepithelial lesion), and cancerous cervical tissue revealed that autophagy is significantly up-regulated in HSILs and carcinoma cervical tissue, which emphasized the role of autophagy in the progression of the disease. The inhibition of autophagy improves the cytotoxicity of a nontoxic

  3. Pentoxifylline sensitizes human cervical tumor cells to cisplatin-induced apoptosis by suppressing NF-kappa B and decreased cell senescence

    Directory of Open Access Journals (Sweden)

    Hernandez-Flores Georgina

    2011-11-01

    Full Text Available Abstract Background Worldwide, cervical cancer is the second most common causes of cancer in women and represents an important mortality rate. Cisplatin (CIS is a very important antitumoral agent and can lead tumor cells toward two important cellular states: apoptosis and senescence. In some types of cancers pentoxifylline (PTX sensitizes these cells to the toxic action of chemotherapeutics drugs such as adriamycin, inducing apoptosis. In the present work, we studied in vitro whether PTX alone or in combination with CIS induces apoptosis and/or senescence in cervix cancer HeLa and SiHa cell lines infected with HPV types 16 and 18, respectively, as well as in immortalized keratinocytyes HaCaT cells. Methods HeLa (HPV 18+, SiHa (HPV 16+ cervix cancer cells and non-tumorigenic immortalized HaCaT cells (control were treated with PTX, CIS or both. The cellular toxicity and survival fraction of PTX and CIS were determinate by WST-1 and clonogenic assays respectively. Apoptosis, caspase activation and phosphorylation of ERK1/2, p38, p65 (NF-κB, Bcl-2 and Bcl-XL anti-apoptotic proteins were determinated by flow cytometry. Senescence by microscopy. Phosphorylation of IκBα and IκB total were measured by ELISA. Pro-apoptotic, anti-apoptotic and senescence genes, as well as HPV-E6/7 mRNA expression, were detected by RT-PCR. Results Our results show that after 24 hours of incubation PTX per se is toxic for cancer cells affecting cell viability and inducing apoptosis. The toxicity in HaCaT cells was minimal. CIS induces apoptosis in HeLa and SiHa cells and its effect was significantly increases when the cells were treated with PTX + CIS. In all studies there was a direct correlation with levels of caspases (-3, -6, -7, -9 and -8 activity and apoptosis. CIS induces important levels of senescence and phosphorylation of ERK1/2, p38, p65/RELA, and IκBα, and decreased the expression of anti-apoptotic protein Bcl-XL. Surprisingly these levels were

  4. Ototoxidade da cisplatina: série de casos Cisplatin ototoxicity: series of cases

    Directory of Open Access Journals (Sweden)

    Luiz Alberto Alves Mota

    2007-08-01

    Full Text Available OBJETIVO: Avaliar a evolução clínica e audiométrica de indivíduos submetidos à quimioterapia com cisplatina. MÉTODOS: Foram avaliadas descritivamente quatro voluntárias, todas do gênero feminino e com idades entre 38 e 69 anos. Todas realizaram exame otorrinolaringológico e avaliação audiológica com audiometria tonal, vocal e imitanciometria antes e após o tratamento com cisplatina. Além disso, todas foram avaliadas subjetivamente pré e pós-quimioterapia por meio de aplicação de questionário. RESULTADOS: Uma voluntária não apresentou alterações auditivas. Três voluntárias apresentaram déficit auditivo sensorioneural, bilateral, de leve a moderado nas freqüências de 6kHz e 8 kHz após quimioterapia com cisplatina. Todas as voluntárias que desenvolveram perda auditiva apresentaram a queixa de zumbido após o tratamento. CONCLUSÃO: Por ser a cisplatina considerada droga ototóxica, é necessário o acompanhamento audiológico de pacientes submetidos à quimioterapia com essa droga, no intuito de realizar o diagnóstico precoce de perdas auditivas.OBJECTIVE: To evaluate the clinic and audiometric evolution of individuals who underwent chemotherapy with cisplatin. METHODS: Four volunteers, all women, between 38 and 69 years of age were descriptively evaluated. All did otorino-laryngoiatric exam and audiometric evaluation with tonal and speech audiometric and impedance tests before and after treatment with cisplatin. In addition, all were subjectively evaluated pre- and post-chemotherapy by a questionnaire. RESULTS: One volunteer did not present auditory disorders. Three volunteers presented bilateral hearing loss, mild to moderate in 6kHz and 8kHz frequencies, after chemotherapy with cisplatin. All volunteers who developed hearing loss after treatment also presented tinnitus. CONCLUSION: Since cisplatin is considered ototoxic, all individuals undergoing chemotherapy with this drug must be submitted to audiometric

  5. Ups and downs of Viagra: revisiting ototoxicity in the mouse model.

    Science.gov (United States)

    Au, Adrian; Stuyt, John Gerka; Chen, Daniel; Alagramam, Kumar

    2013-01-01

    related ototoxicity in humans.

  6. Ups and downs of Viagra: revisiting ototoxicity in the mouse model.

    Directory of Open Access Journals (Sweden)

    Adrian Au

    of Viagra related ototoxicity in humans.

  7. Quinine pharmacokinetics: ototoxic and cardiotoxic effects in healthy Caucasian subjects and in patients with falciparum malaria

    NARCIS (Netherlands)

    Claessen, F. A.; van Boxtel, C. J.; Perenboom, R. M.; Tange, R. A.; Wetsteijn, J. C.; Kager, P. A.

    1998-01-01

    To study the pharmacokinetic behaviour of quinine in Caucasians with and without malaria. Quinine-dihydrochloride was administered intravenously as a single dose of 300 mg to 12 healthy subjects and as multiple doses of 600 mg in 4 h every 8 h in 10 patients with falciparum malaria. Plasma quinine

  8. Caspase Activation of p21-Activated Kinase 2 Occurs During Cisplatin-Induced Apoptosis of SH-SY5Y Neuroblastoma Cells and in SH-SY5Y Cell Culture Models of Alzheimer’s and Parkinson’s Disease

    Directory of Open Access Journals (Sweden)

    Jerry W. Marlin

    2010-04-01

    Full Text Available p21-activated kinase 2 (PAK-2 appears to have a dual function in the regulation of cell survival and cell death. Activation of full-length PAK-2 by the p21 G-proteins Rac or Cdc42 stimulates cell survival. However, PAK-2 is unique among the PAK family because it is also activated through proteolytic cleavage by caspase 3 or similar caspases to generate the constitutively active PAK-2p34 fragment. Caspase activation of PAK-2 correlates with the induction of apoptosis in response to many stimuli and recombinant expression of PAK-2p34 has been shown to stimulate apoptosis in several human cell lines. Here, we show that caspase activation of PAK-2 also occurs during cisplatin-induced apoptosis of SH-SY5Y neuroblastoma cells as well as in SH-SY5Y cell culture models for Alzheimer’s and Parkinson’s disease. Inhibition of mitochondrial complex I or of ubiquitin/proteasome-mediated protein degradation, which both appear to be involved in Parkinson’s disease, induce apoptosis and caspase activation of PAK-2 in SH-SY5Y cells. Overexpression of the amyloid precursor protein, which results in accumulation and aggregation of β-amyloid peptide, the main component of β-amyloid plaques in Alzheimer’s disease, also induces apoptosis and caspase activation of PAK-2 in SH-SY5Y cells. Expression of the PAK-2 regulatory domain inhibits caspase-activated PAK-2p34 and prevents apoptosis in 293T human embryonic kidney cells, indicating that caspase activation of PAK-2 is directly involved in the apoptotic response. This is the first evidence that caspase activation of PAK-2 correlates with apoptosis in cell culture models of Alzheimer’s and Parkinson’s disease and that selective inhibition of caspase-activated PAK-2p34 could prevent apoptosis.

  9. A biochemical mechanism of the ototoxic interaction between neomycin and ethacrynic acid.

    Science.gov (United States)

    Orsulakova, A; Schacht, J

    1982-01-01

    The effects of neomycin on tissue levels of ethacrynic acid was studied in vivo and in vitro. In vitro, the addition of neomycin to incubations of synaptosomes and inner ear tissues of guinea pigs raised the concentration of bound ethacrynate approximately two-fold. In vivo, radioactive ethacrynate was determined in the inner ear of mice by radioautography after intravenous injection of the drug (50 mg/kg body weight). Treatment of animals with neomycin (100 mg/kg body weight, intramuscularly) 60 min prior to ethacrynate led to a three-to five-fold higher accumulation of ethacrynate in cochlear structures. It is suggested that neomycin breaks down hemolabyrinthine or tissue permeability barriers and allows increased penetration of the other drug into the inner ear.

  10. Diallyl Trisulfide Inhibits Growth of NCI-H460 in Vitro and in Vivo, and Ameliorates Cisplatin-Induced Oxidative Injury in the Treatment of Lung Carcinoma in Xenograft Mice

    OpenAIRE

    Jiang, Xiaoyan; Zhu, Xiaosong; Liu, Na; Xu, Hongya; Zhao, Zhongxi; Li, Siying; Li, Shanzhong; Cai, Jianhua; Cao, Jimin

    2017-01-01

    Diallyl trisulfide (DATS), an organosulfuric component of garlic oil, exhibits potential anticancer and chemopreventive effects. Cisplatin (DDP), a common chemotherapeutic agent, has provided great therapeutic contributions to treating solid tumors, but with serious side effects. Here, we verified the anti-tumor properties of DATS on lung cancer in vitro and in vivo, and evaluated synergistic effects of DATS combined with DDP on the NCI-H460 xenograft model. Significantly decreased cell viabi...

  11. Simultaneous exposure to ethyl benzene and noise : synergistic effects on outer hair cells

    NARCIS (Netherlands)

    Cappaert, N.L.M.; Klis, S.F.L.; Muijser, H.; Kulig, B.M.; Smoorenburg, G.F.

    2001-01-01

    The effects on hearing of simultaneous exposure to the ototoxic organic solvent ethyl benzene and broad-band noise were evaluated in rats. The effects of three ethyl benzene concentrations (0, 300 or 400 ppm) and three noise levels (95 or 105 dBlin SPL or background noise at 65 dBlin SPL) and all

  12. Amelioration of behavioural, biochemical, and neurophysiological deficits by combination of monosodium glutamate with resveratrol/alpha-lipoic acid/coenzyme Q10 in rat model of cisplatin-induced peripheral neuropathy.

    Science.gov (United States)

    Bhadri, Naini; Sanji, Tejaswi; Madakasira Guggilla, Hariprasad; Razdan, Rema

    2013-01-01

    Cisplatin or cis-diamminedichloroplatinum (II) (CDDP) is a cytotoxic chemotherapeutic agent with dose-dependent peripheral neuropathy as a foremost side effect characterised by ataxia, pain, and sensory impairment. Cumulative drug therapy of CDDP is known to produce severe oxidative damage. It mainly targets and accumulates in dorsal root ganglia that in turn cause damage resulting in secondary nerve fibre axonopathy. In the present study, we investigated the neuroprotective effect of the combination of monosodium glutamate (MSG) with three individual antioxidants, that is, resveratrol, alpha-lipoic acid (ALA), and coenzyme Q10 (CoQ10), in cisplatin (2 mg/kg i.p. twice weekly) induced peripheral neuropathy in rats. After 8 weeks of treatment the degree of neuroprotection was determined by measuring behavioral and electrophysiological properties and sciatic nerve lipid peroxidation, as well as glutathione and catalase levels. The results suggested that pretreatment with the combination of MSG (500 mg/kg/day po) with resveratrol (10 mg/kg/day i.p.) or ALA (20 mg/kg/day i.p.) or CoQ10 (10 mg/kg weekly thrice i.p.) exhibited neuroprotective effect. The maximum neuroprotection of MSG was observed in the combination with resveratrol.

  13. Amelioration of Behavioural, Biochemical, and Neurophysiological Deficits by Combination of Monosodium Glutamate with Resveratrol/Alpha-Lipoic Acid/Coenzyme Q10 in Rat Model of Cisplatin-Induced Peripheral Neuropathy

    Directory of Open Access Journals (Sweden)

    Naini Bhadri

    2013-01-01

    Full Text Available Cisplatin or cis-diamminedichloroplatinum (II (CDDP is a cytotoxic chemotherapeutic agent with dose-dependent peripheral neuropathy as a foremost side effect characterised by ataxia, pain, and sensory impairment. Cumulative drug therapy of CDDP is known to produce severe oxidative damage. It mainly targets and accumulates in dorsal root ganglia that in turn cause damage resulting in secondary nerve fibre axonopathy. In the present study, we investigated the neuroprotective effect of the combination of monosodium glutamate (MSG with three individual antioxidants, that is, resveratrol, alpha-lipoic acid (ALA, and coenzyme Q10 (CoQ10, in cisplatin (2 mg/kg i.p. twice weekly induced peripheral neuropathy in rats. After 8 weeks of treatment the degree of neuroprotection was determined by measuring behavioral and electrophysiological properties and sciatic nerve lipid peroxidation, as well as glutathione and catalase levels. The results suggested that pretreatment with the combination of MSG (500 mg/kg/day po with resveratrol (10 mg/kg/day i.p. or ALA (20 mg/kg/day i.p. or CoQ10 (10 mg/kg weekly thrice i.p. exhibited neuroprotective effect. The maximum neuroprotection of MSG was observed in the combination with resveratrol.

  14. Salvia Officinalis and Cisplatin Effects on Pentylenetetrazole Induced Seizure Threshold

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    Mir Hadi Khayate-Nouri

    2013-11-01

    Full Text Available Background: Studies have shown that cisplatin have neuropathic effects and Salvia officinalis (SO could have therapeutic effects on nervous system. The aim of this study was to investigate the effects of SO hydroalcoholic extract and cisplatin on pentylenetetrazole (PTZ induced seizure in mice. Materials and methods: This is an experimental interventional study. For this purpose first group received normal saline, second group received SO extract, third group received cisplatin, in the fourth group received SO extract plus cisplatin and the subsequent seizure threshold was determined for each group. Results: The results showed that SO extract significantly (p<0.05 increased and in cisplatin group significantly (p<0.05 decreased seizure threshold. Simultaneous uses of cisplatin and SO extract caused to significantly increased seizure threshold (p<0.05 compared with cisplatin group. Conclusion: Considering different types of ingredients in SO extract which have beneficial effects on nervous system, it might be used to reduce cisplatin induced neuropathic effects. It seems that SO extract could be useful in cisplatin-induced seizure but further investigations are needed.

  15. Effect of low level laser (LLL) on cochlear and vestibular inner ear including tinnitus

    Science.gov (United States)

    Rhee, Chung-Ku; Lim, Eun-Seok; Kim, Young-Saeng; Chung, Yong-Won; Jung, Jae-Yun; Chung, Phil-Sang

    2006-02-01

    Objectives: 1. To investigate preventive effect of LLL on gentamicin-induced vestibular ototoxicity. 2. To evaluate the effectiveness of lower level laser (LLL) in the treatment of tinnitus. Methods: 1. Twenty guinea pigs were divided into control and laser groups. Vestibular ototoxicity was induced by intratympanic injection of gentamicin into left ear. LLL was irradiated into left ear canal of animals in laser group. Vestibular function of the animals was evaluated with vertical and off-vertical axis rotation testing. 2. Forty patients with tinnitus were treated with ginkgo biloba orally and randomly divided into control and laser groups. The 20 patients of laser group received 80.4 J/cm2 of 830 nm laser, 3 times per week for 4 weeks, via transmeatal irradiation. Tinnitus was evaluated by visual analogue scale (VAS) and tinnitus handicap inventory (THI). Results: 1. Preventive effect of LLL to gentamicin induced vestibular ototoxicity was demonstrated by preventing reduction of gain in slow harmonic acceleration test and modulation in the off-vertical axis rotation test. 2. Eleven of 20 laser group patients have shown significant improvement in VAS and THI compared to those of the control group. Conclusions: 1. LLL therapy may have preventive effect to vestibular ototoxicity. 2. LLL therapy in combination with ginkgo biloba seems to be worth trying on patients with tinnitus.

  16. Attenuation of cisplatin-induced nephrotoxicity in rats using ...

    African Journals Online (AJOL)

    The rats received a single dose injection of 10 mg/kg cisplatin. Other groups of rats received zerumbone (100 and 200 mg/kg), corn oil or the vehicle, dimethyl sulfoxide (DMSO) intraperitoneally for 4 days prior to cisplatin-injections. All animals were decapitated 16 h after cisplatin injection. Trunk blood was collected and ...

  17. Ginger Essential Oil Ameliorates Cisplatin-Induced Nephrotoxicity in ...

    African Journals Online (AJOL)

    ... factor (TNF-α) levels of kidney tissues were determined while mRNA expression levels were obtained using real-time polymerase chain reaction. Results: GEO treatment reduced significantly creatinine levels to 0.53 ± 0.02; 0.48 ± 0.008 and 0.46 ± 0.02 at 100, 200 and 400 mg/kg, respectively, compared with control (0.70 ...

  18. Pharmacological Protection From Radiation {+-} Cisplatin-Induced Oral Mucositis

    Energy Technology Data Exchange (ETDEWEB)

    Cotrim, Ana P. [Molecular Physiology and Therapeutics Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD (United States); Yoshikawa, Masanobu [Molecular Physiology and Therapeutics Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD (United States); Department of Clinical Pharmacology, Tokai University School of Medicine, Kanagawa (Japan); Sunshine, Abraham N.; Zheng Changyu [Molecular Physiology and Therapeutics Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD (United States); Sowers, Anastasia L.; Thetford, Angela D.; Cook, John A.; Mitchell, James B. [Radiation Biology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD (United States); Baum, Bruce J., E-mail: bbaum@dir.nidcr.nih.gov [Molecular Physiology and Therapeutics Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD (United States)

    2012-07-15

    Purpose: To evaluate if two pharmacological agents, Tempol and D-methionine (D-met), are able to prevent oral mucositis in mice after exposure to ionizing radiation {+-} cisplatin. Methods and Materials: Female C3H mice, {approx}8 weeks old, were irradiated with five fractionated doses {+-} cisplatin to induce oral mucositis (lingual ulcers). Just before irradiation and chemotherapy, mice were treated, either alone or in combination, with different doses of Tempol (by intraperitoneal [ip] injection or topically, as an oral gel) and D-met (by gavage). Thereafter, mice were sacrificed and tongues were harvested and stained with a solution of Toluidine Blue. Ulcer size and tongue epithelial thickness were measured. Results: Significant lingual ulcers resulted from 5 Multiplication-Sign 8 Gy radiation fractions, which were enhanced with cisplatin treatment. D-met provided stereospecific partial protection from lingual ulceration after radiation. Tempol, via both routes of administration, provided nearly complete protection from lingual ulceration. D-met plus a suboptimal ip dose of Tempol also provided complete protection. Conclusions: Two fairly simple pharmacological treatments were able to markedly reduce chemoradiation-induced oral mucositis in mice. This proof of concept study suggests that Tempol, alone or in combination with D-met, may be a useful and convenient way to prevent the severe oral mucositis that results from head-and-neck cancer therapy.

  19. Attenuation of cisplatin-induced nephrotoxicity in rats using ...

    African Journals Online (AJOL)

    USER

    2010-07-28

    Jul 28, 2010 ... quantitative data. Our study revealed that zerumbone reduced kidney damage and preserved renal functions as proved by microscopic observations and lesion scoring. ... Key words: Zerumbone, cisplatin, nephrotoxicity, oxidative stress, antioxidant glutathione. ..... monohydrated complex in the guinea pig.

  20. Amelioration of Cisplatin-Induced Nephrotoxicity in Rats by ...

    African Journals Online (AJOL)

    Purpose: To investigate the possible protective role of curcumin and α-tocopherol against cisplatininduced nephrotoxicity in rat. Methods: Male Wistar rats were divided into five groups. Groups 1 and 2 were intraperitoneally (i.p.) injected with normal saline and cisplatin (20 mg/kg), respectively. Groups 3, 4 and 5 were ...

  1. Ginger Essential Oil Ameliorates Cisplatin-Induced Nephrotoxicity in ...

    African Journals Online (AJOL)

    HP

    poessess potential benefits to renal patients. However, further investigations are essential to elucidate the mechanism by which GEO treatment ameliorates the nephrotoxicity. ACKNOWLEDGMENT. This study was supported by grants from the. Coordenadoria de Aperfeiçoamento de Pessoal de Nível Superior, Capes, and ...

  2. Effect of creatine and pioglitazone on Hk-2 cell line cisplatin nephrotoxicity.

    Science.gov (United States)

    Genc, Gurkan; Kilinc, Veli; Bedir, Abdulkerim; Ozkaya, Ozan

    2014-08-01

    Cisplatin is a chemotherapeutic agent, which is used in the treatment of various solid organ cancers, and its main dose limiting side effect of cisplatin is nephrotoxicity. The aim of this study is to investigate the role of pioglitazone and creatine on cisplatin nephrotoxicity in vitro. Real-time cell analyzer system (RTCA) was used for real-time and time-dependent analysis of the cellular response of HK-2 cells following incubation with cisplatin and combination with creatine or pioglitazone hydrochloride. First, half-maximal inhibitory concentrations (IC50) of cisplatin, creatine and pioglitazone were calculated by RTCA system. Afterwards creatine and pioglitazone was administered with serial dilutions under RTCA system. IC50 dose for cisplatin was 7.69 M × 10(-5) at 24th hour and 3.93 M × 10(-6) at 48th hour. IC50 dose for pioglitazone was 1.61 M × 10(-3) at 24th hour and 2.85 M × 10(-4) at 48th hour. Although cells were treated the dose of 40,225 mM creatine, IC50 dose could not been reached. Neither pioglitazone nor creatine had additional protective effect in any dose. Consequently, beneficial effect of creatine and pioglitazone on cisplatin-induced cell death could not be found. Further studies and clinical trials are needed to evaluate the effect of different doses of these drugs in cisplatin-induced nephrotoxicity.

  3. The antioxidant and antigenotoxic effects of pycnogenol(®) on rats treated with cisplatin.

    Science.gov (United States)

    Aydin, Birsen; Unsal, Meftun; Sekeroglu, Zulal A; Gülbahar, Yavuz

    2011-09-01

    Oxidative stress and inflammation are implicated in the pathogenesis of cisplatin-induced toxicity. Pycnogenol® is known for its strong antioxidant and anti-inflammatory effects. In this study, the possible protective effects of pycnogenol on kidney, bone marrow, and red blood cells in rats treated with cisplatin were investigated. The rats were divided into four groups. Group 1 was the control and groups 2, 3, and 4 were orally treated with pycnogenol (200 mg/kg bw, o.p) for 5 days, treated with cisplatin (7 mg/kg bw, i.p.) on the fifth day and treated with cisplatin plus pycnogenol, respectively. Antioxidative parameters in kidney and red blood cells were measured. Chromosome anomalies in bone marrow and renal histopathology were also investigated. Activities of pro-oxidant enzymes (myeloperoxidase and xanthine oxidase), malondialdehyde, and nitric oxide levels significantly increased but antioxidant enzymes activities decreased in the kidneys and red blood cells after cisplatin treatment. Pycnogenol treatment prior to the administration of cisplatin significantly decreased cisplatin-induced injury, as evidenced by its normalizing these parameters. Chromosomal aberrations decreased and mitotic index frequencies increased in bone marrow treated with cisplatin plus pycnogenol. These findings suggest that pycnogenol may be a useful protective agent against the toxicity associated with cisplatin therapy.

  4. Cisplatin-based chemotherapy: Add high-frequency audiometry in the regimen.

    Science.gov (United States)

    Arora, R; Thakur, J S; Azad, R K; Mohindroo, N K; Sharma, D R; Seam, R K

    2009-01-01

    Cisplatin-induced ototoxicity shows high interindividual variability and is often accompanied by transient or permanent tinnitus. It is not possible to identify the susceptible individuals before commencement of the treatment. We conducted a prospective, randomized and observational study in a tertiary care centre and evaluated the effects of different doses of cisplatin on hearing. Fifty-seven patients scheduled for cisplatin-based chemotherapy were included in the study. All patients were divided into three groups depending on the dose of cisplatin infused in 3 weeks. The subjective hearing loss was found in seven patients, while six patients had tinnitus during the chemotherapy. The hearing loss was sensorineural, dose dependent, symmetrical, bilateral and irreversible. Higher frequencies were first to be affected in cisplatin chemotherapy. As use of high-frequency audiometry is still limited in research work only, we need a strict protocol of adding high-frequency audiometry in the cisplatin-based chemotherapy regimen.

  5. Dihydroartemisinin potentiates the anticancer effect of cisplatin via mTOR inhibition in cisplatin-resistant ovarian cancer cells: involvement of apoptosis and autophagy

    Energy Technology Data Exchange (ETDEWEB)

    Feng, Xue [Department of Gynecology and Obstetrics, The First Affiliated Hospital of Harbin Medical University, Harbin 150001 (China); Li, Ling [Department of Brain Cognition Computing Lab, University of Kent, Kent CT2 7NZ (United Kingdom); Jiang, Hong; Jiang, Keping; Jin, Ye [Department of Gynecology and Obstetrics, The First Affiliated Hospital of Harbin Medical University, Harbin 150001 (China); Zheng, Jianhua, E-mail: zhengjianhua1115@126.com [Department of Gynecology and Obstetrics, The First Affiliated Hospital of Harbin Medical University, Harbin 150001 (China)

    2014-02-14

    Highlights: • Phosphorylation of mTOR is abnormal activation in SKOV3/DDP ovarian cancer cells. • Downregulation of mTOR by DHA helps to sensitize the SKOV3/DDP cells to chemotherapy. • DHA has the potential of induce autophagy in cancer cells. - Abstract: Dihydroartemisinin (DHA) exhibits anticancer activity in tumor cells but its mechanism of action is unclear. Cisplatin (DDP) is currently the best known chemotherapeutic available for ovarian cancer. However, tumors return de novo with acquired resistance over time. Mammalian target of rapamycin (mTOR) is an important kinase that regulates cell apoptosis and autophagy, and its dysregulation has been observed in chemoresistant human cancers. Here, we show that compared with control ovarian cancer cells (SKOV3), mTOR phosphorylation was abnormally activated in cisplatin-resistant ovarian cancer cells (SKOV3/DDP) following cisplatin monotherapy. Treatment with cisplatin combined with DHA could enhance cisplatin-induced proliferation inhibition in SKOV3/DDP cells. This mechanism is at least partially due to DHA deactivation of mTOR kinase and promotion of apoptosis. Although autophagy was also induced by DHA, the reduced cell death was not found by suppressing autophagic flux by Bafilomycin A1 (BAF). Taken together, we conclude that inhibition of cisplatin-induced mTOR activation is one of the main mechanisms by which DHA dramatically promotes its anticancer effect in cisplatin-resistant ovarian cancer cells.

  6. Brain-derived neurotrophic factor and nitric oxide synthase inhibitor protect the vestibular organ against gentamicin ototoxicity.

    Science.gov (United States)

    Takumida, Masaya; Anniko, Matti

    2002-01-01

    In order to find a way to develop a new treatment for inner ear disorders, the effects of a nitric oxide synthase (NOS) inhibitor [N-nitro-L-arginine methylester (L-NAME)] and a neurotrophin [brain-derived neurotrophic factor (BDNF)] were investigated. The effect of L-NAME and BDNF on gentamicin-induced vestibular hair cell damage was investigated by using the in vitro LIVE/DEAD system. Both L-NAME and BDNF individually reduced the vestibular hair cell damage caused by gentamicin but the combination of L-NAME and BDNF was more successful in preventing damage. It is therefore suggested that treatment with a combination of an NOS inhibitor and a neurotrophin will help us to treat inner ear disorders.

  7. Ototoxicity (Ear Poisoning) (For Parents)

    Science.gov (United States)

    ... Kids For Parents MORE ON THIS TOPIC Balance Disorders Cochlear Implants Delayed Speech or Language Development Speech-Language Therapy Physical Therapy Hearing Evaluation in Children The Danger of Antibiotic Overuse Eardrum Injuries What's ...

  8. Herbal Medicines for the Treatment of Cancer Chemotherapy-Induced Side Effects

    Directory of Open Access Journals (Sweden)

    Shunsuke eOhnishi

    2015-02-01

    Full Text Available Accumulating evidence suggests that Japanese herbal medicines, called Kampo, have beneficial effects on cancer chemotherapy-induced side effects. Rikkunshito ameliorates cisplatin-induced anorexia through an antagonistic effect on the 5-HT receptors and by increasing the serum ghrelin levels. Hangeshashinto improves irinotecan-induced diarrhea and chemotherapy-induced mucositis by inhibiting the activity of β-glucuronidase as well as the synthesis of prostaglandin E2. Goshajinkigan prevents oxaliplatin-induced neurotoxicity, possibly through suppressing functional alterations of the transient receptor potential (TRP channels. In this review, we will summarize the currently available literature regarding the clinical efficacy and potential mechanisms of Kampo medicines in the treatment of cancer chemotherapy-induced side effects.

  9. The Effect of Nystatin Solution on Otoacoustic Emissions in Rats.

    Science.gov (United States)

    Vural, Alperen; Şahin, Mehmet İlhan; Aydın, Mesut; Gündoğdu, Ramazan; Arlı, Turan; Okuducu, Hacı; Dizdar, Denizhan; Külahlı, İsmail

    2017-04-01

    In patients with a perforated tympanic membrane, topically administered medication reaches the middle ear and thus creates a risk of ototoxicity. The aim of the present study was to evaluate the possible ototoxic effect of the antifungal medication nystatin when administered to the rat middle ear cavity. Three groups (negative control, positive control, and study groups), each containing eight rats, were formed. Before the drug administration, distortion product otoacoustic emissions were recorded in both ears of each rat. Saline (0.09% NaCl), gentamycin, and nystatin solutions were transtympanically injected into the middle ear cavities of the negative control, positive control, and study groups, respectively, for five consecutive days. Seven days after the last infiltration, the control otoacoustic emission was measured, and the data of the 2, 3, 4, 6, 8 kHz frequencies were statistically analyzed. There were no significant changes between the 1st and 2nd measures in the negative control group (0.09% NaCl) (p>0.05), whereas there were significant changes between the 1st and 2nd measures in the positive control group (gentamycin) and study group (nystatin) (p<0.05). Ototopical medications carry a risk of ototoxicity in patients with perforated ear drums. In the present study, it was shown that nystatin, an antifungal that can be ototopically used in the treatment of otomycosis, may cause a decrease in otoacoustic emissions in rats when administered into the middle ear cavities.

  10. Emissões otoacústicas x Cisplatina: detecção precoce da ototoxicidade em pacientes oncológicos Otoacoustic emissions x Cisplatin: precocious detection of ototoxicity in oncologic patients

    Directory of Open Access Journals (Sweden)

    Ruysdael Zocoli

    2003-03-01

    Full Text Available Estudos mostram que existem numerosas substâncias reconhecidas como potencialmente ototóxicas e entre as principais, na classe dos medicamentos, destacam-se os quimioterápicos. OBJETIVO: o objetivo deste trabalho foi realizar um estudo da ototoxicidade através das emissões otoacústicas evocadas - produto de distorção (EOA-PD, pré e pós-aplicação do quimioterápico Cisplatina, em indivíduos adultos, moradores da cidade de Blumenau/SC. FORMA DE ESTUDO: Prospectivo clínico. MATERIAL E MÉTODO: Foram estudados 11 indivíduos com patologia oncológica, idade variando entre 29 e 73 anos, através das emissões otoacústicas evocadas - produto de distorção, prévia e posteriormente à aplicação da Cisplatina, utilizando-se o equipamento Madsen Cappela acoplado ao Notebook Toshiba Satélite. RESULTADOS: Os resultados não mostraram mudanças significativas nas respostas das EOA-PD nas freqüências de 2, 3 e 4 kHz, porém, em 1 e 6 kHz, ocorreram alterações na sensibilidade auditiva, após a aplicação da Cisplatina.Studies show that there are numerous substances known as potentially ototoxic and among the main ones in the medicine classes, stands out the chemotherapeutics. AIM: The objective of this work was to achieve a study of the ototoxicity through otoacoustic emissions - product of distortion (EOA - PD, pre and post-application of the chemotherapeutic Cisplatin, in adults individuals, residents of the city of Blumenau/SC. STUDY FORM: Clinic prospective. MATERIAL AND METHOD: There were 11 individuals studied with oncologic pathology, age between 29 and 73 years old, through the otoacoustic emissions - product of distortion, previous and subsequently to the Cisplatin application, using the Madsen Cappela equipment coupled to the notebook Toshiba satellite computer. RESULTS: The results didn't show significant changes on the answers of the EOA - PD on the frequencies of 2, 3 and 4 kHz, however, in 1 and 6 kHz, alterations

  11. Cytotoxic and toxicogenomic effects of silibinin in bladder cancer ...

    Indian Academy of Sciences (India)

    68

    Among urinary bladder tumors, urothelial cell carcinoma (UCC) is one of the ..... human hepatocellular (HuH7) and renal carcinoma (Caki-1) cells, this compound ..... oil (Java) attenuates cisplatin-induced oxidative stress, nephrotoxicity and.

  12. Effects of common topical otic preparations on the morphology of isolated cochlear outer hair cells.

    Science.gov (United States)

    Russell, P T; Church, C A; Jinn, T H; Kim, D J; John, E O; Jung, T T

    2001-01-01

    Otic drops are commonly used not only for otitis externa but also for otorrhea in the presence of tympanostomy tube or tympanic membrane perforation. Many studies have demonstrated the ototoxicity of common otic preparations such as Cortisporin otic drops. Recent studies have suggested the use of fluoroquinolone antibiotic drops as an alternative owing to their excellent antimicrobial coverage and no ototoxic effect. The purpose of this study was to assess the relative ototoxicity of four common otic preparations by direct exposure to isolated cochlear outer hair cells (OHCs). OHCs from adult chinchilla cochlea were exposed to standard bathing solution (control), Cortisporin, Cipro HC, Ciloxan, and Floxin. The cells were observed using an inverted microscope, and the images recorded in digital still-frame and video, and analyzed on the Image Pro-Plus 3.0 program. As measured by time to cell death and change in morphology of OHCs, Cortisporin was most toxic to OHCs. Among the fluoroquinolone drops, Floxin was more toxic than Ciloxan or Cipro HC.

  13. The effect of the carotenoid bixin and annatto seeds on hematological markers and nephrotoxicity in rats subjected to chronic treatment with cisplatin

    Directory of Open Access Journals (Sweden)

    Lucéia F. Souza

    Full Text Available ABSTRACT This study assessed the protective effect of the carotenoid bixin and annatto seeds against possible nephrotoxicity induced with a single peritoneal administration of pharmacological cisplatin in male Wistar rats. After 48 h, the blood cell differential count showed a significant reduction in neutrophil counts in rats that received a diet rich in bixin when compared to the group that received only cisplatin. The use of cisplatin led to an increase in kidney weight. The carotenoid bixin attenuated renal injury, characterized by increased polymorphonuclear infiltration. No protective effect was observed with respect to Annatto. These results demonstrate the role of toxic cisplatin and suggest that bixin affords a protective effect against cisplatin-induced nephrotoxicity in adult Wistar rats.

  14. Protective effects of thymol against nephrotoxicity induced by cisplatin with using 99mTc-DMSA in mice.

    Science.gov (United States)

    Hosseinimehr, Seyed Jalal; Asadian, Reza; Naghshvar, Farshad; Azizi, Soheil; Jafarinejad, Mehdi; Noaparast, Zohreh; Abedi, Seyed Mohammad; Hosseini, Seyed Amir Hossein

    2015-03-01

    In this study, we investigated the protective effect of thymol as a natural compound against cisplatin-induced nephrotoxicity by quantitative renal 99mTc-DMSA uptake and compared its effect with histopathology in mice. Mice were divided into six groups as control, cisplatin (7.5 mg/kg, intraperitoneally), thymol+cisplatin (thymol; 50 and 150 mg/kg+cisplatin; 7.5 mg/kg) and thymol (50 and 150 mg/kg). Thymol was orally administrated for two days before cisplatin injection and continued for 4 days. (99m)Tc-DMSA was injected through the tail of mice after the drug administration. The percentage of the injected dose per gram of kidney tissue (%ID/g) was calculated. In other experiment, kidneys of treated mice were assessed for histopathology. 99mTc-DMSA uptake per gram tissue of the kidneys as %ID/g was 85.27±21.81, 45.55±5.50, 65.02±32.21 and 88.46±20.46 in the control, cisplatin, thymol (50 mg/kg)+cisplatin and thymol (150 mg/kg)+cisplatin. Thymol administration with cisplatin resulted in a significant increase in the level of %ID/g. Histopathological examinations showed a protective effect of thymol against cisplatin nephrotoxicity in mice. The results showed that thymol significantly attenuates the cisplatin-induced nephrotoxicity in mice, and 99mTc-DMSA uptake in kidney is a suitable method for assessment of nephrotoxicity in mice.

  15. Histomorphometric effects of Kigelia africana (Bignoniaceae fruit extract on the testis following short-term treatment with cisplatin in male Sprague–Dawley rats

    Directory of Open Access Journals (Sweden)

    O.O. Azu

    2010-07-01

    Conclusion: The cytoprotection against cisplatin-induced testicular damage by KAFE is likely via an antioxidant modulatory pathway. Also, it is possible that KAFE possesses an androgen-stimulating property.

  16. Cisplatin-Induced Renal Salt Wasting Requiring over 12 Liters of 3% Saline Replacement.

    Science.gov (United States)

    Pham, Phuong-Chi; Reddy, Pavani; Qaqish, Shaker; Kamath, Ashvin; Rodriguez, Johana; Bolos, David; Zalom, Martina; Pham, Phuong-Thu

    2017-01-01

    Cisplatin is known to induce Fanconi syndrome and renal salt wasting (RSW). RSW typically only requires transient normal saline (NS) support. We report a severe RSW case that required 12 liters of 3% saline. A 57-year-old woman with limited stage small cell cancer was admitted for cisplatin (80 mg/m(2)) and etoposide (100 mg/m(2)) therapy. Patient's serum sodium (SNa) decreased from 138 to 133 and 125 mEq/L within 24 and 48 hours of cisplatin therapy, respectively. A diagnosis of syndrome of inappropriate antidiuretic hormone secretion (SIADH) was initially made. Despite free water restriction, patient's SNa continued to decrease in association with acute onset of headaches, nausea, and dizziness. Three percent saline (3%S) infusion with rates up to 1400 mL/day was required to correct and maintain SNa at 135 mEq/L. Studies to evaluate Fanconi syndrome revealed hypophosphatemia and glucosuria in the absence of serum hyperglycemia. The natriuresis slowed down by 2.5 weeks, but 3%S support was continued for a total volume of 12 liters over 3.5 weeks. Attempts of questionable benefits to slow down glomerular filtration included the administration of ibuprofen and benazepril. To our knowledge, this is the most severe case of RSW ever reported with cisplatin.

  17. The ganglioside GM3 is associated with cisplatin-induced apoptosis in human colon cancer cells.

    Directory of Open Access Journals (Sweden)

    Tae-Wook Chung

    Full Text Available Cisplatin (cis-diamminedichloroplatinum, CDDP is a well-known chemotherapeutic agent for the treatment of several cancers. However, the precise mechanism underlying apoptosis of cancer cells induced by CDDP remains unclear. In this study, we show mechanistically that CDDP induces GM3-mediated apoptosis of HCT116 cells by inhibiting cell proliferation, and increasing DNA fragmentation and mitochondria-dependent apoptosis signals. CDDP induced apoptosis within cells through the generation of reactive oxygen species (ROS, regulated the ROS-mediated expression of Bax, Bcl-2, and p53, and induced the degradation of the poly (ADP-ribosyl polymerase (PARP. We also checked expression levels of different gangliosides in HCT116 cells in the presence or absence of CDDP. Interestingly, among the gangliosides, CDDP augmented the expression of only GM3 synthase and its product GM3. Reduction of the GM3 synthase level through ectopic expression of GM3 small interfering RNA (siRNA rescued HCT116 cells from CDDP-induced apoptosis. This was evidenced by inhibition of apoptotic signals by reducing ROS production through the regulation of 12-lipoxigenase activity. Furthermore, the apoptotic sensitivity to CDDP was remarkably increased in GM3 synthase-transfected HCT116 cells compared to that in controls. In addition, GM3 synthase-transfected cells treated with CDDP exhibited an increased accumulation of intracellular ROS. These results suggest the CDDP-induced oxidative apoptosis of HCT116 cells is mediated by GM3.

  18. Epidermal growth factor receptor inhibition with erlotinib partially prevents cisplatin-induced nephrotoxicity in rats

    National Research Council Canada - National Science Library

    Wada, Yukihiro; Iyoda, Masayuki; Matsumoto, Kei; Shindo-Hirai, Yuki; Kuno, Yoshihiro; Yamamoto, Yasutaka; Suzuki, Taihei; Saito, Tomohiro; Iseri, Ken; Shibata, Takanori

    2014-01-01

    ...). Compared to controls, rats treated with erlotinib exhibited significant improvement of renal function and attenuation of tubulointerstitial injury, and reduced the number of apoptotic and proliferating cells...

  19. Protection against cisplatin induced neurotoxicity by ORG 2766: histological and electrophysiological evidence

    NARCIS (Netherlands)

    Gispen, W.H.; Gerritsen van der Hoop, R.; Hamers, F.P.T.; Neijt, J.P.; Veldman, H.; Jennekens, F.G.I.

    1994-01-01

    Prolonged administration of the anti-tumor agent cisplatin may cause a neuropathy in patients. In an animal model, too, neurotoxicity, as evidenced by a decrease in H-related sensory nerve conduction velocity (SNCV), can be induced by repetitive injections of cisplatin. In an attempt to further the

  20. Cisplatin-induced duplex dissociation of complementary and destabilized short GG-containing duplex RNAs.

    Science.gov (United States)

    Polonyi, Christopher; Alshiekh, Alak; Sarsam, Lamya A; Clausén, Maria; Elmroth, Sofi K C

    2014-08-21

    The ability of the anticancer active drug cisplatin to exert biological activity through interference with nucleic acid function is well documented. Since kinetics play a key role in determining product distributions in these systems, methods for accurate documentation of reactivity serve the purpose to identify preferential metal binding sites. In the present study, the aim has been to further explore a recently communicated approach (C. Polonyi and S. K. C. Elmroth, J. Chem. Soc., Dalton Trans., 2013, 42, 14959-14962) utilizing UV/vis spectroscopy and metal induced duplex RNA melting for monitoring of kinetics. More specifically, the sensitivity of the UV/vis-methodology has been evaluated by investigation of how overall length and changes of base-pairing in the close vicinity of a centrally located GG-site affect the rate of cisplatin binding, using the intracellularly active mono-aquated form of cisplatin (cis-Pt(NH3)2Cl(OH2)(+), ()) as the platination reagent. For this purpose, the reactivity of five different 13- to 17 base-pair duplex RNAs was monitored at 38 °C. A common trend of a ca. 10-fold reduction in reactivity was found to accompany an increase of bulk sodium concentration from CNa+ = 122 mM to 1.0 M. Typical half-lives are exemplified by the interaction of with the fully complementary 15-mer RNA-1 with t1/2 = ca. 0.5 and 4.8 hours, at CNa+ = 122 mM and 1.0 M respectively, and C = 45 μM. Lowering of melting temperature (Tm) was found to promote reactivity regardless of whether the change involved a decrease or increase of the RNA length. For example, at CNa+ = 1.0 M, truncation of the fully complementary and GG-containing 15-mer RNA-1 (Tm = 68.9 °C) to the 13-mer RNA-1-1-S (Tm = 63.9 °C) resulted in an increase of k2,app from ca. 0.9 M(-1) s(-1) to 2.0 M(-1) s(-1). Further, the 17-mer RNA-1-4 (Tm = 42.0 °C) with a central U4 bulge exhibited the highest reactivity of the sequences studied with k2,app = 4.0 M(-1) s(-1). The study shows that the reactivity of GG-sequences in RNA exhibit a strong variation depending on exact sequence context, and with imperfectly matched and/or stacked regions as particularly reactive sites.

  1. Risk factors for cisplatin-induced long-term nephrotoxicity in pediatric cancer survivors.

    Science.gov (United States)

    Arga, Mustafa; Oguz, Aynur; Pinarli, Faruk Guclu; Karadeniz, Ceyda; Citak, Elvan Caglar; Emeksiz, Hamdi Cihan; Duran, Esra Akdeniz; Soylemezoglu, Oguz

    2015-06-01

    The aim of this study was to compare the nephrotoxicity risk of cisplatin (CPL) and ifosfamide (IFO) combination treatment (CT) with that of CPL alone and to evaluate the prevalence of CPL-induced long-term nephrotoxicity in pediatric cancer survivors (CS). A total of 33 patients with pediatric solid tumors who have been cured of their disease were included in the study. They were divided into two groups based on the type of chemotherapeutics, either CPL (n = 21) or CT (n = 12), given during cancer treatment and were evaluated for glomerular and tubular function using the Skinner grading system. Nephrotoxicity was found in 15 CS (45.4%): seven (21.3%) of those had moderate, six (18.2%) had mild, and two (6.1%) had severe nephrotoxicity. Neither the rates of overall nephrotoxicity, glomerular toxicity and tubular toxicity, nor the mean overall, glomerular and tubular toxicity scores differed significantly among the CPL and CT groups (P > 0.05 for all parameters). Cumulative IFO dose and age at treatment were found to be independent risk factors for both development and severity of CPL-induced nephrotoxicity (P = 0.025 and P = 0.036 for development of nephrotoxicity; P = 0.004 and P = 0.050 for severity of nephrotoxicity, respectively). Although CPL-induced long-term nephrotoxicity was found in half of the pediatric CS of solid tumors, clinically significant nephrotoxicity was detected only in a minority of them. Both higher cumulative IFO dose and younger age at treatment were found to be independent risk factors for both development and severity of CPL-induced nephrotoxicity. © 2014 Japan Pediatric Society.

  2. Ayurvedic formulations ameliorate cisplatin-induced nephrotoxicity: preclinical studies on Brahma Rasayana and Chyavanaprash.

    Science.gov (United States)

    Menon, Aditya; Krishnan Nair, Cherupally Krishnan

    2013-01-01

    To explore the ability of two Ayurvedic formulations, Brahma Rasayana (BRM) and Chyavanaprash (CHM) in alleviating Cisplatin (Cis-dichlorodiammineplatinum [II] CDDP) induced acute nephrotoxicity. Swiss albino mice were administered with CDDP (12 mg/kg, i.p) and two doses of BRM or CHM (1 and 2 g/kg). Various antioxidant parameters in the kidney as well as release of marker enzymes in the serum were assayed. Histology of the kidney was also performed to check for CDDP induced damages. Administration of either BRM or CHM (1 and 2 g/kg) maintained the antioxidant status in the kidney thereby preventing tissue damage as well as the release of marker enzymes. CDDP induced variation of renal architecture was also prevented by BRM and CHM administration. BRM and CHM administration could prevent CDDP induced acute renal toxicity.

  3. Immunocytochemical analysis of cisplatin-induced platinum-DNA adducts with double-fluorescence video microscopy

    NARCIS (Netherlands)

    Meijer, C.; Vries, E.G.E. de; Dam, W.A.; Wilkinson, M.H.F.; Hollema, H.; Hoekstra, H.J.; Mulder, N.H.

    To detect low-level DNA platination, a sensitive immunocyto- and histochemical technique was developed using a polyclonal antibody. The antibody GPt, derived after immunization of rabbits with highly platinated DNA and purified with affinity chromatography, detected the main platinum (Pt)-containing

  4. Neuroprotection of vestibular sensory cells from gentamicin ototoxicity obtained using nitric oxide synthase inhibitors, reactive oxygen species scavengers, brain-derived neurotrophic factors and calpain inhibitors.

    Science.gov (United States)

    Takumida, Masaya; Anniko, Matti; Shimizu, Akira; Watanabe, Hiroshi

    2003-01-01

    In order to devise a new treatment for inner ear disorders, the efficacy of a nitric oxide synthase inhibitor (L-N(G)-nitroarginine methylester [L-NAME]), a radical scavenger (D-methionine), a neurotrophin (brain-derived neurotrophic factor [BDNF]) and a calpain inhibitor (leupeptin) for protection from hair cell damage was investigated. The effects of these drugs on gentamicin-induced production of nitric oxide (NO) and reactive oxygen species (ROS) were studied by means of the fluorescence indicators 4,5-diaminofluorescein diacetate and dihydrotetramethylrosamine. The effect on gentamicin-induced vestibular hair cell damage was examined by using an in vitro LIVE/DEAD system. L-NAME inhibited the production of NO, D-methionine and BDNF restricted the production of ROS and leupeptin inhibited neither NO nor ROS. All the drugs used limited the vestibular hair cell damage caused by gentamicin. The combinations L-NAME + BDNF, L-NAME + leupeptin and D-methionine + BDNF had a significantly stronger preventive effect on hair cell damage. It is suggested that combined treatment with a radical inhibitor and either a neurotrophin or calpain inhibitor may help to treat inner ear disorders more effectively.

  5. Neurovestibular Compensation following Ototoxic Lesion and Labyrinthectomy

    Directory of Open Access Journals (Sweden)

    Yazdanshenas, Hamed

    2016-03-01

    Full Text Available Introduction Unilateral labyrinthectomy and intra-tympanic gentamycin have been employed in the treatment of Ménière's disease, but the efficacy of these techniques has not been well established. Objective The objective of this study is to measure the time course of recovery from a unilateral labyrinthectomy either after ipsilateral topical treatment with gentamicin to the inner ear or without the previous insult. Methods Twenty-nine adult Mongolian gerbils were randomized into two experimental groups. Group 1 (n = 17 received a right ear gentamicin drug-induced lesion by unilateral labyrinthectomy (UL. Group 2 (n = 12 only received a right unilateral labyrinthectomy lesion. We measured the horizontal vestibulo-ocular responses in gerbils before and after the lesion. The gerbils received an angular acceleration stimulus and their eye movements were recorded. Results The gentamicin lesion resulted in a quicker recovery. Experimental groups underwent a similar time course of recovery. Statistical analysis showed no significant difference between the two groups. Both groups displayed adaptation to the lesion by day 21, but long-term compensation did not completely revert to the original pre-lesion state. Conclusions In a lesion requiring both static and dynamic compensation as in UL, the need for a static compensation may alter pre-existing compensation from a previous dynamic insult and require a new compensation. A previous lesion and adaptation is not preserved for a second lesion and the subject has to re-compensate. Therefore, surgical treatment in Meniere's disease such as UL can be considered without prior gentamicin treatment. Static and dynamic compensations do not appear to be as independent as previous studies have suggested.

  6. Cordycepin enhances cisplatin apoptotic effect through caspase/MAPK pathways in human head and neck tumor cells

    Directory of Open Access Journals (Sweden)

    Chen YH

    2013-07-01

    Full Text Available Ying-Hui Chen,1,2,* Jo-Yu Wang,3,* Bo-Syong Pan,3,4 Yi-Fen Mu,3 Meng-Shao Lai,3,4 Edmund Cheung So,5 Thian-Sze Wong,6 Bu-Miin Huang3,4 1Department of Anesthesia, Chi-Mei Medical Center, Liouying, 2Department of Nursing, Min-Hwei College of Health Care Management, 3Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, 4The Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, 5Department of Anesthesia, An Nan Hospital, China Medical University, Tainan, Taiwan; 6Department of Surgery, University of Hong Kong Medical Center, Faculty of Medicine, The University of Hong Kong, Hong Kong *Authors contributed equally to this work Purpose: The present study aims to investigate whether the combination treatment of cordycepin (an extracted pure compound from Cordyceps sinensis and cisplatin (a platinum-based chemotherapy drug has better apoptotic effect in head and neck squamous cell carcinoma (HNSCC. Methods: The apoptotic influences of cordycepin and/or cisplatin treatments to human OC3, OEC-M1, and FaDu HNSCC cells were investigated by morphological observations, viability assay, flow cytometry assay, and Western blotting methods. Results: Data showed that the cell death phenomenon increased as the dosage of cordycepin or cisplatin increased, and it appeared more in cordycepin plus cisplatin cotreatment among three cell lines. Cell survival rates significantly decreased as the dosage of cordycepin or cisplatin increased, and the better apoptotic effects were observed in cotreatment. Cell cycle analysis further demonstrated that percentages of subG1 cells in cordycepin or cisplatin treatments significantly increased, suggesting that cells underwent apoptosis, and cordycepin plus cisplatin induced many more subG1 cells. Furthermore, cordycepin or cisplatin induced caspase-8, caspase-9, caspase-3, and poly adenosine diphosphate-ribose polymerase protein cleavages, and stimulated c

  7. The Adverse Effects of Heavy Metals with and without Noise Exposure on the Human Peripheral and Central Auditory System: A Literature Review

    Directory of Open Access Journals (Sweden)

    Marie-Josée Castellanos

    2016-12-01

    Full Text Available Exposure to some chemicals in the workplace can lead to occupational chemical-induced hearing loss. Attention has mainly focused on the adverse auditory effects of solvents. However, other chemicals such as heavy metals have been also identified as ototoxic agents. The aim of this work was to review the current scientific knowledge about the adverse auditory effects of heavy metal exposure with and without co-exposure to noise in humans. PubMed and Medline were accessed to find suitable articles. A total of 49 articles met the inclusion criteria. Results from the review showed that no evidence about the ototoxic effects in humans of manganese is available. Contradictory results have been found for arsenic, lead and mercury as well as for the possible interaction between heavy metals and noise. All studies found in this review have found that exposure to cadmium and mixtures of heavy metals induce auditory dysfunction. Most of the studies investigating the adverse auditory effects of heavy metals in humans have investigated human populations exposed to lead. Some of these studies suggest peripheral and central auditory dysfunction induced by lead exposure. It is concluded that further evidence from human studies about the adverse auditory effects of heavy metal exposure is still required. Despite this issue, audiologists and other hearing health care professionals should be aware of the possible auditory effects of heavy metals.

  8. The Adverse Effects of Heavy Metals with and without Noise Exposure on the Human Peripheral and Central Auditory System: A Literature Review.

    Science.gov (United States)

    Castellanos, Marie-Josée; Fuente, Adrian

    2016-12-09

    Exposure to some chemicals in the workplace can lead to occupational chemical-induced hearing loss. Attention has mainly focused on the adverse auditory effects of solvents. However, other chemicals such as heavy metals have been also identified as ototoxic agents. The aim of this work was to review the current scientific knowledge about the adverse auditory effects of heavy metal exposure with and without co-exposure to noise in humans. PubMed and Medline were accessed to find suitable articles. A total of 49 articles met the inclusion criteria. Results from the review showed that no evidence about the ototoxic effects in humans of manganese is available. Contradictory results have been found for arsenic, lead and mercury as well as for the possible interaction between heavy metals and noise. All studies found in this review have found that exposure to cadmium and mixtures of heavy metals induce auditory dysfunction. Most of the studies investigating the adverse auditory effects of heavy metals in humans have investigated human populations exposed to lead. Some of these studies suggest peripheral and central auditory dysfunction induced by lead exposure. It is concluded that further evidence from human studies about the adverse auditory effects of heavy metal exposure is still required. Despite this issue, audiologists and other hearing health care professionals should be aware of the possible auditory effects of heavy metals.

  9. The small-molecule TNF-alpha modulator, UTL-5g, reduces side effects induced by cisplatin and enhances the therapeutic effect of cisplatin in vivo.

    Science.gov (United States)

    Shaw, JiaJiu; Chen, Ben; Huang, Wen-Hsin; Lee, An-Rong; Media, Joseph; Valeriote, Frederick A

    2011-01-01

    We investigated a small-molecule modulator of tumor necrosis factor alpha (TNF-alpha), UTL-5g (also referred to as GBL-5g), as a potential chemoprotective agent against cisplatin-induced side effects including nephrotoxicity, hepatotoxicity and hematotoxicity. Pretreatment of UTL-5g i.p. in BDF1 mice reduced the levels of blood urea nitrogen (BUN) and creatinine induced by cisplatin treatment. The levels of both aspartate transaminase (AST) and alanine transaminase (ALT) in these animals were also reduced by UTL-5g. Pretreatment of UTL-5g did not significantly affect the number of white blood cells (WBC) under current experimental conditions, yet it markedly increased blood platelet counts by more than threefold. Therapeutic assessment in SCID mice inoculated with human HCT-15 tumor cells showed that UTL-5g did not attenuate the anti-tumor effect of cisplatin but increased the therapeutic efficacy of cisplatin. The LD50 of UTL-5g was determined to be > 2,000 mg/kg by an acute toxicity study. In summary, our studies showed that 1) UTL-5g significantly reduces nephrotoxicity and hepatotoxicity induced by cisplatin in mice, presumably by lowering the levels of TNF-alpha, 2) UTL-5g markedly increased blood platelet counts in mice and 3) UTL-5g treatment increased the therapeutic efficacy of cisplatin against HCT-15 cells inoculated in SCID mice.

  10. A 2-DE-based proteomic study on the toxicological effects of cisplatin in L02 cells.

    Science.gov (United States)

    Liu, Shu; Wang, Wei; Zhou, Xueyi; Ding, Zongli; Gu, Runhuan

    2015-01-01

    Cisplatin is a chemotherapeutic agent for the treatment of various cancers. In this study, cisplatin-induced effects were characterized in vitro model of human liver cells (L02) using 2-DE-based proteomics. Results indicated that different cisplatin treatments primarily induced disturbances in protein synthesis and oxidative stress via differential mechanisms. Since the experimental concentrations of cisplatin described a hormesis effect in cell proliferation of L02 cells, it was expected to reveal the hormesis effects using proteomic markers. However, only confilin-1 was commonly up-regulated in three concentrations of cisplatin treatments showing a hormesis effects with a U-shape regulation. These results were highly consistent with many other toxico-proteomic studies, indicating that the toxico-proteomic responses based on dose-dependent protein responses were incongruent with the theoretically linear or hormetic concentration-effect relationship. Our findings suggested that a macroscopic hormesis phenomenon on the cell proliferation could not be reflected by proteomic responses induced by cisplatin treatments. Copyright © 2014 Elsevier B.V. All rights reserved.

  11. Synergistic effects of free radical scavengers and cochlear vasodilators: a new otoprotective strategy for age-related hearing loss

    Science.gov (United States)

    Alvarado, Juan Carlos; Fuentes-Santamaría, Verónica; Melgar-Rojas, Pedro; Valero, María Llanos; Gabaldón-Ull, María Cruz; Miller, Josef M.; Juiz, José M.

    2015-01-01

    The growing increase in age-related hearing loss (ARHL), with its dramatic reduction in quality of life and significant increase in health care costs, is a catalyst to develop new therapeutic strategies to prevent or reduce this aging-associated condition. In this regard, there is extensive evidence that excessive free radical formation along with diminished cochlear blood flow are essential factors involved in mechanisms of other stress-related hearing loss, such as that associated with noise or ototoxic drug exposure. The emerging view is that both play key roles in ARHL pathogenesis. Therapeutic targeting of excessive free radical formation and cochlear blood flow regulation may be a useful strategy to prevent onset of ARHL. Supporting this idea, micronutrient-based therapies, in particular those combining antioxidants and vasodilators like magnesium (Mg2+), have proven effective in reducing the impact of noise and ototoxic drugs in the inner ear, therefore improving auditory function. In this review, the synergistic effects of combinations of antioxidant free radicals scavengers and cochlear vasodilators will be discussed as a feasible therapeutic approach for the treatment of ARHL. PMID:26029103

  12. Co-administration of Cisplatin and Furosemide Causes Rapid and Massive Loss of Cochlear Hair Cells in Mice

    Science.gov (United States)

    Li, Yongqi; Ding, Dalian; Jiang, Haiyan; Fu, Yong

    2011-01-01

    The expanding arsenal of transgenic mice has created a powerful tool for investigating the biological mechanisms involved in ototoxicity. However, cisplatin ototoxicity is difficult to investigate in mice because of their small size and vulnerability to death by nephrotoxicity. To overcome this problem, we developed a strategy for promoting cisplatin-induced ototoxicity by coadministration of furosemide a loop diuretic. A dose–response study identified 200 mg/kg of furosemide as the optimal dose for disrupting the stria vascularis and opening the blood–ear barrier. Our analysis of stria pathology indicated that the optimal period for administering cisplatin was 1 h after furosemide treatment. Combined treatment with 0.5 mg/kg of cisplatin and 200 mg/kg furosemide resulted in only moderate loss of outer hair cells in the basal 20% of the cochlea, only mild threshold shifts and minimal loss of distortion product otoacoustic emission (DPOAE). In contrast, 1 mg/kg of cisplatin plus 200 mg/kg of furosemide resulted in a permanent 40–50 dB elevation of auditory brainstem response thresholds, almost complete elimination of DPOAE, and nearly total loss of outer hair cells. The widespread outer hair cell lesions that develop in mice treated with cisplatin plus furosemide could serve as extremely useful murine model for investigating techniques for regenerating outer hair cells, studying the mechanisms of cisplatin and furosemide ototoxicity and assessing the perceptual and electrophysiological consequences of outer hair cell loss on central auditory plasticity. PMID:21455790

  13. Urinary metabolic profiling of cisplatin nephrotoxicity and nephroprotective effects of Orthosiphon stamineus leaves elucidated by 1H NMR spectroscopy.

    Science.gov (United States)

    Pariyani, Raghunath; Ismail, Intan Safinar; Azam, Amalina; Khatib, Alfi; Abas, Faridah; Shaari, Khozirah; Hamza, Hazilawati

    2017-02-20

    Orthosiphon stamineus (OS) is a popular medicinal herb used in traditional Chinese medicine as a diuretic agent and for renal system disorders. This study employed 1H NMR based metabolomics approach to investigate the possible protective activity of OS in cisplatin induced nephrotoxicity owing to its diuretic and antioxidant activities. Aqueous (OSAE) and 50% aqueous ethanolic (OSFE) extracts of OS leaves were orally administered at 400mg/kg BW doses to rats which were then intraperitoneally injected with cisplatin at 5mg/kg BW dose. The 1H NMR profile of the urine samples collected on day 5 after cisplatin administration were analyzed by multivariate pattern recognition techniques, whereby 19 marker metabolites suggestive in the involvement of TCA cycle, disturbed energy metabolism, altered gut microflora and BCAA metabolism pathways were identified. It was observed that OSFE caused significant changes (pcisplatin nephrotoxicity by inducing significant increase in glucose, glycine, creatinine, citrate, TMAO, acetate and creatine levels. A Principal Component Analysis (PCA) of the 1H NMR spectra of OS extracts identified that OSFE had higher concentrations of the secondary metabolites such as caffeic acid, chlorogenic acid, protocatechuic acid and orthosiphol, among others. Whereas, OSAE was characterized by higher concentrations of acetate, lactate, succinic acid, valine and phosphatidylcholine. This research denotes the first comprehensive analysis to identify the effects of OS extracts on cisplatin nephrotoxicity. Copyright © 2016 Elsevier B.V. All rights reserved.

  14. Significance of downregulation of renal organic cation transporter (SLC47A1 in cisplatin-induced proximal tubular injury

    Directory of Open Access Journals (Sweden)

    Mizuno T

    2015-07-01

    Full Text Available Tomohiro Mizuno,1–3 Waichi Sato,2,3 Kazuhiro Ishikawa,4 Yuki Terao,1 Kazuo Takahashi,2 Yukihiro Noda,5 Yukio Yuzawa,2 Tadashi Nagamatsu1 1Department of Analytical Pharmacology, Meijo University Faculty of Pharmacy, Nagoya, 2Department of Nephrology, School of Medicine, Fujita Health University, Toyoake, 3Department of Nephrology, Nagoya University School of Medicine, Nagoya, 4Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya, 5Division of Clinical Sciences and Neuropsychopharmacology, Meijo University Faculty of Pharmacy, Nagoya, Japan Background/aim: To elucidate the mechanism responsible for developing acute kidney injury in patients with diabetes mellitus, we also evaluated the issue of whether advanced glycation endproducts (AGEs influence the expressions of multi antimicrobial extrusion protein (MATE1/SLC47A1 in tubular cells. Materials and methods: To detect changing expression of MATE1/SLC47A1 in dose- and time-dependent manners, human proximal tubular epithelial cells were incubated with AGE-aggregated-human serum albumin. As a function assay for MATE1/SLC47A1, human proximal tubular epithelial cells were incubated with cisplatin or carboplatin. Results: On incubation with AGEs, the expressions of MATE1/SLC47A1 were decreased in tubular cells. In addition, the toxicities of cisplatin were increased in tubular cells that had been pretreated with AGEs. However, the toxicities of carboplatin were smaller than that of cisplatin in proximal tubular epithelial cells. Conclusion: The expression of the MATE1/SLC47A1 is decreased by AGEs, which increases the risk for proximal tubular injury. Keywords: advanced glycation endproducts, cisplatin, SLC47A1, diabetes mellitus, acute kidney injury

  15. Selectivity analysis of protein kinase CK2 inhibitors DMAT, TBB and resorufin in cisplatin-induced stress responses

    DEFF Research Database (Denmark)

    Fritz, Gerhard; Issinger, Olaf-Georg; Olsen, Birgitte Brinkmann

    2009-01-01

    by phosphorylation of JNK and H2AX). In the case of resorufin no interference with the stress-signaling pathway is observed, supporting the notion that TBB and DMAT interfere with upstream molecules involved in genotoxic stress signaling. We have also tested the protein kinase CK2 inhibitors with respect to cell......Targeting protein kinases as a therapeutic approach to treat various diseases, especially cancer is currently a fast growing business. Although many inhibitors are available, exhibiting remarkable potency, the major challenge is their selectivity. Here we show that the protein kinase CK2 inhibitors...

  16. Analysis of baseline and cisplatin-inducible gene expression in Fanconi anemia cells using oligonucleotide-based microarrays

    Directory of Open Access Journals (Sweden)

    Liu Johnson M

    2002-11-01

    Full Text Available Abstract Background Patients with Fanconi anemia (FA suffer from multiple defects, most notably of the hematological compartment (bone marrow failure, and susceptibility to cancer. Cells from FA patients show increased spontaneous chromosomal damage, which is aggravated by exposure to low concentrations of DNA cross-linking agents such as mitomycin C or cisplatin. Five of the identified FA proteins form a nuclear core complex. However, the molecular function of these proteins remains obscure. Methods Oligonucleotide microarrays were used to compare the expression of approximately 12,000 genes from FA cells with matched controls. Expression profiles were studied in lymphoblastoid cell lines derived from three different FA patients, one from the FA-A and two from the FA-C complementation groups. The isogenic control cell lines were obtained by either transfecting the cells with vectors expressing the complementing cDNAs or by using a spontaneous revertant cell line derived from the same patient. In addition, we analyzed expression profiles from two cell line couples at several time points after a 1-hour pulse treatment with a discriminating dose of cisplatin. Results Analysis of the expression profiles showed differences in expression of a number of genes, many of which have unknown function or are difficult to relate to the FA defect. However, from a selected number of proteins involved in cell cycle regulation, DNA repair and chromatin structure, Western blot analysis showed that p21waf1/Cip1 was significantly upregulated after low dose cisplatin treatment in FA cells specifically (as well as being expressed at elevated levels in untreated FA cells. Conclusions The observed increase in expression of p21waf1/Cip1 after treatment of FA cells with crosslinkers suggests that the sustained elevated levels of p21waf1/Cip1 in untreated FA cells detected by Western blot analysis likely reflect increased spontaneous damage in these cells.

  17. Vanadium(III)-L-cysteine protects cisplatin-induced nephropathy through activation of Nrf2/HO-1 pathway.

    Science.gov (United States)

    Basu, Abhishek; Singha Roy, Somnath; Bhattacharjee, Arin; Bhuniya, Avishek; Baral, Rathindranath; Biswas, Jaydip; Bhattacharya, Sudin

    2016-01-01

    Cisplatin (CDDP) is one of the first-line anticancer drugs; however, the major limitation of CDDP therapy is development of nephrotoxicity (25-35% cases), whose precise mechanism mainly involves oxidative stress, inflammation and cell death. Therefore, in search of a potential chemoprotectant, an organovanadium complex, viz., vanadium(III)-L-cysteine (VC-III) was evaluated against CDDP-induced nephropathy in mice. CDDP was administered intraperitoneally (5 mg/kg b.w.) and VC-III was given by oral gavage (1 mg/kg b.w.) in concomitant and pre-treatment schedule. The results showed that VC-III administration reduced (p HO-1. Moreover, treatment with VC-III significantly (p < 0.001) enhanced CDDP-mediated cytotoxicity in MCF-7 and NCI-H520 human cancer cell lines. Thus, VC-III can serve as a suitable chemoprotectant and increase the therapeutic window of CDDP in cancer patients.

  18. Mutagenesis of the HMGB (high-mobility group B) protein Cmb1 (cytosine-mismatch binding 1) of Schizosaccharomyces pombe: effects on recognition of DNA mismatches and damage.

    Science.gov (United States)

    Kunz, Christophe; Zurbriggen, Karin; Fleck, Oliver

    2003-06-01

    Cmb1 (cytosine-mismatch binding 1) is a high-mobility group (HMG) protein of Schizosaccharomyces pombe, which consists of 223 amino acids and has a single HMG domain at the C-terminal end. We have created several mutant and deletion forms of the Cmb1 protein and studied the effects on general DNA binding and specific binding to DNA mismatches and damaged DNA. Cmb1Delta41 (i.e. Cmb1 from which the 41 N-terminal amino acids have been deleted) bound specifically to cytosine-containing mismatches, to the cisplatin-induced intrastrand cross-links cis -GG and cis -AG and to an O (6)-methylguanine lesion. DNA binding was not affected when the 45 N-terminal amino acids were deleted, but was abolished in the absence of the 50 N-terminal amino acids, and was reduced when Cmb1 was truncated by between five and eleven C-terminal amino acids. Cmb1, both with and without the C-terminal truncations, retained its DNA binding affinity after heating at 95 degrees C. The cmb1 gene was induced when S. pombe cells were treated with cisplatin. Mitotic mutation rates were increased in a S. pombe cmb1 null mutant and in a cmb1-(1-212) mutant, which encodes a Cmb1 protein lacking the 11 C-terminal amino acids. We conclude that mutation avoidance by Cmb1 is distinct from Msh2-dependent mismatch repair, but related to nucleotide excision repair.

  19. Bcl-2 degradation is an additional pro-apoptotic effect of polo-like kinase inhibition in cholangiocarcinoma cells

    Science.gov (United States)

    Sydor, Svenja; Jafoui, Sami; Wingerter, Lena; Swoboda, Sandra; Mertens, Joachim C; Gerken, Guido; Canbay, Ali; Paul, Andreas; Fingas, Christian D

    2017-01-01

    AIM To examine the influence on apoptotic mechanisms following inhibition of polo-like kinases as therapeutically approach for cholangiocellular cancer treatment. METHODS As most cholangiocarcinomas are chemotherapy-resistant due to mechanisms preventing tumor cell death, we investigated the effect of Cisplatin on cholangiocellular carcinoma (CCA) cell lines KMCH-1 and Mz-Ch-1. Polo-like kinases (PLK) are important regulators of the cell cycle and their inhibition is discussed as a potential therapy while PLK inhibition can regulate apoptotic mediators. Here, cells were treated with PLK inhibitor BI6727 (Volasertib), Cisplatin, and in combination of both compounds. Cell viability was assessed by MTT; apoptosis was measured by DAPI staining and caspase-3/-7 assay. Western blot and qRT-PCR were used to measure expression levels of apoptosis-related molecules Bax and Bcl-2. RESULTS The cell viability in the CCA cell lines KMCH-1 and Mz-Ch-1 was reduced in all treatment conditions compared to vehicle-treated cells. Co-treatment with BI6727 and cisplatin could even enhance the cytotoxic effect of cisplatin single treatment. Thus, co-treatment of cisplatin with BI6727 could slightly enhance the cytotoxic effect of the cisplatin in both cell lines whereas there was evidence of increased apoptosis induction solely in Mz-Ch-1 as compared to KMCH-1. Moreover, PLK inhibition decreases protein levels of Bcl-2; an effect that can be reversed by the proteasomal degradation inhibitor MG-132. In contrast, protein levels of Bax were not found to be altered by PLK inhibition. These findings indicate that cytotoxic effects of Cisplatin in Mz-Ch-1 cells can be enhanced by cotreatment with BI6727. CONCLUSION In conclusion, BI6727 treatment can sensitize CCA cells to cisplatin-induced apoptosis with proteasomal Bcl-2 degradation as an additional pro-apoptotic effect. PMID:28652654

  20. [Preventive effects of cerebro cellular growth peptide on gentamycin-induced inner ear damage in guinea pigs].

    Science.gov (United States)

    Kang, Song-Jian; Shi, Xian-Jun; Wei, You-Zhen; Hong, An; Jiang, Xin-Quan

    2003-02-01

    To investigate the preventive effects of the cerebro cellular growth peptide (CCGP) on gentamycin-induced inner ear damage in guinea pigs, and to clarify its mechanism. The hypoacusis severity and enzymatic activity in the cochlear hair cells were examined by brainstem auditory evoked potential (BAEP) and histochemistry, respectively. The damaged hair cells was counted in three groups. CCGP reduced the elevated BAEP reaction thresholds. It protected activities of mitochondrial succinate dehydrogenase and lysosome acid phosphatase in the cochlear hair cells. The number of damaged hair cells in the CCGP group was less than that in the gentamycin (GM) group. CCGP can reduce GM ototoxicity. The mechanism may be associated with the protective activity of mitochondrial enzyme, the maintenance of lysosome intactness, energy metabolism of the cochlear hair cells, and reduction of autolysis of hair cells induced by hydrolase over flowing from lysosome.

  1. Relationship between cisplatin administration and the development of ototoxicity

    NARCIS (Netherlands)

    Rademaker-Lakhai, Jeany M.; Crul, Mirjam; Zuur, Lot; Baas, Paul; Beijnen, Jos H.; Simis, Yvonne J. W.; van Zandwijk, Nico; Schellens, Jan H. M.

    2006-01-01

    PURPOSE: To determine the auditory toxicity associated with dose- and schedule- intensive cisplatin/gemcitabine chemotherapy in non-small-cell lung carcinoma patients. PATIENTS AND METHODS: Patients were treated with gemcitabine followed by cisplatin according to an interpatient dose-escalation

  2. An overview of pharmacotherapy-induced ototoxicity | Schellack ...

    African Journals Online (AJOL)

    Precaution should be taken to prevent any auditory impairment that might occur through appropriate administration and monitoring. Although some otoprotective substances have been used successfully in certain studies, further trials must be performed to assess their clinical utility. The clinical pharmacist and audiologist ...

  3. The Role of Wild-Type p53 in Cisplatin-Induced Chk2 Phosphorylation and the Inhibition of Platinum Resistance with a Chk2 Inhibitor

    Directory of Open Access Journals (Sweden)

    Xiaobing Liang

    2011-01-01

    Full Text Available The major obstacle in platinum chemotherapy is the repair of platinum-damaged DNA that results in increased resistance, reduced apoptosis, and finally treatment failure. Our research goal is to determine and block the mechanisms of platinum resistance. Our recent studies demonstrate that several kinases in the DNA-repair pathway are activated after cells are exposed to cisplatin. These include ATM, p53, and Chk2. The increased Chk2 phosphorylation is modulated by p53 in a wild-type p53 model. Overexpression of p53 by cDNA transfection in wt-p53 (but not p53 deficient cells doubled the amount of Chk2 phosphorylation 48 hours after cisplatin treatment. p53 knockdown by specific siRNA greatly reduced Chk2 phosphorylation. We conclude that wild-type p53, in response to cisplatin stimulation, plays a role in the upstream regulation of Chk2 phosphorylation at Thr-68. Cells without normal p53 function survive via an alternative pathway in response to the exogenous influence of cisplatin. We strongly suggest that it is very important to include the p53 mutational status in any p53 involved studies due to the functional differentiation of wt p53 and p53 mutant. Inhibition of Chk2 pathway with a Chk2 inhibitor (C3742 increased cisplatin efficacy, especially those with defective p53. Our findings suggest that inhibition of platinum resistance can be achieved with a small-molecule inhibitor of Chk2, thus improving the therapeutic indices for platinum chemotherapy.

  4. Constitutively active ErbB2 regulates cisplatin-induced cell death in breast cancer cells via pro- and antiapoptotic mechanisms

    DEFF Research Database (Denmark)

    Sigurðsson, Haraldur H; Olesen, Christina Wilkens; Dybboe, Rie

    2015-01-01

    UNLABELLED: Despite the frequent expression of N-terminally truncated ErbB2 (ΔNErbB2/p95HER2) in breast cancer and its association with Herceptin resistance and poor prognosis, it remains poorly understood how ΔNErbB2 affects chemotherapy-induced cell death. Previously it was shown that ΔNErbB2...

  5. Total antioxidant and oxidant status of plasma and renal tissue of cisplatin-induced nephrotoxic rats: protection by floral extracts of Calendula officinalis Linn.

    Science.gov (United States)

    Verma, Pawan Kumar; Raina, Rajinder; Sultana, Mudasir; Singh, Maninder; Kumar, Pawan

    2016-01-01

    The present study was aimed to determine the total antioxidant status (TAS), total oxidant status (TOS) and oxidative stress index (OSI) of plasma and renal tissue in cisplatin (cDDP) induced nephrotoxic rats and its protection by treatments with floral extracts of Calendula officinalis Linn. Treatment with cDDP elevated (p officinalis along with cDDP restored (p > 0.05) CR, albumin, TOS, GSH and activities of antioxidant enzymes in blood and renal tissue. Ethanolic extract treatments reduced (p officinalis protect cDDP induced nephrotoxicity by restoring antioxidant system of the renal tissue.

  6. Mechanisms of Cisplatin-Induced Apoptosis and of Cisplatin Sensitivity: Potential of BIN1 to Act as a Potent Predictor of Cisplatin Sensitivity in Gastric Cancer Treatment

    OpenAIRE

    Satoshi Tanida; Tsutomu Mizoshita; Keiji Ozeki; Hironobu Tsukamoto; Takeshi Kamiya; Hiromi Kataoka; Daitoku Sakamuro; Takashi Joh

    2012-01-01

    Cisplatin is the most important and efficacious chemotherapeutic agent for the treatment of advanced gastric cancer. Cisplatin forms inter- and intrastrand crosslinked DNA adducts and its cytotoxicity is mediated by propagation of DNA damage recognition signals to downstream pathways involving ATR, p53, p73, and mitogen-activated protein kinases, ultimately resulting in apoptosis. Cisplatin resistance arises through a multifactorial mechanism involving reduced drug uptake, increased drug inac...

  7. Variation in the HFE gene is associated with the development of bleomycin-induced pulmonary toxicity in testicular cancer patients

    NARCIS (Netherlands)

    Schoot, van der Garbiela G.F.; Westerink, Nico-Derk L; Lubberts, Sjoukje; Nuver, Janine; Zwart, Nynke; Walenkamp, Annemiek M E; Wempe, Johan B; Meijer, Coby; Gietema, Jourik A

    BACKGROUND: Bleomycin and cisplatin are of key importance in testicular cancer treatment. Known potential serious adverse effects are bleomycin-induced pulmonary toxicity (BIP) and cisplatin-induced renal toxicity. Iron handling may play a role in development of this toxicity. Carriage of allelic

  8. Author Details

    African Journals Online (AJOL)

    Baxter-Grillo, D. Vol 14, No 1 (2015) - Articles Cytoarchitectural effects of ethanolic leaf extract of Newbouldia laevis (P. Beauv.) on cisplatin-induced testicular damage in wistar rats. Abstract. ISSN: 1596-6569. AJOL African Journals Online. HOW TO USE AJOL... for Researchers · for Librarians · for Authors · FAQ's · More ...

  9. The genome-wide expression profile of Curcuma longa-treated cisplatin-stimulated HEK293 cells

    Science.gov (United States)

    Sohn, Sung-Hwa; Ko, Eunjung; Chung, Hwan-Suck; Lee, Eun-Young; Kim, Sung-Hoon; Shin, Minkyu; Hong, Moochang; Bae, Hyunsu

    2010-01-01

    AIM The rhizome of turmeric, Curcuma longa (CL), is a herbal medicine used in many traditional prescriptions. It has previously been shown that CL treatment showed greater than 47% recovery from cisplatin-induced cell damage in human kidney HEK 293 cells. This study was conducted to evaluate the recovery mechanisms of CL that occur during cisplatin induced nephrotoxicity by examining the genome wide mRNA expression profiles of HEK 293 -cells. METHOD Recovery mechanisms of CL that occur during cisplatin-induced nephrotoxicity were determined by microarray, real-time PCR, immunofluorescent confocal microscopy and Western blot analysis. RESULTS The results of microarray analysis and real-time PCR revealed that NFκB pathway-related genes and apoptosis-related genes were down-regulated in CL-treated HEK 293 cells. In addition, immunofluorescent confocal microscopy and Western blot analysis revealed that NFκB p65 nuclear translocation was inhibited in CL-treated HEK 293 cells. Therefore, the mechanism responsible for the effects of CL on HEK 293 cells is closely associated with regulation of the NFκB pathway. CONCLUSION CL possesses novel therapeutic agents that can be used for the prevention or treatment of cisplatin-induced renal disorders. PMID:20840446

  10. Effects of polylactic acid film on middle ear mucosa and cochlear function in Guinea pigs.

    Science.gov (United States)

    Ensari, Nuray; Tutar, Hakan; Ekinci, Ozgur; Ugur, Mehmet Birol; Bayazıt, Yıldırım A; Gokdogan, Cagil; Goksu, Nebil

    2015-05-01

    Our aim was to assess the effects of polylactic acid (PLA) on middle ear mucosa and cochlea, to be used as a film barrier for postoperative adhesion prevention in the middle ear. Twenty-one albino Guinea pigs were included in the study. A window was opened on both tympanic bulla and on one side PLA material was placed in the middle ear and on the other side only fenestration was performed and used as a control. All Guinea pigs underwent evaluation of tympanic membranes microscopically; functional hearing was analyzed by auditory brainstem responses preoperatively, in the first and the sixth month. All Guinea pigs were killed on the sixth month for histopathologic evaluation of their temporal bones. There was no statistical difference between both groups regarding hearing thresholds, interpeak wave latencies preoperatively and on first and the sixth months postoperatively. Histopathological evaluation revealed no specific changes. There was a mild local inflammation both in the PLA implanted and control ears. PLA film barrier most likely has no toxic effects on Guinea pig middle ear and does not show any ototoxic side effects.

  11. MicroRNA-375 Is Induced in Cisplatin Nephrotoxicity to Repress Hepatocyte Nuclear Factor 1-β.

    Science.gov (United States)

    Hao, Jielu; Lou, Qiang; Wei, Qingqing; Mei, Shuqin; Li, Lin; Wu, Guangyu; Mi, Qing-Sheng; Mei, Changlin; Dong, Zheng

    2017-03-17

    Nephrotoxicity is a major adverse effect of cisplatin-mediated chemotherapy in cancer patients. The pathogenesis of cisplatin-induced nephrotoxicity remains largely unclear, making it difficult to design effective renoprotective approaches. Here, we have examined the role of microRNAs (miRNAs) in cisplatin-induced nephrotoxicity. We show that cisplatin nephrotoxicity was not affected by overall depletion of both beneficial and detrimental miRNAs from kidney proximal tubular cells in mice in which the miRNA-generating enzyme Dicer had been conditionally knocked out. To identify miRNAs involved in cisplatin nephrotoxicity, we used microarray analysis to profile miRNA expression and identified 47 up-regulated microRNAs and 20 down-regulated microRNAs in kidney cortical tissues. One up-regulated miRNA was miR-375, whose expression was also induced in cisplatin-treated renal tubular cells. Interestingly, inhibition of miR-375 decreased cisplatin-induced apoptosis, suggesting that miR-375 is a cell-damaging or pro-apoptotic agent. Blockade of P53 or NF-κB attenuated cisplatin-induced miR-375 expression, supporting a role of P53 and NF-κB in miR-375 induction. We also identified hepatocyte nuclear factor 1 homeobox B (HNF-1β) as a key downstream target of miR-375. Of note, we further demonstrated that HNF-1β protected renal cells against cisplatin-induced apoptosis. Together, these results suggest that upon cisplatin exposure, P53 and NF-κB collaboratively induce miR-375 expression, which, in turn, represses HNF-1β activity, resulting in renal tubular cell apoptosis and nephrotoxicity. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  12. The effect of alpha-lipoic acid on temporary threshold shift in humans: a preliminary study.

    Science.gov (United States)

    Quaranta, N; Dicorato, A; Matera, V; D'Elia, A; Quaranta, A

    2012-12-01

    Noise-induced hearing loss (NHIL) is a significant source of hearing loss in industrialized countries. Recent research on the cellular bases of NIHL has led to new avenues for protection through prophylactic drugs. Although in experimental animal models several compounds have shown a protective effect in NIHL, limited data are available in humans. Many authors are focusing their attention on the role of antioxidant on hearing protection. Alpha-lipoic acid (ALA), an essential cofactor in mitochondrial enzymes, is a novel biological antioxidant and a potent free radical scavenger and, in animal models, it has been shown to protect from age-induced and cisplatin-induced hearing loss. The aim of our study was to evaluate the effect of alpha-lipoic acid on temporary threshold shift measured 2 minutes after the end of exposure (TTS(2)) induced by a 3 kHz tone in young normally hearing subjects. Thirty young normal hearing volunteers served as control subjects. Individuals were randomly assigned to three groups. Group A (10 subjects) subjects were exposed to a 90 dB HL 3 kHz pure tone for 10 min. Group B (10 subjects) subjects were exposed to a 90 dB HL 3 kHz pure tone one hour after oral ingestion of 600 mg of ALA. Group C (10 subjects) were exposed to a 90 dB HL 3 kHz pure tone after 10 days of oral ingestion of 600 mg of ALA. Statistical analysis showed that prior to the exposure the hearing thresholds did not differ significantly among the three groups. TTS(2) of group C was significantly lower that TTS2 of Groups A and B at 6 kHz (p 0.03), and TEOAEs amplitude change after noise exposure was lower for group C compared to Groups A (p = 0.089) and B (p = 0.03). ALA is a powerful lipophilic antioxidant and free radical scavenger currently used in clinical practice. A single dose of 600 mg of dose ALA did not induce any protection on the TTS(2) induced by a 90 dB HL 3 kHz tone, while 10 days of therapeutic dosage assumption of ALA was associated with significant

  13. Does exogenous GM1 ganglioside enhance the effects of electrical stimulation in ameliorating degeneration after neonatal deafness?

    Science.gov (United States)

    Osofsky, M R; Moore, C M; Leake, P A

    2001-09-01

    This study examined the combined effects of administration of exogenous GM1 ganglioside and electrical stimulation on the cochlear nucleus (CN) of cats deafened neonatally by ototoxic drugs. Five normal hearing adult cats served as controls. Another 12 cats were deafened bilaterally by daily injections of neomycin sulfate (60 mg/kg) for 17-21 days after birth until auditory brainstem testing demonstrated profound hearing loss. Six of the deaf animals comprised the GM1 group, which received daily injections of GM1 ganglioside (30 mg/kg) for 28-38 days during the period after profound deafness was confirmed, and prior to receiving a cochlear implant. The non-GM1 group (n=6) received no treatment during this interim period. All the deafened animals underwent unilateral cochlear implantation at 6-9 weeks postnatal and received several months (mean duration, 32 weeks) of chronic electrical stimulation (4 h/day, 5 days/week). Stimulation was delivered by intracochlear bipolar electrodes, using electrical signals that were designed to be temporally challenging to the central auditory system. Results showed that in the neonatally deafened animals, both the GM1 and non-GM1 groups, the volume of the CN was markedly reduced (to 76% of normal), but there was no difference between the animals that received GM1 and those that did not. The cross sectional areas of spherical cell somata in both GM1 and non-GM1 groups also showed a highly significant reduction in size, to < or =75% of normal after neonatal deafening. Moreover, in both the GM1 and non-GM1 groups, the spherical cells in the CN ipsilateral to the implanted cochlea were significantly larger (6%) than cells in the control, unstimulated CN. Again, however, there was no significant difference between the GM1 group and the non-GM1 group in spherical cell size. These results contrast sharply with previous reports that exogenous GM1 prevents CN degeneration after neonatal conductive hearing loss and partially prevents spiral

  14. Investigations of the Effects of Altered Vestibular System Function on Hindlimb Anti-Gravity Muscles

    Science.gov (United States)

    Lowery, Mary Sue

    1998-01-01

    Exposure to different gravitational environments, both the microgravity of spaceflight and the hypergravity of centrifugation, result in altered vestibulo-spinal function which can be reversed by reacclimation to earth gravity (2). Control of orientation, posture, and locomotion are functions of the vestibular system which are altered by changes in gravitational environment. Not only is the vestibular system involved with coordination and proprioception, but the gravity sensing portion of the vestibular system also plays a major role in maintaining muscle tone through projections to spinal cord motoneurons that control anti-gravity muscles. I have been involved with investigations of several aspects of the link between vestibular inputs and muscle morphology and function during my work with Dr. Nancy Daunton this summer and the previous summer. We have prepared a manuscript for submission (4) to Aviation, Space, and Environmental Medicine based on work that I performed last summer in Dr. Daunton's lab. Techniques developed for that project will be utilized in subsequent experiments begun in the summer of 1998. I have been involved with the development of a pilot project to test the effects of vestibular galvanic stimulation (VGS) on anti-gravity muscles and in another project testing the effects of the ototoxic drug streptomycin on the otolith-spinal reflex and anti-gravity muscle morphology.

  15. [Effects of erlong zuoci pills and its effective disassembled prescriptions on gentamycin induced hair cell apoptosis].

    Science.gov (United States)

    Wang, Jing; Guo, Chunrong; Dong, Yang; Jin, Guoqin; Guo, Ruixin; Han, Zhifen; Cai, Xichen; Shi, Jianrong

    2010-09-01

    To investigate the effects of erlong zuoci (ELZC) pills and its disassembled prescriptions (Shudi-huang-Zexie group and Zexie group) on the enzymatic activity and protein expression changes of the key apoptosis molecules in the gentamycin injured hair cells. The model of gentamycin induced ototoxicity in mice cochlear primary cultures was copied. Cochlear organotypic cultures of postnatal day 3-5 (P3-P5) mice were treated with gentamycin alone or in combination with ELZC pills, Shudihuang-Zexie group or Zexie group respectively. The enzymatic activity of Caspase-9 and Caspase-3 was determined by means of fluorescence staining in situ. The protein expression of Bcl-2 and Bax in the hair cell area was examined by immunofluorescence in normal and treated specimens. Average optical density analysis indicated that, compared to the normal group, 0.03 mmol x L(-1) gentamycin could significantly activate Caspase-9 and Caspase-3, downregulate the ratio of Bcl-2 and Bax protein expression. Compared to the gentamycin model group, ELZC pills significantly inhibited the enzymatic activity of Caspase-9 and upregulated the ratio of Bcl-2 and Bax protein expression, showing inhibition trend toward the enzymatic activity of Caspase-3. Both Shudihuang-Zexie group and Zexie group could effectively inhibit the enzymatic activity of Caspase-9 and Caspase-3, upregulate the ratio of Bcl-2 and Bax protein expression. ELZC pills, Shudihuang-Zexie group and Zexie group can effectively protect hair cells from gentamycin by correcting the abnormal changes of the mitochondrion-dependent signal transduction pathway.

  16. Effects of record music on hearing loss among young workers in a shipyard.

    Science.gov (United States)

    Mori, T

    1985-01-01

    Effects of record music on hearing were studied by measuring the hearing loss among 175 shipyard workers ranging from 20 to 29 years, who did not have any history of ear or nose diseases, familial hearing loss or ingestion of oto-toxic drugs. There were 120 record-listeners and 55 non-listeners. It was found that there were more high frequency hearing impairments among the ears of record-listeners than non-listeners. Means of hearing losses of the record-listeners' ears were 4.73 dB and at 4000 Hz and 9.24 dB at 6000 Hz. Failure rates (percentage of ears which had 20 dB or more hearing loss) were 8.4% at 4000 Hz and 18.8% at 6000 Hz. Three factors, "monthly listening hours", "duration of listening to records" and "favourite type of music", contributed to the high frequency hearing loss. The young shipyard workers should be warned against non-occupational noise exposure, such as record music outside of the workplace, because this will significantly worsen hearing impairment due to the occupational noise exposure.

  17. Effective drug delivery system for duchenne muscular dystrophy using hybrid liposomes including gentamicin along with reduced toxicity.

    Science.gov (United States)

    Yukihara, Mamiko; Ito, Kaori; Tanoue, Osamu; Goto, Koichi; Matsushita, Taku; Matsumoto, Yoko; Masuda, Masako; Kimura, Shigemi; Ueoka, Ryuichi

    2011-01-01

    It is known that gentamicin (GM) could be a possible treatment for Duchenne Muscular Dystrophy (DMD). However, GM therapy has been hindered by several problems such as severe side effects of GM. In order to resolve these problems, we developed the drug delivery system (DDS) of GM using hybrid liposomes (HL) composed of L-α-dimyristoylphosphatidylcholine (DMPC) and polyoxyethylene(23) lauryl ether (C₁₂(EO)₂₃). The hydrodynamic diameters of HL including GM (GM-HL) were 60-90 nm with a narrow range of the size distribution and the sizes were kept almost constant for over 4 weeks, suggesting that GM-HL could avoid the reticuloendothelial system in vivo. Furthermore, GM-HL accumulated more to the skeletal muscle cells of X chromosome-linked muscular distrophy (mdx) mice as compared to those of normal mice. Significantly, we succeeded in increasing dystrophin positive fibers in skeletal muscle cells of mdx mice using GM-HL along with the reduction of ototoxicity. It is suggested that GM should be carried more efficiently into the muscular cells of mdx mice by HL. These results indicate that HL could be an effective carrier in the DDS of GM therapy for DMD.

  18. Effect of Taurine on the antimicrobial efficiency of Gentamicin

    Directory of Open Access Journals (Sweden)

    Islambulchilar Mina

    2011-12-01

    Full Text Available Context: Gentamicin is mainly used in severe infections caused by gram-negatives. However toxicity including nephrotoxicity and ototoxicity is one of the most important complications of its treatment. The production of free radicals seems to be involved in gentamicin toxicity mechanism. Taurine, a major intracellular free β-amino acid, is known to be an endogenous antioxidant. So potentially the co-therapy of taurine and gentamicin would reduce the adverse effects of the antibiotic. Objectives: In this study, we wished to know the effect of taurine on the antibiotic capacity of gentamicin. methods: strains of P. aeruginosa, E. coli, S. aureus and S. epidermidis were used as test organisms. Minimum inhibitory concentrations of gentamicin in the presence and absence of taurine at quantities from 40 to 2 mg/L were determined using macro-dilution method. Results: MICs were determined in the various concentrations of taurine for bacterial indicators. The MIC values of gentamicin for P. aeruginosa, S. aureus and E. coli remained unchanged in the values of 2.5, 5 and 20 μg/ml respectively in the absence and presences of different concentrations of taurine. The bactericidal activity of gentamicin against S. epidermidis was increased by addition of taurine in the concentrations higher than 6 mg/L. Conclusion: According to our study the antibacterial activity of gentamicin against the indicator microorganisms were not interfere with taurine at selected concentrations. Further in vivo studies are needed to establish if a combination of gentamicin and taurine would have the same effect.

  19. Effects of age at onset of deafness and electrical stimulation on the developing cochlear nucleus in cats.

    Science.gov (United States)

    Stakhovskaya, Olga; Hradek, Gary T; Snyder, Russell L; Leake, Patricia A

    2008-09-01

    This study examined the effects of deafness and intracochlear electrical stimulation on the anatomy of the cochlear nucleus (CN) after a brief period of normal auditory development early in life. Kittens were deafened by systemic ototoxic drug injections either as neonates or starting at postnatal day 30. Total CN volume, individual CN subdivision volumes, and cross-sectional areas of spherical cell somata in the anteroventral CN (AVCN) were compared in neonatally deafened and 30-day deafened groups at 8 weeks of age and in young adults after approximately 6 months of electrical stimulation initiated at 8 weeks of age. Both neonatal and early acquired hearing loss resulted in a reduction in CN volume as compared to normal hearing cats. Comparison of 8- and 32-week old groups indicated that the CN continued to grow in both deafened groups despite the absence of auditory input. Preserving normal auditory input for 30 days resulted in a significant increase in both total CN volume and cross-sectional areas of spherical cell somata, as compared to neonatally deafened animals. Restoring auditory input in these developing animals by unilateral intracochlear electrical stimulation did not elicit any difference in CN volume between the two sides, but resulted in 7% larger spherical cell size on the stimulated side. Overall, the brief period of normal auditory development and subsequent electrical stimulation maintained CN volume at 80% of normal and spherical cell size at 86% of normal ipsilateral to the implant as compared to 67% and 74%, respectively, in the neonatally deafened group.

  20. The effect of intratympanic gentamicin for treatment of Ménière's disease on lower frequency hearing.

    Science.gov (United States)

    Sam, Gerben; Chung, Dick Wong; van der Hoeven, Ruud; Verweij, Sjoerd; Becker, Matthijs

    2016-08-01

    Background The intratympanic application of the ototoxic aminoglycoside gentamicin has shown promising results as an ablative treatment for vertigo associated with Ménière's disease. Objective To evaluate the efficacy and safety of intratympanic gentamicin and to specifically analyse the effect of this treatment on high and low hearing frequencies in patients with unilateral definite Ménière's disease. Method Subjects were treated with intratympanic gentamicin and were evaluated on vertigo, tinnitus, mean pure tone audiometry threshold and speech discrimination score. Subjects were followed for evaluation for up to 2 years after treatment. Results The number of vertigo spells per month decreased and subjects experienced less tinnitus. During follow up there was an increase of hearing loss in the low (0.25-, 0.5-, 1-kHz) frequency range (13.3 dB; p = 0.03). There was no significant increase of hearing loss in the high (2-, 4-, 8-kHz) frequency range. A clinically significant change in speech discrimination score was found in 50 % of the subjects. Conclusion Our results indicate that intratympanic gentamicin especially affects the mean pure tone audiometry threshold in the low frequency range, which may have clinical implications. Though many of our results are (statistically) substantial the study was limited by the small cohort size.

  1. The noncoding RNA expression profile and the effect of lncRNA AK126698 on cisplatin resistance in non-small-cell lung cancer cell.

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    Yong Yang

    Full Text Available BACKGROUND: The efficacy of cisplatin-based chemotherapy in non-small-cell lung cancer is limited by the acquired drug resistance. Identification the RNAs related to the cisplatin resistance may help to improve clinical response rates. METHODS: Microarray expression profiling of mRNAs, lncRNA and miRNA was undertaken in A549 cells and cisplatin resistant A549/CDDP cells. Differentially expressed mRNAs, lncRNAs and miRNAs, verified by realtime RT-PCR, were subjected to pathway analysis. Expression of NKD2 and β-catenin was assessed by realtime RT-PCR and western blot analysis. The effect of lncRNA AK126698 on cisplatin induced apoptosis was investigated by annexin-V/PI flow cytometry. RESULTS: In total, 1471 mRNAs, 1380 lncRNAs and 25 miRNAs differentially expressed in A549/CDDP and A549 cells. Among them, 8 mRNAs, 8 lncRNAs and 5 miRNAs differentially expressed in gene chip analysis were validated. High-enrichment pathway analysis identified that some classical pathways participated in proliferation, differentiation, avoidance of apoptosis, and drug metabolism were differently expressed in these cells lines. Gene co-expression network identified many genes like FN1, CTSB, EGFR, and NKD2; lncRNAs including BX648420, ENST00000366408, and AK126698; and miRNAs such as miR-26a and let-7i potentially played a key role in cisplatin resistance. Among which, the canonical Wnt pathway was investigated because it was demonstrated to be targeted by both lncRNAs and miRNAs including lncRNA AK126698. Knockdown lncRNA AK126698 not only greatly decreased NKD2 which can negatively regulate Wnt/β-catenin signaling but also increased the accumulation and nuclear translocation of β-catenin, and significantly depressed apoptosis rate induced by cisplatin in A549 cells. CONCLUSION: Cisplatin resistance in non-small-cell lung cancer cells may relate to the changes in noncoding RNAs. Among these, AK126698 appears to confer cisplatin resistance by targeting the Wnt

  2. Enhancement of Cisplatin Nephrotoxicity by Morphine and Its Attenuation by the Opioid Antagonist Naltrexone

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    Atefeh Aminian

    2016-07-01

    Full Text Available Nephrotoxicity is a major side effect of cisplatin, a widely used chemotherapy agent. Morphine and other opioids are also used extensively in different types of cancer for the clinical management of pain associated with local or metastatic neoplastic lesions. In addition to its analgesic effects, morphine has also been reported to possess potential immunomodulatory and antioxidant properties. Herein, we investigated the effects of morphine in a rat model of cisplatin-induced nephrotoxicity. Following administration of a single dose of cisplatin (5 mg/kg, animals received intraperitoneal injections of morphine (5 mg/kg/day and/or naltrexone (20 mg/kg/day, an opioid antagonist, for 5 days. Cisplatin-induced nephrotoxicity was detected by a significant increase in plasma urea and creatinine levels in addition to alterations in kidney tissue morphology. Levels of TNF-α and IL-1β were significantly increased in the renal tissue in cisplatin group. Moreover, glutathione (GSH concentration and superoxide dismutase activity were significantly reduced in renal tissue in cisplatin group compared with control animals. Treatment with morphine aggravated the deleterious effects of cisplatin at clinical, biochemical and histopathological levels; whereas naltrexone diminished the detrimental effects of morphine in animals receiving morphine and cisplatin. Morphine or naltrexone alone had no effect on the mentioned parameters. Our findings indicate that concomitant treatment with morphine might intensify cisplatin-induced renal damage in rats. These findings suggest that morphine and other opioids should be administered cautiously in patients receiving cisplatin chemotherapy.

  3. A comprehensive survey of the mutagenic impact of common cancer cytotoxics.

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    Szikriszt, Bernadett; Póti, Ádám; Pipek, Orsolya; Krzystanek, Marcin; Kanu, Nnennaya; Molnár, János; Ribli, Dezső; Szeltner, Zoltán; Tusnády, Gábor E; Csabai, István; Szallasi, Zoltan; Swanton, Charles; Szüts, Dávid

    2016-05-09

    Genomic mutations caused by cytotoxic agents used in cancer chemotherapy may cause secondary malignancies as well as contribute to the evolution of treatment-resistant tumour cells. The stable diploid genome of the chicken DT40 lymphoblast cell line, an established DNA repair model system, is well suited to accurately assay genomic mutations. We use whole genome sequencing of multiple DT40 clones to determine the mutagenic effect of eight common cytotoxics used for the treatment of millions of patients worldwide. We determine the spontaneous mutagenesis rate at 2.3 × 10(-10) per base per cell division and find that cisplatin, cyclophosphamide and etoposide induce extra base substitutions with distinct spectra. After four cycles of exposure, cisplatin induces 0.8 mutations per Mb, equivalent to the median mutational burden in common leukaemias. Cisplatin-induced mutations, including short insertions and deletions, are mainly located at sites of putative intrastrand crosslinks. We find two of the newly defined cisplatin-specific mutation types as causes of the reversion of BRCA2 mutations in emerging cisplatin-resistant tumours or cell clones. Gemcitabine, 5-fluorouracil, hydroxyurea, doxorubicin and paclitaxel have no measurable mutagenic effect. The cisplatin-induced mutation spectrum shows good correlation with cancer mutation signatures attributed to smoking and other sources of guanine-directed base damage. This study provides support for the use of cell line mutagenesis assays to validate or predict the mutagenic effect of environmental and iatrogenic exposures. Our results suggest genetic reversion due to cisplatin-induced mutations as a distinct mechanism for developing resistance.

  4. Chemotherapy-induced pica and anorexia are reduced by common hepatic branch vagotomy in the rat.

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    De Jonghe, Bart C; Horn, Charles C

    2008-03-01

    Anticancer agents, such as cisplatin, induce vomiting, nausea, and anorexia. Cisplatin primarily acts on vagal afferents to produce emesis, but little is known about how this drug generates nausea and anorexia. Electrophysiology indicates that cisplatin activates vagal afferents of the common hepatic branch (CHB). Rats lack an emetic response but do ingest kaolin clay (a pica response) when made sick by toxins, and this behavior can be inhibited by antiemetic drugs. It has been postulated that pica may serve as a proxy for emesis in the rat. The goal of this study was to assess the effect of CHB or ventral gastric (Gas) or celiac (Cel) branch vagotomies on pica and anorexia produced by cisplatin in the rat. The effects of apomorphine, a dopamine receptor agonist, which induces emesis via a central mechanism, were also assessed. Cisplatin-induced pica was suppressed by CHB vagotomy (a 61% reduction) but not by Gas and Cel vagotomy. Suppression of daily food intake and body weight following cisplatin treatment was also blunted by CHB ablation but not by Gas or Cel vagotomy. No vagotomy condition exhibited altered apomorphine-induced pica. The results indicate that the CHB, which innervates primarily the duodenum, plays an important role in cisplatin-induced malaise. These data suggest that pica has sensory pathways similar to emetic systems, since a vagotomy condition inhibited cisplatin-induced pica but had no effect on apomorphine-induced pica. This investigation contributes to the delineation of the physiology of pica and neural systems involved in malaise in the nonvomiting rat.

  5. Ethyl benzene-induced ototoxicity in rats : a dose-dependent mild-frequency hearing loss

    NARCIS (Netherlands)

    Cappaert, N.L.M.; Klis, S.F.L.; Baretta, A.B.; Muijser, H.; Smoorenburg, G.F.

    2000-01-01

    Rats were exposed to ethyl benzene at 0, 300, 400 and 550 ppm for 8 hours/day for 5 consecutive days. Three to six weeks after the exposure, auditory function was tested by measuring compound action potentials (CAP) in the frequency range of 1-24 kHz and 2f1-f2 distortion product otoacoustic

  6. Enhanced ototoxicity of gentamicin and salicylate caused by Mg deficiency and Zn deficiency.

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    Günther, T; Rebentisch, E; Vormann, J; König, M; Ising, H

    1988-06-01

    In rats, Mg deficiency caused a moderate hearing loss, measured by means of evoked potentials at 10 and 20 kHz, which was repaired after refeeding a normal diet. Application of 700 mg/kg salicylic acid or injection of 5 x 100 mg/kg gentamicin also caused a reversible hearing loss in normally fed rats. Treatment of Zn-deficient rats with salicylic acid produced a stronger although reversible hearing loss than in normally fed salicylate-treated rats. Treatment of Mg-deficient rats with gentamicin induced a strong hearing loss that was nearly complete and irreversible in 9 of 25 rats.

  7. Estudo da ototoxicidade em trabalhadores expostos a organofosforados Ototoxicity study in workers exposed to organophosphate

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    Ana Cristina Hiromi Hoshino

    2008-12-01

    Full Text Available A exposição ocupacional e ambiental aos agrotóxicos evidencia-se como um grave problema de Saúde Pública em nosso país. Entre os sintomas apresentados, a tonteira se destaca, em decorrência de uma provável ação tóxica. OBJETIVO: O objetivo do estudo é caracterizar os resultados do exame vestibular de trabalhadores rurais expostos ocupacionalmente e ambientalmente aos agrotóxicos organofosforados. MATERIAL E MÉTODO: Foi realizado um estudo de coorte com corte transversal em 18 trabalhadores rurais de Teresópolis, RJ. A faixa etária variou de 16 a 59 anos com uma média de 39,6 anos, sendo 5 trabalhadores do sexo masculino e 13 do sexo feminino. Foram utilizados três questionários com perguntas relacionadas à saúde geral e auditiva e perguntas específicas à tonteira e suas relações com o trabalho. Todos os trabalhadores passaram por uma avaliação clínica e realizaram os exames vectoeletronistagmografia e audiometria. RESULTADOS: Os resultados mostraram que 16 trabalhadores apresentaram alterações do equilíbrio corporal de tipo periférico irritativo e 7 trabalhadores apresentaram perdas auditivas do tipo neurossensorial, sugerindo que os agrotóxicos induzem alterações do sistema vestibular através de uma intoxicação lenta e silenciosa. CONCLUSÕES: O olhar clínico sobre esta população exposta a substâncias neuro-ototóxicas requer uma abordagem interdisciplinar, assegurando uma intervenção terapêutica e preventiva eficaz.Occupational and environmental exposure to agricultural pesticides represent an important health care problem in our country. Among the symptoms presented, dizziness stands out, because of a probable toxic action. AIM: The goal of our study was to characterize vestibular test results from rural workers occupationally and environmentally exposed to organophosphates used in agricultural pesticides. MATERIALS AND METHODS: We carried out a cohort cross-sectional study with 18 rural workers from Teresópolis, RJ. Age ranged between 16 and 59 years, with a mean value of 39.6 years, 5 were males and 13 females. We used three questionnaires with questions associated with general and auditory health, and more specific questions about dizziness and its association with work. All workers underwent clinical evaluation, audiometry and vectoelectronystagmography. RESULTS: results showed that 16 workers had irritative peripheral body balance disorder and 7 workers had sensorineural hearing loss, thus suggesting that agricultural pesticides cause vestibular alterations through a slow and silent intoxication. CONCLUSIONS: medical care for this population exposed to neurotoxic substances require an interdisciplinary approach, to guarantee efficient preventive and therapeutic measures.

  8. Honey feeding protects kidney against cisplatin nephrotoxicity through suppression of inflammation.

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    Hamad, Rania; Jayakumar, Calpurnia; Ranganathan, Punithavathi; Mohamed, Riyaz; El-Hamamy, Mahmoud M I; Dessouki, Amina A; Ibrahim, Abdelazim; Ramesh, Ganesan

    2015-08-01

    Cisplatin is a highly effective chemotherapeutic drug used to treat a wide variety of solid tumors. However, its use was limited due its dose-limiting toxicity to the kidney. Currently, there are no therapies available to treat or prevent cisplatin nephrotoxicity. Honey is a naturally occurring complex liquid and widely used in traditional Ayurvedic medicine to treat many illnesses. However, its effect on cisplatin nephrotoxicity is unknown. To determine the role of honey in cisplatin nephrotoxicity, animals were pretreated orally for a week and then cisplatin was administered. Honey feeding was continued for another 3 days. Our results show that animals with cisplatin-induced kidney dysfunction, as determined by increased serum creatinine, which received honey feeding had less kidney dysfunction. Improved kidney function was associated with better preservation of kidney morphology in honey-treated group as compared to the cisplatin alone-treated group. Interestingly, honey feeding significantly reduced cisplatin-induced tubular epithelial cell death, immune infiltration into the kidney as well as cytokine and chemokine expression and excretion as compared to cisplatin treated animals. Western blot analysis shows that cisplatin-induced increase in phosphorylation of NFkB was completely suppressed with honey feeding. In conclusion, honey feeding protects the kidney against cisplatin nephrotoxicity through suppression of inflammation and NFkB activation. © 2015 Wiley Publishing Asia Pty Ltd.

  9. Origanum majorana Attenuates Nephrotoxicity of Cisplatin Anticancer Drug through Ameliorating Oxidative Stress.

    Science.gov (United States)

    Soliman, Amel M; Desouky, Shreen; Marzouk, Mohamed; Sayed, Amany A

    2016-05-05

    Despite the fact that cisplatin is an important anticancer drug, its clinical utilization is limited by nephrotoxicity during long term medication. Combined cisplatin chemotherapy with plant extracts can diminish toxicity and enhance the antitumor efficacy of the drug. This study evaluated the effect of Originum majorana ethanolic extract (OMEE) on cisplatin-induced nephrotoxicity. Eighteen male rats were divided into three groups as follows: a control group, a group treated with cisplatin (3 mg/kg body weight), and a group that received both cisplatin and OMEE (500 mg/kg body weight) for 14 days. Cisplatin induced a significant increase in creatinine, urea, uric acid, blood urea nitrogen, malondialdehyde, and nitric oxide levels. However, glutathione, superoxide dismutase, and catalase levels were significantly diminished. Conversely, OMEE significantly modulated the renal and oxidative markers negatively impacted by cisplatin. OMEE significantly reduced the effects of cisplatin-induced changes in renal and oxidative markers, possibly through its free radical scavenging activity. Thus, OMEE may be combined with cisplatin to alleviate nephrotoxicity in cancer chemotherapy.

  10. Decreased drug accumulation and increased tolerance to DNA damage in tumor cells with a low level of cisplatin resistance.

    Science.gov (United States)

    Lanzi, C; Perego, P; Supino, R; Romanelli, S; Pensa, T; Carenini, N; Viano, I; Colangelo, D; Leone, R; Apostoli, P; Cassinelli, G; Gambetta, R A; Zunino, F

    1998-04-15

    In an attempt to examine the cellular changes associated with cisplatin resistance, we selected a cisplatin-resistant (A43 1/Pt) human cervix squamous cell carcinoma cell line following continuous in vitro drug exposure. The resistant subline was characterized by a 2.5-fold degree of resistance. In particular, we investigated the expression of cellular defence systems and other cellular factors probably involved in dealing with cisplatin-induced DNA damage. Resistant cells exhibited decreased platinum accumulation and reduced levels of DNA-bound platinum and interstrand cross-link frequency after short-term drug exposure. Analysis of the effect of cisplatin on cell cycle progression revealed a cisplatin-induced G2M arrest in sensitive and resistant cells. Interestingly, a slowdown in S-phase transit was found in A431/Pt cells. A comparison of the ability of sensitive and resistant cells to repair drug-induced DNA damage suggested that resistant cells were able to tolerate higher levels of cisplatin-induced DNA damage than their parental counterparts. Analysis of the expression of proteins involved in DNA mismatch repair showed a decreased level of MSH2 in resistant cells. Since MSH2 seems to be involved in recognition of drug-induced DNA damage, this change may account for the increased tolerance to DNA damage observed in the resistant subline. In conclusion, the involvement of accumulation defects and the increased tolerance to cisplatin-induced DNA damage in these cisplatin-resistant cells support the notion that multiple changes contribute to confer a low level of cisplatin resistance.

  11. Hepato and reno protective action of Calendula officinalis L. flower extract.

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    Preethi, Korengath Chandran; Kuttan, Ramadasan

    2009-03-01

    Flower extract of C. officinalis L. was evaluated for its protective effect against CCl4 induced acute hepatotoxicity and cisplatin induced nephrotoxicity. The activities of serum marker enzymes of liver injury like glutamate pyruvate transaminase (SGPT), glutamate oxaloacetate transaminase (SGOT) and alkaline phosphatase (ALP) which were increased by CCl4 injection was found to be significantly reduced by the pretreatment of the flower extract at 100 and 250 mg/kg body weight. The lipid peroxidation in liver, the marker of membrane damage and the total bilirubin content in serum were also found to be at significantly low level in the extract pretreated group, indicating its protective role. The kidney function markers like urea and creatinine were significantly increased in cisplatin treated animals. However, their levels were found to be lowered in the extract pretreated groups (100 and 250 mg/kg body weight). Moreover, cisplatin induced myelosuppression was ameliorated by the extract pretreatment. Treatment with the extract produced enhancement of antioxidant enzymes--superoxide dismutase and catalase and glutathione. Results suggest a protective role of the flower extract of C. officinalis against CCl4 induced acute hepatotoxicity and cisplatin induced nephrotoxicity. Extract has been found to contain several carotenoids of which lutein, zeaxanthin and lycopene predominates. Possible mechanism of action of the flower extract may be due to its antioxidant activity and reduction of oxygen radicals.

  12. Chemotherapy refractory testicular germ cell tumor is associated with a variant in Armadillo Repeat gene deleted in Velco-Cardio-Facial syndrome (ARVCF

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    Chunkit eFung

    2012-12-01

    Full Text Available Introduction: There is evidence that inherited genetic variation affects both testicular germ cell tumor (TGCT treatment outcome and risks of late-complications arising from cisplatin-based chemotherapy. Using a candidate gene approach, we examined associations of three genes involved in the cisplatin metabolism pathway, GSTP1, COMT, and TPMT, with TGCT outcome and cisplatin-induced neurotoxicity. Material and Methods: Our study population includes a subset of patients (n=137 from a genome-wide association study at the University of Pennsylvania that evaluates inherited genetic susceptibility to TGCT. All patients in our study had at least one course of cisplatin-based chemotherapy with at least one year of follow up. A total of 90 markers in GSTP1, COMT and TPMT and their adjacent genomic regions (± 20 kb were analyzed for associations with refractory TGCT after first course of chemotherapy, progression-free survival (PFS, overall survival (OS, peripheral neuropathy, and ototoxicity. Results: After adjustment for multiple comparisons, one SNP, rs2073743, in the flanking region (± 20 kb of COMT was associated with refractory TGCT after initial chemotherapy. This SNP lies within the intron region of the Armadillo Repeat gene deleted in Velco-Cardio-Facial syndrome (ARVCF. The G allele of rs2073743 predisposed patients to refractory disease with a relative risk of 2.6 (95% CI 1.1, 6.3; P=0.03. Assuming recessive inheritance, patients with the GG genotype had 22.7 times higher risk (95% CI 3.3, 155.8; P=0.04 of developing refractory disease when compared to those with the GC or CC genotypes. We found no association of our candidate genes with peripheral neuropathy, ototoxicity, PFS and OS. Discussion: This is the first study to suggest that germline genetic variants of ARVCF may affect TGCT outcome. The result of this study is hypothesis generating and should be validated in future studies.

  13. Effects of peroxisome proliferator activated receptors (PPAR-γ and -α agonists on cochlear protection from oxidative stress.

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    Marijana Sekulic-Jablanovic

    Full Text Available Various insults cause ototoxicity in mammals by increasing oxidative stress leading to apoptosis of auditory hair cells (HCs. The thiazolidinediones (TZDs; e.g., pioglitazone and fibrate (e.g., fenofibrate drugs are used for the treatment of diabetes and dyslipidemia. These agents target the peroxisome proliferator-activated receptors, PPARγ and PPARα, which are transcription factors that influence glucose and lipid metabolism, inflammation, and organ protection. In this study, we explored the effects of pioglitazone and other PPAR agonists to prevent gentamicin-induced oxidative stress and apoptosis in mouse organ of Corti (OC explants. Western blots showed high levels of PPARγ and PPARα proteins in mouse OC lysates. Immunofluorescence assays indicated that PPARγ and PPARα proteins are present in auditory HCs and other cell types in the mouse cochlea. Gentamicin treatment induced production of reactive oxygen species (ROS, lipid peroxidation, caspase activation, PARP-1 cleavage, and HC apoptosis in cultured OCs. Pioglitazone mediated its anti-apoptotic effects by opposing the increase in ROS induced by gentamicin, which inhibited the subsequent formation of 4-hydroxy-2-nonenal (4-HNE and activation of pro-apoptotic mediators. Pioglitazone mediated its effects by upregulating genes that control ROS production and detoxification pathways leading to restoration of the reduced:oxidized glutathione ratio. Structurally diverse PPAR agonists were protective of HCs. Pioglitazone (PPARγ-specific, tesaglitazar (PPARγ/α-specific, and fenofibric acid (PPARα-specific all provided >90% protection from gentamicin toxicity by regulation of overlapping subsets of genes controlling ROS detoxification. This study revealed that PPARs play important roles in the cochlea, and that PPAR-targeting drugs possess therapeutic potential as treatment for hearing loss.

  14. Effect of combined occupational exposure to noise and organic solvents on hearing.

    Science.gov (United States)

    Metwally, Fateheya Mohamed; Aziz, Hisham Mohamed; Mahdy-Abdallah, Heba; ElGelil, Khaled Said Abd; El-Tahlawy, Eman M

    2012-11-01

    Noise exposure has been commonly regarded as the main hazard of occupational hearing loss. Recent studies indicate that several chemicals, including organic solvents have ototoxic effects. This study aimed at evaluating the hearing of workers exposed to both noise and a mixture of organic solvents at concentrations anticipated as safe. The study comprised three groups. The first one included 70 workers exposed to noise only, the second group consisted of 93 workers exposed to organic solvents and noise, and the control group included 59 individuals exposed to neither noise nor organic solvents. The three groups were matched for age, socioeconomic status, and smoking habit. The results of this study revealed that there was no statistically significant difference between the two exposed groups as regards the duration of exposure. There was a highly statistically significant difference between the two exposed groups as regards the different types of hearing loss (conductive deafness, sensory neural hearing loss, and mixed type) compared with the control one. Our study reported that sensory neural hearing loss occurred earlier in subjects with combined exposure to noise and solvents at a mean duration of exposure (16.38 ± 9.44 years) compared to (24.53 ± 9.59 years) the subjects with sole exposure to noise. The difference between the two groups was statistically significant regarding this type of hearing impairment (p exposure in the two exposed groups. As regards the results of the environmental monitoring, both noise exposure levels (dB) and levels of different organic solvents measured (mg/m(3)) in different work departments were less than the levels recommended by Egyptian Environmental Law No. 4 for 1994. It is recommended that in the case of combined exposure, noise and solvent levels should be lowered than the permissible limits recommended for either alone.

  15. SKY1 is involved in cisplatin-induced cell kill in Saccharomyces cerevisiae, and inactivation of its human homologue, SRPK1, induces cisplatin resistance in a human ovarian carcinoma cell line

    NARCIS (Netherlands)

    P.W. Schenk (Paul); A.W.M. Boersma (Anton); J.A. Brandsma (Jourica); H. den Dulk (Hans); H. Burger (Herman); G. Stoter (Gerrit); J. Brouwer (Jaap); K. Nooter (Kees)

    2001-01-01

    textabstractThe therapeutic potential of cisplatin, one of the most active and widely used anticancer drugs, is severely limited by the occurrence of cellular resistance. In this study, using budding yeast Saccharomyces cerevisiae as a model organism to identify novel drug

  16. Effects

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    S.B. Hassan

    2015-01-01

    Full Text Available The effects of eggshell particles (ES on the microstructures and properties of Al–Cu–Mg/ES particulate composites have been studied. A total of 2–12 wt.% ES particles were added. The microstructures of the Al–Cu–Mg/eggshell particulate composites produced were examined by a scanning electron microscope with energy dispersive spectrometer (SEM/EDS. The physical and mechanical properties measured included: density, tensile strength, hardness values and impact energy. The results revealed that the tensile strength increased by 8.16% at 12 wt.% uncarbonized ES and 14.28% at 12 wt.% carbonized ES, the hardness values increased by 10.01% at 12 wt.% uncarbonized ES and 25.4% at 12 wt.% carbonized ES with decrease in the density by 6.50% at 12 wt.% uncarbonized ES and 7.4% at 12 wt.% carbonized ES. The impact energy decreased by 23.5% at 12 wt.% uncarbonized ES and 24.67% at 12 wt.% carbonized ES particles, respectively. These increases in strength and hardness values are attributed to the distribution of hard phases of the ES particles in the ductile Al–Cu–Mg alloy matrix. These results showed that using the carbonized eggshell as reinforcement in the Al–Cu–Mg alloy gives better physical and mechanical properties as compared to uncarbonized ES particles. Hence addition of ES particles upto 12 wt.% can be used as a low cost reinforcement for the production of metal matrix composites for engineering applications.

  17. Effects of topical oxiconazole and boric acid in alcohol solutions to rat inner ears.

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    Özdemir, Süleyman; Tuncer, Ülkü; Tarkan, Özgür; Akar, Funda; Sürmelioğlu, Özgür

    2013-06-01

    The aim of this study is to evaluate the ototoxicity of topical oxiconazole and boric acid in alcohol solutions. Prospective controlled animal study. Research laboratory. Fifty adult Wistar albino rats were divided into 5 groups consisting of 10 animals each. The right tympanic membranes were perforated, and baseline and posttreatment distortion product otoacoustic emission (DPOAE) measurements were performed. The solutions were applied through the external ear canal to the middle ear twice a day for 14 days. The rats in group I and group II received 0.1 mL of oxiconazole-containing solution drops and 4% boric acid in alcohol solution drops, respectively. Group III received gentamicin solution (40 mg/mL) (ototoxic control), group IV received saline solution, and group V was followed without any medication. The baseline DPOAE results of the right ears of all animals tested were normal. Animals in groups I, II, IV, and V showed no statistically significant change in the DPOAE amplitudes. The rats in the gentamicin group showed a significant decrease. This study demonstrates that topically used oxiconazole and boric acid in alcohol solutions to the middle ear appear to be safe on the inner ear of rats. The safety of these drugs has not yet been confirmed in humans. Caution should be taken when prescribing these drugs, especially to patients who had tympanic membrane perforation. Ear drops should be chosen more carefully in an external ear infection for patients with tympanic membrane perforation to avoid ototoxicity.

  18. Mechanisms of Cisplatin Nephrotoxicity

    Science.gov (United States)

    Miller, Ronald P.; Tadagavadi, Raghu K.; Ramesh, Ganesan; Reeves, William Brian

    2010-01-01

    Cisplatin is a widely used and highly effective cancer chemotherapeutic agent. One of the limiting side effects of cisplatin use is nephrotoxicity. Research over the past 10 years has uncovered many of the cellular mechanisms which underlie cisplatin-induced renal cell death. It has also become apparent that inflammation provoked by injury to renal epithelial cells serves to amplify kidney injury and dysfunction in vivo. This review summarizes recent advances in our understanding of cisplatin nephrotoxicity and discusses how these advances might lead to more effective prevention. PMID:22069563

  19. A new cerebroside from the fruiting bodies of Hericium erinaceus and its applicability to cancer treatment.

    Science.gov (United States)

    Lee, Seoung Rak; Jung, Kiwon; Noh, Hyung Jun; Park, Yong Joo; Lee, Hye Lim; Lee, Kang Ro; Kang, Ki Sung; Kim, Ki Hyun

    2015-12-15

    A new cerebroside, cerebroside E (1) was isolated from the fruiting bodies of Hericium erinaceus (Hericiaceae). The structure of 1 was elucidated by a combination of extensive spectroscopic analyses, including extensive 2D NMR, HR-MS, and chemical reactions. Compound 1 was evaluated for its applicability to medicinal use in several human diseases using cell-based assays. As a result, compound 1 attenuated cisplatin-induced nephrotoxicity in LLC-PK1 cells and exhibited a significant inhibitory effect on angiogenesis in HUVECs. These results collectively reflect the beneficial effects of compound 1 in cancer treatment. Copyright © 2015 Elsevier Ltd. All rights reserved.

  20. Anorexia in human and experimental animal models: physiological aspects related to neuropeptides.

    Science.gov (United States)

    Yoshimura, Mitsuhiro; Uezono, Yasuhito; Ueta, Yoichi

    2015-09-01

    Anorexia, a loss of appetite for food, can be caused by various physiological and pathophysiological conditions. In this review, firstly, clinical aspects of anorexia nervosa are summarized in brief. Secondly, hypothalamic neuropeptides responsible for feeding regulation in each hypothalamic nucleus are discussed. Finally, three different types of anorexigenic animal models; dehydration-induced anorexia, cisplatin-induced anorexia and cancer anorexia-cachexia, are introduced. In conclusion, hypothalamic neuropeptides may give us novel insight to understand and find effective therapeutics strategy essential for various kinds of anorexia.

  1. Cisplatin treatment induces a transient increase in tumorigenic potential associated with high interleukin-6 expression in head and neck squamous cell carcinoma.

    Science.gov (United States)

    Poth, Kim J; Guminski, Alexander D; Thomas, Gethin P; Leo, Paul J; Jabbar, Ibtissam A; Saunders, Nicholas A

    2010-08-01

    Head and neck squamous cell carcinoma (HNSCC) is characterized by the 5-year survival rate of approximately 50%. Despite aggressive surgical, radiation, and chemotherapeutic interventions, 30% to 40% of patients die from the development of recurrent or disseminated disease that is resistant to chemotherapy. As a model of recurrence, we examined the effects of cisplatin on the ability of head and neck cancer cells to initiate tumors in a xenotransplant model. HNSCC cells were treated in vitro with cisplatin at a concentration that elicited >99% cytotoxicity and assessed for tumorigenic potential in nonobese diabetic/severe combined immunodeficient mice. HNSCC cells that survived cisplatin treatment formed tumors in nonobese diabetic/severe combined immunodeficient mice more efficiently than nontreated cells. Cisplatin-resistant cells were characterized using clonal analysis, in vivo imaging, and transcriptomic profiling. Preliminary functional assessment of a gene, interleukin-6 (IL-6), highly upregulated in cisplatin-treated cells was carried out using clonogenicity and tumorigenicity assays. We show that cisplatin-induced IL-6 expression can contribute to the increase in tumorigenic potential of head and neck cancer cells but does not contribute to cisplatin resistance. Finally, through clonal analysis, we show that cisplatin-induced IL-6 expression and cisplatin-induced tumorigenicity are stochastically derived. We report that cisplatin treatment of head and neck cancer cells results in a transient accumulation of cisplatin-resistant, small, and IL-6-positive cells that are highly tumorigenic. These data also suggest that therapies that reduce IL-6 action may reduce recurrence rates and/or increase disease-free survival times in head and neck cancer patients, and thus, IL-6 represents a promising new target in HNSCC treatment. (c) 2010 AACR.

  2. The anti-diabetic drug metformin protects against chemotherapy-induced peripheral neuropathy in a mouse model.

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    Qi-Liang Mao-Ying

    Full Text Available Chemotherapy-induced peripheral neuropathy (CIPN characterized by loss of sensory sensitivity and pain in hands and feet is the major dose-limiting toxicity of many chemotherapeutics. At present, there are no FDA-approved treatments for CIPN. The anti-diabetic drug metformin is the most widely used prescription drug in the world and improves glycemic control in diabetes patients. There is some evidence that metformin enhances the efficacy of cancer treatment. The aim of this study was to test the hypothesis that metformin protects against chemotherapy-induced neuropathic pain and sensory deficits. Mice were treated with cisplatin together with metformin or saline. Cisplatin induced increased sensitivity to mechanical stimulation (mechanical allodynia as measured using the von Frey test. Co-administration of metformin almost completely prevented the cisplatin-induced mechanical allodynia. Co-administration of metformin also prevented paclitaxel-induced mechanical allodynia. The capacity of the mice to detect an adhesive patch on their hind paw was used as a novel indicator of chemotherapy-induced sensory deficits. Co-administration of metformin prevented the cisplatin-induced increase in latency to detect the adhesive patch indicating that metformin prevents sensory deficits as well. Moreover, metformin prevented the reduction in density of intra-epidermal nerve fibers (IENFs in the paw that develops as a result of cisplatin treatment. We conclude that metformin protects against pain and loss of tactile function in a mouse model of CIPN. The finding that metformin reduces loss of peripheral nerve endings indicates that mechanism underlying the beneficial effects of metformin includes a neuroprotective activity. Because metformin is widely used for treatment of type II diabetes, has a broad safety profile, and is currently being tested as an adjuvant drug in cancer treatment, clinical translation of these findings could be rapidly achieved.

  3. Hearing loss after platinum treatment is irreversible in noncranial irradiated childhood cancer survivors

    NARCIS (Netherlands)

    Clemens, Eva; de Vries, Andrica C. H.; Zehnhoff-Dinnesen, Antoinette Am; Tissing, Wim J. E.; Loonen, Jacqueline J.; Pluijm, Saskia F. M.; van Dulmen-den Broeder, Eline; Bresters, Dorine; Versluys, Birgitta; Kremer, Leontien C. M.; van der Pal, Helena J.; Neggers, Sebastian J. C. C. M.; van Grotel, Martine; van den Heuvel-Eibrink, Marry M.

    2017-01-01

    Cisplatin and carboplatin are effective antineoplastic agents. They are also considered to be potentially highly ototoxic. To date, no long-term follow-up data from well-documented cohorts with substantial numbers of childhood cancer survivors (CCS) with platinum-related hearing loss are available.

  4. When students become patients: TB disease among medical ...

    African Journals Online (AJOL)

    A self-administered questionnaire was distributed via email and social media to current medical students and recently graduated doctors (2010 - 2015) at two medical schools in Cape ... Students with DR-TB interrupted their studies and experienced severe side-effects (hepatotoxicity, depression and permanent ototoxicity).

  5. Platinum-induced hearing loss after treatment for childhood cancer

    NARCIS (Netherlands)

    van As, Jorrit W.; van den Berg, Henk; van Dalen, Elvira C.

    2016-01-01

    Background Platinum-based therapy, including cisplatin, carboplatin, oxaliplatin or a combination of these, is used to treat a variety of paediatric malignancies. Unfortunately, one of the most important adverse effects is the occurrence of hearing loss or ototoxicity. There is a wide variation in

  6. Different infusion durations for preventing platinum-induced hearing loss in children with cancer

    NARCIS (Netherlands)

    van As, Jorrit W.; van den Berg, Henk; van Dalen, Elvira C.

    2014-01-01

    Platinum-based therapy, including cisplatin, carboplatin or oxaliplatin, or a combination of these, is used to treat a variety of paediatric malignancies. Unfortunately, one of the most important adverse effects is the occurrence of hearing loss or ototoxicity. In an effort to prevent this

  7. Different infusion durations for preventing platinum-induced hearing loss in children with cancer

    NARCIS (Netherlands)

    van As, Jorrit W.; van den Berg, Henk; van Dalen, Elvira C.

    2016-01-01

    Background Platinum-based therapy, including cisplatin, carboplatin or oxaliplatin, or a combination of these, is used to treat a variety of paediatric malignancies. Unfortunately, one of the most important adverse effects is the occurrence of hearing loss or ototoxicity. In an effort to prevent

  8. Identification and evaluation of improved 4'-O-(alkyl) 4,5-disubstituted 2-deoxystreptamines as next-generation aminoglycoside antibiotics.

    Science.gov (United States)

    Duscha, Stefan; Boukari, Heithem; Shcherbakov, Dimitri; Salian, Sumantha; Silva, Sandrina; Kendall, Ann; Kato, Takayuki; Akbergenov, Rashid; Perez-Fernandez, Deborah; Bernet, Bruno; Vaddi, Swapna; Thommes, Pia; Schacht, Jochen; Crich, David; Vasella, Andrea; Böttger, Erik C

    2014-09-30

    The emerging epidemic of drug resistance places the development of efficacious and safe antibiotics in the spotlight of current research. Here, we report the design of next-generation aminoglycosides. Discovery efforts were driven by rational synthesis focusing on 4' alkylations of the aminoglycoside paromomycin, with the goal to alleviate the most severe and disabling side effect of aminoglycosides-irreversible hearing loss. Compounds were evaluated for target activity in in vitro ribosomal translation assays, antibacterial potency against selected pathogens, cytotoxicity against mammalian cells, and in vivo ototoxicity. The results of this study produced potent compounds with excellent selectivity at the ribosomal target, promising antibacterial activity, and little, if any, ototoxicity upon chronic administration. The favorable biocompatibility profile combined with the promising antibacterial activity emphasizes the potential of next-generation aminoglycosides in the treatment of infectious diseases without the risk of ototoxicity. The ever-widening epidemic of multidrug-resistant infectious diseases and the paucity of novel antibacterial agents emerging from modern screening platforms mandate the reinvestigation of established drugs with an emphasis on improved biocompatibility and overcoming resistance mechanisms. Here, we describe the preparation and evaluation of derivatives of the established aminoglycoside antibiotic paromomycin that effectively remove its biggest deficiency, ototoxicity, and overcome certain bacterial resistance mechanisms. Copyright © 2014 Duscha et al.

  9. Prevention of renal dysfunction by nutraceuticals prepared from oil rich plant foods

    Directory of Open Access Journals (Sweden)

    Sahar Y. Al-Okbi

    2014-08-01

    Conclusions: Administration of the studied nutraceuticals proved to possess protective role against cisplatin-induced nephrotoxicity, chromosomal aberration and abnormal sperms. All studied nutraceuticals showed complete safety.

  10. Ambient noise levels in the chemotherapy clinic

    Directory of Open Access Journals (Sweden)

    Dana K Gladd

    2011-01-01

    Full Text Available Many of the drugs used for chemotherapy treatments are known to be ototoxic, and can result in permanent hearing threshold shifts. The degree of ototoxic damage can be influenced by many factors including dosage, duration of exposure, genetics, and coadministration with other ototoxic agents. Cisplatin is known for its ototoxic effects on hearing thresholds, particularly in the high frequencies. Recent studies have indicated a synergistic relationship between Cisplatin administration and moderate to high noise level exposure starting between 70-85 dB SPL. This study measured the noise levels in the Portland Veteran′s Affairs Medical Center′s outpatient chemotherapy clinic. Average (LAeq and peak (LCpeak noise measures were recorded every minute from 7 am until 6 pm on the two busiest clinic days. Patients, visitors, and staff members filled out anonymous surveys regarding their reactions to noise levels. Cumulative noise levels were not at levels known to interact with Cisplatin for a significant period of time. Noise measurement analysis indicated that levels were at or above 70 dB SPL for less than ten minutes during the 11-hour recording window. The patient and visitor surveys indicated that both groups were unbothered by noise in the clinic. However, most staff members were bothered by or concerned about noise levels, and many felt that it caused stress and difficulty communicating on the phone.

  11. Lidocaine Sensitizes the Cytotoxicity of Cisplatin in Breast Cancer Cells via Up-Regulation of RARβ2 and RASSF1A Demethylation

    Science.gov (United States)

    Li, Kehan; Yang, Jianxue; Han, Xuechang

    2014-01-01

    It has been reported that lidocaine is toxic to various types of cells. And a recent study has confirmed that lidocaine exerts a demethylation effect and regulates the proliferation of human breast cancer cell lines. To recognize a potential anti-tumor effect of lidocaine, we evaluated the DNA demethylation by lidocaine in human breast cancer lines, MCF-7 and MDA-MB-231 cells, and determined the influence of demethylation on the toxicity to these cells of cisplatin, which is a commonly utilized anti-tumor agent for breast cancer. Results demonstrated that lidocaine promoted a significant global genomic demethylation, and particularly in the promoters of tumor suppressive genes (TSGs), RARβ2 and RASSF1A. Further, the lidocaine treatment increased cisplatin-induced apoptosis and enhanced cisplatin-induced cytotoxicity. The combined treatment with both lidocaine and cisplatin promoted a significantly higher level of MCF-7 cell apoptosis than singular lidocaine or cisplatin treatment. Moreover, the abrogation of RARβ2 or RASSF1A expression inhibited such apoptosis. In conclusion, the present study confirms the demethylation effect of lidocaine in breast cancer cells, and found that the demethylation of RARβ2 and RASSF1A sensitized the cytotoxicity of cisplatin in breast cancer cells. PMID:25526566

  12. Phosphoproteome and transcription factor activity profiling identify actions of the anti-inflammatory agent UTL-5g in LPS stimulated RAW 264.7 cells including disrupting actin remodeling and STAT-3 activation.

    Science.gov (United States)

    Carruthers, Nicholas J; Stemmer, Paul M; Chen, Ben; Valeriote, Frederick; Gao, Xiaohua; Guatam, Subhash C; Shaw, Jiajiu

    2017-09-15

    UTL-5g is a novel small-molecule TNF-alpha modulator. It reduces cisplatin-induced side effects by protecting kidney, liver, and platelets, thereby increasing tolerance for cisplatin. UTL-5g also reduces radiation-induced acute liver toxicity. The mechanism of action for UTL-5g is not clear at the present time. A phosphoproteomic analysis to a depth of 4943 phosphopeptides and a luminescence-based transcription factor activity assay were used to provide complementary analyses of signaling events that were disrupted by UTL-5g in RAW 264.7 cells. Transcriptional activity downstream of the interferon gamma, IL-6, type 1 Interferon, TGF-β, PKC/Ca2+ and the glucocorticoid receptor pathways were disrupted by UTL-5g. Phosphoproteomic analysis indicated that hyperphosphorylation of proteins involved in actin remodeling was suppressed by UTL-5g (gene set analysis, FDR 5g. This global characterization of UTL-5g activity in a macrophage cell line discovered that it disrupts selected aspects of LPS signaling including Stat3 activation and actin remodeling providing new insight on how UTL-5g acts to reduce cisplatin-induced side effects. Copyright © 2017 Elsevier B.V. All rights reserved.

  13. Effect of gentamicin and levels of ambient sound on hearing screening outcomes in the neonatal intensive care unit: A pilot study.

    Science.gov (United States)

    Garinis, Angela C; Liao, Selena; Cross, Campbell P; Galati, Johnathan; Middaugh, Jessica L; Mace, Jess C; Wood, Anna-Marie; McEvoy, Lindsey; Moneta, Lauren; Lubianski, Troy; Coopersmith, Noe; Vigo, Nicholas; Hart, Christopher; Riddle, Artur; Ettinger, Olivia; Nold, Casey; Durham, Heather; MacArthur, Carol; McEvoy, Cynthia; Steyger, Peter S

    2017-06-01

    Hearing loss rates in infants admitted to neonatal intensive care units (NICU) run at 2-15%, compared to 0.3% in full-term births. The etiology of this difference remains poorly understood. We examined whether the level of ambient sound and/or cumulative gentamicin (an aminoglycoside) exposure affect NICU hearing screening results, as either exposure can cause acquired, permanent hearing loss. We hypothesized that higher levels of ambient sound in the NICU, and/or gentamicin dosing, increase the risk of referral on the distortion product otoacoustic emission (DPOAE) assessments and/or automated auditory brainstem response (AABR) screens. This was a prospective pilot outcomes study of 82 infants (sound pressure level dosimeter was used to collect daily sound exposure in the NICU for each neonate. Gentamicin dosing was also calculated for each infant, including the total daily dose based on body mass (mg/kg/day), as well as the total number of treatment days. DPOAE and AABR assessments were conducted prior to discharge to evaluate hearing status. Exclusion criteria included congenital infections associated with hearing loss, and congenital craniofacial or otologic abnormalities. The mean level of ambient sound was 62.9 dBA (range 51.8-70.6 dBA), greatly exceeding American Academy of Pediatrics (AAP) recommendation of 4172 Hz) was 44%. DPOAE referrals were significantly greater for infants receiving >2 days of gentamicin dosing compared to fewer doses (p = 0.004). The effect of sound exposure and gentamicin treatment on hearing could not be determined due to the low number of NICU infants without gentamicin exposure (for control comparisons). All infants were exposed to higher levels of ambient sound that substantially exceed AAP guidelines. More referrals were generated by DPOAE assessments than with AABR screens, with significantly more DPOAE referrals with a high-frequency F2 range, consistent with sound- and/or gentamicin-induced cochlear dysfunction. Adding

  14. Hearing thresholds at high frequency in patients with cystic fibrosis: a systematic review.

    Science.gov (United States)

    Caumo, Debora T M; Geyer, Lúcia B; Teixeira, Adriane R; Barreto, Sérgio S M

    High-frequency audiometry may contribute to the early detection of hearing loss caused by ototoxic medications. Many ototoxic drugs are widely used in the treatment of patients with cystic fibrosis. Early detection of hearing loss should allow known harmful drugs to be identified before the damage affects speech frequencies. The damage caused by ototoxicity is irreversible, resulting in important social and psychological consequences. In children, hearing loss, even when restricted to high frequencies, can affect the development of language. To investigate the efficacy and effectiveness of hearing monitoring through high-frequency audiometry in pediatric patients with cystic fibrosis. Electronic databases PubMed, MedLine, Web of Science and LILACS were searched, from January to November 2015. The selected studies included those in which high-frequency audiometry was performed in patients with cystic fibrosis, undergoing treatment with ototoxic drugs and published in Portuguese, English and Spanish. The GRADE system was chosen for the evaluation of the methodological quality of the articles. During the search process carried out from January 2015 to November 2015, 512 publications were identified, of which 250 were found in PubMed, 118 in MedLine, 142 in Web of Science and 2 in LILACS. Of these, nine articles were selected. The incidence of hearing loss was identified at high frequencies in cystic fibrosis patients without hearing complaints. It is assumed that high-frequency audiometry can be an early diagnostic method to be recommended for hearing investigation of patients at risk of ototoxicity. Copyright © 2016 Associação Brasileira de Otorrinolaringologia e Cirurgia Cérvico-Facial. Published by Elsevier Editora Ltda. All rights reserved.

  15. Hearing thresholds at high frequency in patients with cystic fibrosis: a systematic review

    Directory of Open Access Journals (Sweden)

    Debora T.M. Caumo

    Full Text Available Abstract Introduction: High-frequency audiometry may contribute to the early detection of hearing loss caused by ototoxic medications. Many ototoxic drugs are widely used in the treatment of patients with cystic fibrosis. Early detection of hearing loss should allow known harmful drugs to be identified before the damage affects speech frequencies. The damage caused by ototoxicity is irreversible, resulting in important social and psychological consequences. In children, hearing loss, even when restricted to high frequencies, can affect the development of language. Objective: To investigate the efficacy and effectiveness of hearing monitoring through high-frequency audiometry in pediatric patients with cystic fibrosis. Methods: Electronic databases PubMed, MedLine, Web of Science and LILACS were searched, from January to November 2015. The selected studies included those in which high-frequency audiometry was performed in patients with cystic fibrosis, undergoing treatment with ototoxic drugs and published in Portuguese, English and Spanish. The GRADE system was chosen for the evaluation of the methodological quality of the articles. Results: During the search process carried out from January 2015 to November 2015, 512 publications were identified, of which 250 were found in PubMed, 118 in MedLine, 142 in Web of Science and 2 in LILACS. Of these, nine articles were selected. Conclusion: The incidence of hearing loss was identified at high frequencies in cystic fibrosis patients without hearing complaints. It is assumed that high-frequency audiometry can be an early diagnostic method to be recommended for hearing investigation of patients at risk of ototoxicity.

  16. Adenovirus-Mediated Over-Expression of Nrf2 Within Mesenchymal Stem Cells (MSCs Protected Rats Against Acute Kidney Injury

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    Mohammad Mohammadzadeh-Vardin

    2015-06-01

    Full Text Available Purpose: Recent developments in the field of cell therapy have led to a renewed interest in treatment of acute kidney injury (AKI. However, the early death of transplanted mesenchymal stem cells (MSCs in stressful microenvironment of a recipient tissue is a major problem with this kind of treatment. The objective of this study was to determine whether overexpression of a cytoprotective factor, nuclear factor erythroid-2 related factor 2 (Nrf2, in MSCs could protect rats against AKI. Methods: The Nrf2 was overexpressed in MSCs by recombinant adenoviruses, and the MSCs were implanted to rats suffering from cisplatin-induced AKI. Results: The obtained results showed that transplantation with the engineered MSCs ameliorates cisplatin-induced AKI. Morphologic features of the investigated kidneys showed that transplantation with the MSCs in which Nrf2 had been overexpressed significantly improved the complications of AKI. Conclusion: These findings suggested that the engineered MSCs might be a good candidate to be further evaluated in clinical trials. However, detailed studies must be performed to investigate the possible carcinogenic effect of Nrf2 overexpression.

  17. Effect of oleuropein against chemotherapy drug-induced histological changes, oxidative stress, and DNA damages in rat kidney injury

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    Fatime Geyikoglu

    2017-04-01

    Full Text Available Cisplatin-based chemotherapy is responsible for a large number of renal failures, and it is still associated with high rates of mortality today. Oleuropein (OLE presents a plethora of pharmacological beneficial properties. In this study we investigated whether OLE could provide sufficient protection against cisplatin-induced nephrotoxicity. With this aim, Sprague-Dawley rats were divided into eight groups: control; 7 mg/kg/d cisplatin, 50 mg/kg, 100 mg/kg, and 200 mg/kg OLE; and treatment with OLE for 3 days starting at 24 hours following cisplatin injection. After exposure to the chemotherapy agent and OLE, oxidative DNA damage was quantitated in the renal tissue of experimental animals by measuring the amount of 8-hydroxy-2′-deoxyguanosine (8-OHdG adducts. Malondialdehyde (MDA level, total oxidative stress (TOS, and total antioxidant status (TAS were assessed to determine the oxidative injury in kidney cells. The histology of the kidney was examined using four different staining methods: hematoxylin-eosin (H&E, periodic acid Schiff (PAS, Masson trichrome, and amyloid. In addition, the blood urea nitrogen (BUN, uric acid (UA, and creatinine (CRE levels were established. Our experimental data showed that tissue 8-OHdG levels were significantly higher in the cisplatin group when compared to the control group. The glomerular cells were sensitive to cisplatin as tubular cells. In addition, treatment with cisplatin elevated the levels of BUN, UA, CRE, and TOS, but lowered the level of TAS compared to the control group. The OLE therapy modulated oxidative stress in order to restore normal kidney function and reduced the formation of 8-OHdG induced by cisplatin. Furthermore, the OLE treatment significantly reduced pathological findings in renal tissue. We demonstrate for the first time that OLE presents significant cytoprotective properties against cisplatin-induced genotoxicity by restoring the antioxidant system of the renal tissue

  18. The effects of CoenzymeQ10 on gentamicin induced nephrotoxicity

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    Zeinab Hameidi Zad

    2016-10-01

    Full Text Available Abstract Background: Gentamicin (GM is one the aminoglycoside antibiotics which isroutinelyused to treatinfections gram-negative, either alone or insynergistic withbeta-lactamantibioticsused. However, frequent useleads toserious side effectssuch asrenal toxicity, ototoxicity. Coenzyme Q10 has antioxidant, anti-inflammatory and vasodilatory properties. According to these properties of Coenzyme Q10 and tissue damage mechanism in GM induced-nephrotoxicity, in this study, the effects of these two substances for the co-treatment and post -treatment on renal injury induced by gentamicin were investigated. Materials and Methods: Experiments has been done on 77 male Wistar rats in weight range of 200 to 250 g. Animals were divided randomly into 5 groups of 7 numbers. Renal nephrotoxicity induced by i.p injection of gentamicin (100mg/kg Therapeutic effect of coenzyme Q10 (10mg/kgin the two protocols co-treatment and post-treatmentwas investigated.The animals after the last injectionon the ninth day of co-treatment andthe seventeenth day of post-treatmentwere placed into individual metabolic cages so as to collection urine and urine volume was measured gravimetrically. Afteranesthesia, systolic blood pressure and renal blood flow was measured. Then blood sampling was done. Amount of urea, creatinin, sodium, potassium and osmolarity was measured in plasma and urine samples. Left kidney, for doing histological experiments in 10% buffered formaldehyde and right kidney for biochemical experiments in fluid nitrogen was preserved. Results: Co-treatment with Coenzyme Q10 significantly decreased fractional excretion of sodium (6.37±1.33 %; p<0.001 and decreased fractional excretion of potassium(219.14±83.8 %; p<0.001 MDA levels (2.13 ±0.24µmol/gkw; p<0.001, and significantly increased renal blood flow (6.38 ±0.1ml/min: p<0.01 and FRAP levels (24.44±0.42mmol/gkw; p<0.001. Post-treatment with coenzyme Q10 significantly decreased fractional excretion of sodium

  19. Geldanamycin induces production of heat shock protein 70 and partially attenuates ototoxicity caused by gentamicin in the organ of Corti explants

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    Haupt Heidemarie

    2009-09-01

    Full Text Available Abstract Background Heat shock protein 70 (HSP70 protects inner ear cells from damage and death induced by e.g. heat or toxins. Benzoquinone ansamycin antibiotic geldanamycin (GA was demonstrated to induce the expression of HSP70 in various animal cell types. The aim of our study was to investigate whether GA induces HSP70 in the organ of Corti (OC, which contains the auditory sensory cells, and whether GA can protect these cells from toxicity caused by a common aminoglycoside antibiotic gentamicin. Methods To address these questions, we used the OC explants isolated from p3-p5 rats. As a read-out, we used RT-PCR, ELISA and immunofluorescence. Results We found that GA at the concentration of 2 μM efficiently induced HSP70 expression on mRNA and protein level in the OC explants. Confocal microscopy revealed that HSP70 induced by GA is expressed by hair cells and interdental cells of spiral limbus. Preincubation of explants with 2 μM GA prior to adding gentamicin (500 μM significantly reduced the loss of outer but not inner hair cells, suggesting different mechanisms of otoprotection needed for these two cell types. Conclusion GA induced HSP70 in the auditory sensory cells and partially protected them from toxicity of gentamicin. Understanding the molecular mechanisms of GA otoprotection may provide insights for preventative therapy of the hearing loss caused by aminoglycoside antibiotics.

  20. What are the audiometric frequencies affected are the responsible for the hearing complaint in the hearing loss for ototoxicity after the oncological treatment?

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    Liberman, Patricia Helena Pecora

    2012-01-01

    Full Text Available Introduction: The neurosensory bilateral simetric hearing loss resulting of the oncological treatment is underestimated, because the patients has the hearing detection preserved, reporting complaints in determined situation, or the not comprehension of part of the message. Objective: Investigate which are the audiometric frequencies affected are the responsible by the presence of hearing complaints. Method: Prospective study evaluating 200 patients with cancer in the childhood out of the oncological treatment in at least 8 years, with average age to the diagnosis of 6,21 years (4,71. Was applied anamnesis to investigate the presence of hearing complaints and performed a tonal threshold audiometry. To check the association between the complaint and the hearing loss, was applied the Exact test of Fisher, with one error a=5%, the patients were split into: normal hearing, hearing loss in 8kHz, loss in 6-8 kHz, loss in 4-8 kHz, loss in 2-8 kHz and loss in < 1-8 kHz. Results: We found 125 patients with hearing loss, 10 presented hearing complaints. Between the patients with hearing loss, 16 presented loss only at 8kHz, and 1 with complaint; 22 with loss in 6-8 kHz, being 3 with complaint; 16 with loss in 4-8 kHz, from them 10 with complaint; 15 with loss 2-8 kHz, being 14 with complaint and 6 with loss in < 1-8 kHz all with complaints. There were a significant relationship between the loss and hearing complaint (p<0,001, when the frequency of 4 kHz was involved. Conclusion: The bigger the number of affected frequencies the bigger the occurrence of hearing complaint, most of all when the speech frequencies are involved, and the involvement of 4 kHz already determines the appearing of the complaints.

  1. Survival of Cochlear Spiral Ganglion Neurons Improved In vivo by Anti-miR204 via TMPRSS3.

    Science.gov (United States)

    Peng, A; Li, Y; Pan, X; Ge, S; Wang, Q; Li, S; Zhu, G; Liu, J

    2015-05-08

    Sensorineural hearing loss (SNHL) is caused by damage to hair cells followed by degeneration of the spiral ganglion neurons (SGNs), and cochlear implanting is an effective treatment. Unfortunately, the progressive hearing loss is still found due to ongoing degeneration of cochlear SGNs. The aim of this study was to investigate the neuroprotective effect of anti-miR204 on SGNs in vivo. Our recent in vitro work suggested that anti-miR204 could be a potential therapeutic strategy in SNHL via rescue cochlear SGNs. In order to further our knowledge of miR204 on SGNs in vivo, we made a kanamycin ototoxicity model and then virus containing the anti-miR204 gene (AAV1-anti-miR204) was microinjected into the cochlear of the model to monitor the effect. The SGNs were rescued by anti-miR204 in the kanamycin ototoxicity mouse group compared to the sham group. Moreover, expression of TMPRSS3 in SGNs was saved by anti-miR204 treatment. Anti-miR204 might be an alternate way to alleviate the degeneration of cochlear SGNs of kanamycin ototoxicity mice.

  2. L-Carnitine Protection Against Cisplatin Nephrotoxicity In Rats: Comparison with Amifostin Using Quantitative Renal Tc 99m DMSA Uptake

    Directory of Open Access Journals (Sweden)

    Yakup Yürekli

    2011-04-01

    Full Text Available Objective: In this study, we aimed to investigate the cytoprotective effect of L-carnitine against cisplatin-induced nephrotoxicity and to compare its efficacy with that of amifostin by quantitative renal Tc 99m DMSA uptake. Material and Methods: Male Wistar rats were randomly divided into six groups of six animals each. 1 Control (saline; 5 ml/kg intraperitoneally; 2 L-carnitine (CAR; 300 mg/kg intraperitoneally; 3 Amifostine (AMI; 200 mg /kg intraperitoneally; 4 Cisplatin (CIS;7 mg/kg intraperitoneally; 5 Cisplatin plus L-carnitine (CIS + CAR; 6 Cisplatin plus amifostine (CIS + AMI. L-carnitine and amifostine were injected 30 minutes before cisplatin in Group 5 and 6. Tc 99m DMSA, 7.4 MBq/0.2 ml, was injected through the tail vein 72 hours after the drug administration. Rats were killed and kidneys removed by dissection 2 hours after the injection of the radiopharmaceutical. The percentage of the injected dose per gram of kidney tissue (%ID/g was calculated. Renal function was monitored by measuring BUN and plasma levels of creatinine. Lipid peroxidation and glutathione content were determined by measuring malondialdehyde (MDA and reduced glutathione (GSH in kidney tissue homogenates. Results: Tc 99m DMSA uptake per gram tissue of the kidney as %ID/g was 29.54±4.72, 29.86 ± 7.47 and 26.37 ± 4.54 in the control, CAR and AMI groups respectively. %ID/g was the lowest of all the groups, 11.60±3.59 (p<0.01, in the cisplatin group. Carnitine or amifostine administration 30 minutes before cisplatin injection resulted a significant increase in %ID/g, 21.28±7.73 and 18.97±3.24 respectively, compared to those of cisplatin-treated rats (p<0.002. A marked increase in plasma BUN and creatinine indicating nephrotoxicity and acute renal failure was observed in the cisplatin-treated group. MDA and GSH levels were concordant with cisplatin-induced oxidative stress in the kidney tissue. Conclusion: The results showed that L-carnitine significantly

  3. Sodium arsenite and hyperthermia modulate cisplatin-DNA damage responses and enhance platinum accumulation in murine metastatic ovarian cancer xenograft after hyperthermic intraperitoneal chemotherapy (HIPEC

    Directory of Open Access Journals (Sweden)

    Muenyi Clarisse S

    2011-06-01

    Full Text Available Abstract Background Epithelial ovarian cancer (EOC is the leading cause of gynecologic cancer death in the USA. Recurrence rates are high after front-line therapy and most patients eventually die from platinum (Pt - resistant disease. Cisplatin resistance is associated with increased nucleotide excision repair (NER, decreased mismatch repair (MMR and decreased platinum uptake. The objective of this study is to investigate how a novel combination of sodium arsenite (NaAsO2 and hyperthermia (43°C affect mechanisms of cisplatin resistance in ovarian cancer. Methods We established a murine model of metastatic EOC by intraperitoneal injection of A2780/CP70 human ovarian cancer cells into nude mice. We developed a murine hyperthermic intraperitoneal chemotherapy model to treat the mice. Mice with peritoneal metastasis were perfused for 1 h with 3 mg/kg cisplatin ± 26 mg/kg NaAsO2 at 37 or 43°C. Tumors and tissues were collected at 0 and 24 h after treatment. Results Western blot analysis of p53 and key NER proteins (ERCC1, XPC and XPA and MMR protein (MSH2 suggested that cisplatin induced p53, XPC and XPA and suppressed MSH2 consistent with resistant phenotype. Hyperthermia suppressed cisplatin-induced XPC and prevented the induction of XPA by cisplatin, but it had no effect on Pt uptake or retention in tumors. NaAsO2 prevented XPC induction by cisplatin; it maintained higher levels of MSH2 in tumors and enhanced initial accumulation of Pt in tumors. Combined NaAsO2 and hyperthermia decreased cisplatin-induced XPC 24 h after perfusion, maintained higher levels of MSH2 in tumors and significantly increased initial accumulation of Pt in tumors. ERCC1 levels were generally low except for NaAsO2 co-treatment with cisplatin. Systemic Pt and arsenic accumulation for all treatment conditions were in the order: kidney > liver = spleen > heart > brain and liver > kidney = spleen > heart > brain respectively. Metal levels generally decreased in systemic

  4. A comprehensive survey of the mutagenic impact of common cancer cytotoxics

    DEFF Research Database (Denmark)

    Szikriszt, Bernadett; Poti, Adam; Pipek, Orsolya

    2016-01-01

    Background: Genomic mutations caused by cytotoxic agents used in cancer chemotherapy may cause secondary malignancies as well as contribute to the evolution of treatment-resistant tumour cells. The stable diploid genome of the chicken DT40 lymphoblast cell line, an established DNA repair model...... system, is well suited to accurately assay genomic mutations. Results: We use whole genome sequencing of multiple DT40 clones to determine the mutagenic effect of eight common cytotoxics used for the treatment of millions of patients worldwide. We determine the spontaneous mutagenesis rate at 2.3 x 10......, hydroxyurea, doxorubicin and paclitaxel have no measurable mutagenic effect. The cisplatin-induced mutation spectrum shows good correlation with cancer mutation signatures attributed to smoking and other sources of guanine-directed base damage. Conclusion: This study provides support for the use of cell line...

  5. Nanoparticle Mediated Drug Delivery of Rolipram to Tyrosine Kinase B Positive Cells in the Inner Ear with Targeting Peptides and Agonistic Antibodies

    Directory of Open Access Journals (Sweden)

    Rudolf eGlueckert

    2015-05-01

    Full Text Available AimSystemic pharmacotherapies have limitation due to blood-labyrinth barrier, so local delivery via the round window membrane opens a path for effective treatment. Multifunctional nanoparticle (NP mediated cell specific drug delivery may enhance efficacy and reduce side effects. Different NPs with ligands to target TrkB receptor were tested. Distribution, uptake mechanisms, trafficking, and bioefficacy of drug release of rolipram loaded NPs were evaluated.Methods We tested lipid based nanocapsules (LNCs, Quantum Dot, silica NPs with surface modification by peptides mimicking TrkB or TrkB activating antibodies. Bioefficacy of drug release was tested with rolipram loaded LNCs to prevent cisplatin induced apoptosis. We established different cell culture models with SH-SY-5Y and inner ear derived cell lines and used neonatal and adult mouse explants. Uptake and trafficking was evaluated with FACS and confocal as well as transmission electron microscopy. ResultsPlain NPs show some selectivity in uptake related to the in-vitro system properties, carrier material and NP size. Some peptide ligands provide enhanced targeted uptake to neuronal cells but failed to show this in cell cultures. Agonistic antibodies linked to silica NPs showed TrkB activation and enhanced binding to inner ear derived cells. Rolipram loaded LNCs proved as effective carriers to prevent cisplatin induced apoptosis.DiscussionMost NPs with targeting ligands showed limited effects to enhance uptake. NP aggregation and unspecific binding may change uptake mechanisms and impair endocytosis by an overload of NPs. This may affect survival signaling. NPs with antibodies activate survival signaling and show effective binding to TrkB positive cells but needs further optimization for specific internalization. Bioefficiacy of rolipram release confirms LNCs as encouraging vectors for drug delivery of lipophilic agents to the inner ear with ideal release characteristics independent of

  6. Nanoparticle mediated drug delivery of rolipram to tyrosine kinase B positive cells in the inner ear with targeting peptides and agonistic antibodies.

    Science.gov (United States)

    Glueckert, Rudolf; Pritz, Christian O; Roy, Soumen; Dudas, Jozsef; Schrott-Fischer, Anneliese

    2015-01-01

    Systemic pharmacotherapies have limitation due to blood-labyrinth barrier, so local delivery via the round window membrane opens a path for effective treatment. Multifunctional nanoparticle (NP)-mediated cell specific drug delivery may enhance efficacy and reduce side effects. Different NPs with ligands to target TrkB receptor were tested. Distribution, uptake mechanisms, trafficking, and bioefficacy of drug release of rolipram loaded NPs were evaluated. We tested lipid based nanocapsules (LNCs), Quantum Dot, silica NPs with surface modification by peptides mimicking TrkB or TrkB activating antibodies. Bioefficacy of drug release was tested with rolipram loaded LNCs to prevent cisplatin-induced apoptosis. We established different cell culture models with SH-SY-5Y and inner ear derived cell lines and used neonatal and adult mouse explants. Uptake and trafficking was evaluated with FACS and confocal as well as transmission electron microscopy. Plain NPs show some selectivity in uptake related to the in vitro system properties, carrier material, and NP size. Some peptide ligands provide enhanced targeted uptake to neuronal cells but failed to show this in cell cultures. Agonistic antibodies linked to silica NPs showed TrkB activation and enhanced binding to inner ear derived cells. Rolipram loaded LNCs proved as effective carriers to prevent cisplatin-induced apoptosis. Most NPs with targeting ligands showed limited effects to enh