Chrysin protects against cisplatin-induced colon. toxicity via amelioration of oxidative stress and apoptosis: Probable role of p38MAPK and p53

International Nuclear Information System (INIS)

Khan, Rehan; Khan, Abdul Quaiyoom; Qamar, Wajhul; Lateef, Abdul; Tahir, Mir; Rehman, Muneeb U; Ali, Farrah; Sultana, Sarwat

2012-01-01

Cisplatin, an antineoplastic drug, is widely used as a foremost therapy against numerous forms of cancer but it has pronounced adverse effects viz., nephrotoxicity, ototoxicity etc. CDDP-induced emesis and diarrhea are also marked toxicities that may be due to intestinal injury. Chrysin (5,7-dihydroxyflavone), a natural flavone commonly found in many plants possesses multiple biological activities, such as antioxidant, anti-inflammatory and anti-cancer effects. In the present study, we investigated the protective effect of chrysin against CDDP-induced colon toxicity. The plausible mechanism of CDDP-induced colon toxicity and damage includes oxidative stress, activation of p38MAPK and p53, and colonic epithelial cell apoptosis via upregulating the expression of Bak and cleaved caspase-3. Chrysin was administered to Wistar rats once daily for 14 consecutive days at the doses of 25 and 50 mg/kg body weight orally in corn oil. On day 14, a single intraperitoneal injection of cisplatin was given at the dose of 7.5 mg/kg body weight and animals were euthanized after 24 h of cisplatin injection. Chrysin ameliorated CDDP-induced lipid peroxidation, xanthine oxidase activity, glutathione depletion, decrease in antioxidant (catalase, glutathione reductase, glutathione peroxidase and glucose-6 phosphate dehydrogenase) and phase-II detoxifying (glutathione-S-transferase and quinone reductase) enzyme activities. Chrysin also attenuated goblet cell disintegration, expression of phospho-p38MAPK and p53, and apoptotic tissue damage which were induced by CDDP. Histological findings further supported the protective effects of chrysin against CDDP-induced colonic damage. The results of the present study suggest that the protective effect of chrysin against CDDP-induced colon toxicity was related with attenuation of oxidative stress, activation of p38MAPK and p53, and apoptotic tissue damage. Highlights: ► Cisplatin-induced colon toxicity is associated with oxidative stress and

Estrogen-related receptor α is essential for maintaining mitochondrial integrity in cisplatin-induced acute kidney injury.

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Tsushida, Keigo; Tanabe, Katsuyuki; Masuda, Kana; Tanimura, Satoshi; Miyake, Hiromasa; Arata, Yuka; Sugiyama, Hitoshi; Wada, Jun

2018-04-15

Acute kidney injury (AKI) has been associated with not only higher in-hospital mortality but also the subsequent development of chronic kidney disease (CKD). Recent evidence has suggested the involvement of mitochondrial dysfunction and impaired dynamics in the pathogenesis of AKI. Estrogen-related receptor α (ERRα) is an orphan nuclear receptor that acts as a transcription factor to regulate the transcription of genes required for mitochondrial biogenesis and oxidative phosphorylation. In the present study, we examined the effects of ERRα deficiency on the progression of AKI induced by cisplatin. Male C57BL/6 J wild-type and ERRα -/- mice received a single intraperitoneal injection of 20 mg/kg cisplatin. Seventy-two hours after the injection, kidney function and morphology were evaluated. ERRα expression was observed in renal tubules, and cisplatin inhibited its translocation into nuclei. ERRα deficiency exacerbated cisplatin-induced renal dysfunction and tubular injury, as well as oxidative stress and apoptosis. ERRα -/- mice kidneys revealed lower mitochondrial DNA content and swollen mitochondria with reduced cristae. In addition, these mice had lower expression of the mitochondrial fusion protein mitofusin-2. The cisplatin-induced decrease in mitochondrial DNA and altered mitochondrial structure were more severe in ERRα -/- mice. In cultured mouse proximal tubular epithelial cells, the ERRα inverse agonist XCT-790 significantly inhibited mitofusin-2 expression and induced mitochondrial fragmentation. Taken together, our findings suggest the involvement of ERRα in the progression of cisplatin-induced AKI probably through impaired mitochondrial dynamics. Copyright © 2018 Elsevier Inc. All rights reserved.

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.

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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.

Action of (R)-sila-venlafaxine and reboxetine to antagonize cisplatin-induced acute and delayed emesis in the ferret

International Nuclear Information System (INIS)

Warneck, Julie B.; Cheng, Frankie H.M.; Barnes, Matthew J.; Mills, John S.; Montana, John G.; Naylor, Robert J.; Ngan, Man-P.; Wai, Man-K.; Daiss, Juergen O.; Tacke, Reinhold; Rudd, John A.

2008-01-01

The chemotherapeutic drug cisplatin is associated with severe gastrointestinal toxicity that can last for several days. A recent strategy to treat the nausea and emesis includes the combination of a 5-HT 3 receptor antagonist, a glucocorticoid, and an NK 1 receptor antagonist. The present studies explore the use of the selective noradrenaline reuptake inhibitors, (R)-sila-venlafaxine, (R,R)-reboxetine and (S,S)-reboxetine to prevent cisplatin (5 mg/kg, i.p.)-induced acute (0-24 h) and delayed (24-72 h) emesis in ferrets. The positive control regimen of ondansetron and dexamethasone, both at 1 mg/kg/8 h, reduced acute and delayed emesis by 100 (P 0.05). In conclusion, the studies provide the first evidence for an anti-emetic potential of noradrenaline reuptake inhibitors to reduce chemotherapy-induced acute and delayed emesis

Gastric myoelectric activity during cisplatin-induced acute and delayed emesis reveals a temporal impairment of slow waves in ferrets: effects not reversed by the GLP-1 receptor antagonist, exendin (9-39).

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Lu, Zengbing; Ngan, Man P; Lin, Ge; Yew, David T W; Fan, Xiaodan; Andrews, Paul L R; Rudd, John A

2017-11-17

Preclinical studies show that the glucagon-like peptide-1 (GLP-1) receptor antagonist, exendin (9-39), can reduce acute emesis induced by cisplatin. In the present study, we investigate the effect of exendin (9-39) (100 nmol/24 h, i.c.v), on cisplatin (5 mg/kg, i.p.)-induced acute and delayed emesis and changes indicative of 'nausea' in ferrets. Cisplatin induced 37.2 ± 2.3 and 59.0 ± 7.7 retches + vomits during the 0-24 (acute) and 24-72 h (delayed) periods, respectively. Cisplatin also increased ( P Advanced multifractal detrended fluctuation analysis revealed that the slow wave signal shape became more simplistic during delayed emesis. Cisplatin did not affect blood pressure (BP), but transiently increased heart rate, and decreased heart rate variability (HRV) during acute emesis; HRV spectral analysis indicated a shift to 'sympathetic dominance'. A hyperthermic response was seen during acute emesis, but hypothermia occurred during delayed emesis and there was also a decrease in HR. Exendin (9-39) did not improve feeding and drinking but reduced cisplatin-induced acute emesis by ~59 % ( P waves may represent a novel approach to treat the side effects of chemotherapy.

Protective effect of riboflavin on cisplatin induced toxicities: a gender-dependent study.

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Naseem, Imrana; Hassan, Iftekhar; Alhazza, Ibrahim M; Chibber, Sandesh

2015-01-01

The toxicity exerted by the anticancer drug, cisplatin in vivo is functional to many factors such as dose, duration, gender and age etc. The present study is aimed to investigate if ameliorative potential of riboflavin on cisplatin induced toxicity is gender dependent. Eighty four adult mice from male and female sex were divided into seven groups (n=6) for both sexes. They were treated with riboflavin (2mg/kg), cisplatin (2mg/kg) and their two different combinations (cisplatin at 2mg/kg with 1mg/kg and 2mg/kg of riboflavin) under photoillumination with their respective controls for the combination groups without photoillumination. After treatment, all groups were sacrificed and their kidney, liver and serum were collected for biochemical estimations, comet assay and histopathology. In the present investigation, it was evident from antioxidant and detoxification studies (SOD, CAT, GSH, GST, MDA and carbonyl level) that the female mice exhibited better tolerance towards cisplatin inducted toxicity and the ameliorative effect of riboflavin against cisplatin toxicity was found stronger in their combination groups as compared to the male groups as the activity of all antioxidant enzymes were found better concomitant with lower level of MDA and carbonyl contents in the female combination groups than their male counterparts. Furthermore, single cell gel electrophoresis and histopathological examination confirmed that restoration of normal nuclear and cellular integrity was more prominent in female with respect to the males after treatment in the combination groups in a dose-dependent manner. Hence, this study reveals that cisplatin is more toxic in male mice and the ameliorative effect of riboflavin against cisplatin toxicity is stronger in female mice. Copyright © 2014. Published by Elsevier GmbH.

Xanthohumol attenuates cisplatin-induced nephrotoxicity through inhibiting NF-κB and activating Nrf2 signaling pathways.

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Li, Fan; Yao, Yunyi; Huang, Hui; Hao, Hua; Ying, Mingzhong

2018-06-12

Cisplatin is a chemotherapeutic agent that widely used in the treatment of cancer. However, cisplatin has been reported to induce nephrotoxicity by directly inducing inflammatory response and oxidative stress. In this study, we aimed to investigate the protective effects and mechanism of xanthohumol on cisplatin-induced nephrotoxicity. The model of nephrotoxicity was induced by intraperitoneal injection of cisplatin and xanthohumol was given intraperitoneally for three consecutive days. The results showed that xanthohumol significantly attenuated kidney histological changes and serum creatinine and BUN production. The levels of TNF-α, IL-1ß and IL-6 in kidney tissues were suppressed by xanthohumol. The levels of malondialdehyde (MDA) and ROS were suppressed by treatment of xanthohumol. The activities of glutathione (GSH) and superoxide dismutase (SOD) decreased by cisplatin were reversed by xanthohumol. Furthermore, the expression of TLR4 and the activation of NF-κB induced by cisplatin were significantly inhibited by xanthohumol. The expression of Nrf2 and HO-1 were dose-dependently up-regulated by the treatment of xanthohumol. In conclusion, xanthohumol protects against cisplatin-induced nephrotoxicity by ameliorating inflammatory and oxidative responses. Copyright © 2018 Elsevier B.V. All rights reserved.

Benfotiamine enhances antioxidant defenses and protects against cisplatin-induced DNA damage in nephrotoxic rats.

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Harisa, Gamaleldin I

2013-08-01

The objective of the present study was to assess superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx), paraoxonase (PON1), glutathione reductase (GR), and catalase (CAT) activities ratio and their relationship with DNA oxidative damage in rats treated with cisplatin (3 mg/kg bwt/day) in the presence and absence of benfotiamine (100 mg/kg/day) for 25 days. Cisplatin-induced renal damage was evidenced by renal dysfunction and elevated oxidative stress markers. SOD activity and levels of nitric oxide, protein carbonyl, malondialdehyde, and 8-hydroxy-2'-deoxyguanosine were significantly increased by cisplatin treatment. Moreover, the ratios of GPx/GR, SOD/GPx, SOD/CAT, and SOD/PON1 were significantly increased compared to control. In contrast, glutathione levels were significantly decreased by cisplatin treatment. Simultaneous treatment of rats with cisplatin and benfotiamine ameliorate these variables to values near to those of control rats. This study suggests that benfotiamine can prevent cisplatin-induced nephrotoxicity by inhibiting formation reactive species of oxygen and nitrogen. © 2013 Wiley Periodicals, Inc.

Ebselen attenuates cisplatin-induced ROS generation through Nrf2 activation in auditory cells.

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Kim, Se-Jin; Park, Channy; Han, A Lum; Youn, Myung-Ja; Lee, Jeong-Han; Kim, Yunha; Kim, Eun-Sook; Kim, Hyung-Jin; Kim, Jin-Kyung; Lee, Ho-Kyun; Chung, Sang-Young; So, Hongseob; Park, Raekil

2009-05-01

Ebselen, an organoselenium compound that acts as a glutathione peroxidase mimetic, has been demonstrated to possess antioxidant and anti-inflammatory activities. However, the molecular mechanism underlying this effect is not fully understood in auditory cells. The purpose of the present study is to investigate the protective effect of ebselen against cisplatin-induced toxicity in HEI-OC1 auditory cells, organotypic cultures of cochlear explants from two-day postnatal rats (P(2)) and adult Balb/C mice. Pretreatment with ebselen ameliorated apoptotic death induced by cisplatin in HEI-OC1 cells and organotypic cultures of Corti's organ. Ebselen pretreatment also significantly suppressed cisplatin-induced increases in intracellular reactive oxygen species (ROS), intracellular reactive nitrogen species (RNS) and lipid peroxidation levels. Ebselen dose-dependently increased the expression level of an antioxidant response element (ARE)-luciferase reporter in HEI-OC1 cells through the translocation of Nrf2 into the nucleus. Furthermore, we found that pretreatment with ebselen significantly restored Nrf2 function, whereas it ameliorated the cytotoxicity of cisplatin in cells transfectants with either a pcDNA3.1 (control) or a DN-Nrf2 (dominant-negative) plasmid. We also observed that Nrf2 activation by ebselen increased the expression of phase II antioxidant genes, including heme oxygenase (HO-1), NAD(P)H:quinine oxidoreductase, and gamma-glutamylcysteine synthetase (gamma-GCS). Treatment with ebselen resulted in an increased expression of HO-1 and intranuclear Nrf2 in hair cells of organotypic cultured cochlea. After intraperitoneal injection with cisplatin, auditory brainstem responses (ABRs) threshold was measured on 8th day in Balb/C mice. ABR threshold shift was marked occurred in mice injected with cisplatin (16 mg/kg, n=5; Click and 8-kHz stimuli, pebselen was not significantly changed. These results suggest that ebselen activates the Nrf2-ARE signaling pathway

Amelioration of Cisplatin-Induced Nephrotoxicity in Rats by Curcumin

African Journals Online (AJOL)

Keywords: Cisplatin, Oxidative stress, Curcumin, α-Tocopherol, Nephrotoxicity. Tropical ... exerts various side effects in several organs particularly in ... Previous study provides evidence which ..... chemotherapy by cisplatin but further in vivo.

Tropisetron attenuates cisplatin-induced nephrotoxicity in mice.

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Zirak, Mohammad Reza; Rahimian, Reza; Ghazi-Khansari, Mahmoud; Abbasi, Ata; Razmi, Ali; Mehr, Shahram Ejtemaei; Mousavizadeh, Kazem; Dehpour, Ahmad Reza

2014-09-05

Nephrotoxicity is one of the most important complications of cisplatin, a potent chemotherapeutic agent used in the treatment of various malignancies. 5-HT3 antagonists are widely used to counteract chemotherapy-induced emesis and new studies reveal that they poses notable anti-inflammatory properties. In current study, we investigated the effects of 5-HT3 antagonists on cisplatin induced nephrotoxicity in mice. To identify the underlying mechanism of renal protection by tropisetron, we investigated the probable involvement of alpha7 nicotinic acetylcholine receptor (α7nAChR). A single injection of cisplatin (20mg/kg; i.p) induced nephrotoxicity, 5-HT3 antagonists (tropisetron, granisetron and ondansetron,) were given twice daily for 3 day (3mg/kg; i.p). Finally animals were euthanized and blood sample was collected to measure urea and creatinin level. Also kidneys were removed for histopathological examination and biochemical measurements including glutathione (GSH), malondialdehyde (MDA), superoxide dismutase (SOD) activity, inducible nitric oxide synthase (iNOS) expression and inflammatory cytokines. Tropisetron decreased the expression of inflammatory molecules including tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β) and iNOS and improved histopathological damage and renal dysfunction. However other 5-HT3 antagonists, granisetron or ondansetron do not have any elicit effects on biochemical markers and histological damages. Since methyllycaconitine, antagonist of α7nAChR, was unable to reverse the beneficial effect of tropisetron, we concluded that this effect of tropisetron is not mediated by α7nAChR.Our results showed that tropisetron treatment markedly ameliorated the experimental cisplatin induced-nephrotoxicity and this effect might be 5-HT3 receptor and α7nAChR independent. Copyright © 2014 Elsevier B.V. All rights reserved.

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

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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.

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

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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.

Therapeutic Potential and Molecular Mechanisms of Emblica officinalis Gaertn in countering nephrotoxicity in rats induced by the chemotherapeutic agent cisplatin

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Salma Malik

2016-10-01

Full Text Available Emblica officinalis Gaertn. belonging to family Euphorbiaceae is commonly known as Indian gooseberry or Amla in India. It is used as a ‘rejuvenating herb’ in traditional system of Indian medicine. It has been shown to possess antioxidant, anti-inflammatory and anti-apoptotic effects. Thus, on the basis of its biological effects, the present study was undertaken to evaluate the protective effect of the dried fruit extract of the E. Officinalis (EO in cisplatin-induced nephrotoxicity in rats and also to evaluate the mechanism of its nephroprotection. The study was done on male albino Wistar rats. They were divided into 6 groups (n=6 viz. control, cisplatin-control, cisplatin and EO (150, 300 and 600 mg/kg; p.o. respectively in different groups and EO only (600 mg/kg; p.o. only. EO was administered orally to the rats for a period of 10 days and on the 7th day, a single injection of cisplatin (8 mg/kg; i.p. was administered to the cisplatin-control and EO treatment groups. The rats were sacrificed on the 10th day. Cisplatin-control rats had deranged renal function parameters and the kidney histology confirmed the presence of acute tubular necrosis. Furthermore, there were increased oxidative stress, apoptosis and inflammation along with higher expression of MAPK pathway proteins in the rat kidney from the cisplatin-control group. Contrary to this, EO (600 mg/kg significantly normalized renal function, bolstered antioxidant status and ameliorated histological alterations. The inflammation and apoptosis were markedly lower in comparison to cisplatin-control rats. Furthermore, EO (600 mg/kg inhibited MAPK phosphorylation which was instrumental in preserving renal function and morphology. In conclusion, the results of our study demonstrated that EO attenuated cisplatin-induced nephrotoxicity in rats through suppression of MAPK induced inflammation and apoptosis.

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

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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.

Dunnione ameliorates cisplatin ototoxicity through modulation of NAD(+) metabolism.

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Kim, Hyung-Jin; Pandit, Arpana; Oh, Gi-Su; Shen, AiHua; Lee, Su-Bin; Khadka, Dipendra; Lee, SeungHoon; Shim, Hyeok; Yang, Sei-Hoon; Cho, Eun-Young; Kwak, Tae Hwan; Choe, Seong-Kyu; Park, Raekil; So, Hong-Seob

2016-03-01

Ototoxicity is an important issue in patients receiving cisplatin chemotherapy. Numerous studies have demonstrated that cisplatin-induced ototoxicity is related to oxidative stress and DNA damage. However, the precise mechanism underlying cisplatin-associated ototoxicity is still unclear. The cofactor nicotinamide adenine dinucleotide (NAD(+)) has emerged as an important regulator of energy metabolism and cellular homeostasis. Here, we demonstrate that the levels and activities of sirtuin-1 (SIRT1) are suppressed by the reduction of intracellular NAD(+) levels in cisplatin-mediated ototoxicity. We provide evidence that the decreases in SIRT1 activity and expression facilitated by increasing poly(ADP-ribose) polymerase-1 (PARP-1) activation and microRNA-34a levels through cisplatin-mediated p53 activation aggravate the associated ototoxicity. Furthermore, we show that the induction of cellular NAD(+) levels using dunnione, which targets intracellular NQO1, prevents the toxic effects of cisplatin through the regulation of PARP-1 and SIRT1 activity. These results suggest that direct modulation of cellular NAD(+) levels by pharmacological agents could be a promising therapeutic approach for protection from cisplatin-induced ototoxicity. Copyright © 2015 Elsevier B.V. All rights reserved.

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.

Cisplatin-Induced Eosinophilic Pneumonia

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Hideharu Ideguchi

2014-01-01

Full Text Available A 67-year-old man suffering from esophageal cancer was admitted to our hospital complaining of dyspnea and hypoxemia. He had been treated with cisplatin, docetaxel, and fluorouracil combined with radiotherapy. Chest computed tomography revealed bilateral ground-glass opacity, and bronchoalveolar lavage fluid showed increased eosinophils. Two episodes of transient eosinophilia in peripheral blood were observed after serial administration of anticancer drugs before the admission, and drug-induced lymphocyte stimulation test to cisplatin was positive. Thus cisplatin-induced eosinophilic pneumonia was suspected, and corticosteroid was effectively administered. To our knowledge, this is the first reported case of cisplatin-induced eosinophilic pneumonia.

Luteolin ameliorates cisplatin-induced nephrotoxicity in mice through inhibition of platinum accumulation, inflammation and apoptosis in the kidney

International Nuclear Information System (INIS)

Domitrović, Robert; Cvijanović, Olga; Pugel, Ester Pernjak; Zagorac, Gordana Blagojević; Mahmutefendić, Hana; Škoda, Marko

2013-01-01

The aim of this study was to investigate the effects of flavone luteolin against cisplatin (CP)-induced kidney injury in mice. Luteolin at doses of 10 mg/kg was administered intraperitoneally (ip) once daily for 3 days following single CP (10 or 20 mg/kg) ip injection. Mice were sacrificed 24 h after the last dose of luteolin. The CP treatment significantly increased serum creatinine and blood urea nitrogen and induced pathohistological changes in the kidneys. Renal oxidative/nitrosative stress was evidenced by decreased glutathione (GSH) levels and increased 3-nitrotyrosine (3-NT) and 4-hydroxynonenal (4-HNE) formation as well as cytochrome P450 2E1 (CYP2E1) expression. The CP administration triggered inflammatory response in mice kidneys through activation of nuclear factor-kappaB (NF-κB) and overexpression of tumor necrosis factor-alpha (TNF-α) and cyclooxygenase-2 (COX-2). Simultaneously, the increase in renal p53 and caspase-3 expression indicated apoptosis of tubular cells. The administration of luteolin significantly reduced histological and biochemical changes induced by CP, decreased platinum (Pt) levels and suppressed oxidative/nitrosative stress, inflammation and apoptosis in the kidneys. These results suggest that luteolin is an effective nephroprotective agent, with potential to reduce Pt accumulation in the kidneys and ameliorate CP-induced nephrotoxicity

Taurine protects cisplatin induced cardiotoxicity by modulating inflammatory and endoplasmic reticulum stress responses.

Science.gov (United States)

Chowdhury, Sayantani; Sinha, Krishnendu; Banerjee, Sharmistha; Sil, Parames C

2016-11-12

Oxidative stress, ER stress, inflammation, and apoptosis results in the pathogenesis of cisplatin-induced cardiotoxicity. The present study was designed to investigate the signaling mechanisms involved in the ameliorating effect of taurine, a conditionally essential amino acid, against cisplatin-mediated cardiac ER stress dependent apoptotic death and inflammation. Mice were simultaneously treated with taurine (150 mg kg -1 body wt, i.p.) and cisplatin (10 mg kg -1 body wt, i.p.) for a week. Cisplatin exposure significantly altered serum creatine kinase and troponin T levels. In addition, histological studies revealed disintegration in the normal radiation pattern of cardiac muscle fibers. However, taurine administration could abate such adverse effects of cisplatin. Taurine administration significantly mitigated the reactive oxygen species production, alleviated the overexpression of nuclear factor-κB (NF-κB), and inhibited the elevation of proinflammatoy cytokines, adhesion molecules, and chemokines. Cisplatin exposure resulted in the unfolded protein response (UPR)-regulated CCAAT/enhancer binding protein (CHOP) up-regulation, induction of GRP78: a marker of ER stress and eIF2α signaling. Increase in calpain-1 expression level, activation of caspase-12 and caspase-3, cleavage of the PARP protein as well as the inhibition of antiapoptotic protein Bcl-2 were reflected on cisplatin-triggered apoptosis. Taurine could, however, combat against such cisplatin induced cardiac-abnormalities. The above mentioned findings suggest that taurine plays a beneficial role in providing protection against cisplatin-induced cardiac damage by modulating inflammatory responses and ER stress. © 2016 BioFactors, 42(6):647-664, 2016. © 2016 International Union of Biochemistry and Molecular Biology.

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

International Nuclear Information System (INIS)

Liu, Tao; Meng, Qiang; Wang, Changyuan; Liu, Qi; Guo, Xinjin; Sun, Huijun; Peng, Jinyong

2012-01-01

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.

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

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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.

Curcumin prevents cisplatin-induced renal alterations in mitochondrial bioenergetics and dynamic.

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Ortega-Domínguez, Bibiana; Aparicio-Trejo, Omar Emiliano; García-Arroyo, Fernando E; León-Contreras, Juan Carlos; Tapia, Edilia; Molina-Jijón, Eduardo; Hernández-Pando, Rogelio; Sánchez-Lozada, Laura Gabriela; Barrera-Oviedo, Diana; Pedraza-Chaverri, José

2017-09-01

Cisplatin is widely used as chemotherapeutic agent for treatment of diverse types of cancer, however, acute kidney injury (AKI) is an important side effect of this treatment. Diverse mechanisms have been involved in cisplatin-induced AKI, such as oxidative stress, apoptosis and mitochondrial damage. On the other hand, curcumin is a polyphenol extracted from the rhizome of Curcuma longa L. Previous studies have shown that curcumin protects against the cisplatin-induced AKI; however, it is unknown whether curcumin can reduce alterations in mitochondrial bioenergetics and dynamic in this model. It was found that curcumin prevents cisplatin-induced: (a) AKI and (b) alterations in the following mitochondrial parameters: bioenergetics, ultrastructure, hydrogen peroxide production and dynamic. In fact, curcumin prevented the increase of mitochondrial fission 1 protein (FIS1), the decrease of optic atrophy 1 protein (OPA1) and the decrease of NAD + -dependent deacetylase sirtuin-3 (SIRT3), a mitochondrial dynamic regulator as well as the increase in the mitophagy associated proteins parkin and phosphatase and tensin homologue (PTEN)-induced putative kinase protein 1 (PINK1). In conclusion, the protective effect of curcumin in cisplatin-induced AKI was associated with the prevention of the alterations in mitochondrial bioenergetics, ultrastructure, redox balance, dynamic, and SIRT3 levels. Copyright © 2017 Elsevier Ltd. All rights reserved.

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.

Cisplatin Induced Nephrotoxicity

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Seyed Seifollah Beladi Mousavi

2014-02-01

The standard approach to prevent cisplatin-induced nephrotoxicity is the administration of lower doses of cisplatin in combination with the administration of full intravenous isotonic saline before and after cisplatin administration. Although a number of pharmacologic agents including sodium thiosulfate, N-acetylcysteine, theophylline and glycine have been evaluated for prevention of nephrotoxicity, none have proved to have an established role, thus, additional clinical studies will be required to confirm their probable effects.

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.

Dexamethasone loaded nanoparticles exert protective effects against Cisplatin-induced hearing loss by systemic administration.

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Sun, Changling; Wang, Xueling; Chen, Dongye; Lin, Xin; Yu, Dehong; Wu, Hao

2016-04-21

Ototoxicity is one of the most important adverse effects of cisplatin chemotherapy. As a common treatment of acute sensorineural hearing loss, systemic administration of steroids was demonstrated ineffective against cisplatin-induced hearing loss (CIHL) in published studies. The current study aimed to evaluate the potential protective effect of dexamethasone (DEX) encapsulated in polyethyleneglycol-coated polylactic acid (PEG-PLA) nanoparticles (DEX-NPs) against cisplatin-induced hearing loss following systemic administration. DEX was fabricated into PEG-PLA nanoparticles using emulsion and evaporation technique as previously reported. DEX or DEX-NPs was administered intraperitoneally to guinea pigs 1h before cisplatin administration. Auditory brainstem response (ABR) threshold shifts were measured at four frequencies (4, 8, 16, and 24kHz) 1 day before and three days after cisplatin injection. Cochlear morphology was examined to evaluate inner ear injury induced by cisplatin exposure. A single dose of DEX-NPs 1h before cisplatin treatment resulted in a significant preservation of the functional and structural properties of the cochlea, which was equivalent to the effect of multidose (3 days) DEX injection. In contrast, no significant protective effect was observed by single dose injection of DEX. The results of histological examination of the cochleae were consistent with the functional measurements. In conclusion, a single dose DEX-NPs significantly attenuated cisplatin ototoxicity in guinea pigs after systemic administration at both histological and functional levels indicating the potential therapeutic benefits of these nanoparticles for enhancing the delivery of DEX in acute sensorineural hearing loss. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Protective effect of selenium on cisplatin induced nephrotoxicity: A double-blind controlled randomized clinical trial.

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Ghorbani, Ali; Omidvar, Bita; Parsi, Abazar

2013-04-01

Renal injury is common following cisplatin infusion. Some agents have been used to attenuate cisplatin nephrotoxicity. However, except hydration, none of them has been proved to be effective. In this study selenium as an antioxidant supplement was tested on cisplatin induced renal injury. 122 cancerous patients (85 male and 37 female; age range of 14 to 82 years old) were enrolled to receive chemotherapy regimens consisting cisplatin. They were allocated into two groups using a random number list . Investigators, patients and analyzers all, were blinded in allocation by using sealed opaque envelopes. Intervention group received a single 400 mcg selenium tablet and patients in control group took a placebo tablet which was similar with selenium preparation in color, weight, shape and taste. Primary end points were an increase in plasma creatinine above 1.5 mg/dl in men and 1.4mg/dl in women, or increase of plasma creatinine more than 50% from baseline or urine flow rate less than 0.5 ml/kg/h. Creatinine level was measured initially and on the 5th day after cisplatin therapy. There was no difference in cumulative dose of cisplatin between the groups (p=0.54). There were not evidences of acute renal failure (ARF) in cases. While, among placebo group, 7 patients had criteria of acute kidney injury. Conclusions :selenium could probably prevent cisplatin-induced acute kidney injury, when it is added to hydration therapy in cancerous patients.

Mitochondrial Modulation by Epigallocatechin 3-Gallate Ameliorates Cisplatin Induced Renal Injury through Decreasing Oxidative/Nitrative Stress, Inflammation and NF-kB in Mice

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Wang, Xueping; Wang, Ping; Fu, Guanghou; Meng, Hongzhou; Wang, Yimin; Jin, Baiye

2015-01-01

Cancer chemotherapy drug cisplatin is known for its nephrotoxicity. The aim of this study is to investigate whether Epigallocatechin 3-Gallate (EGCG) can reduce cisplatin mediated side effect in kidney and to understand its mechanism of protection against tissue injury. We used a well-established 3-day cisplatin induced nephrotoxicity mice model where EGCG were administered. EGCG is a major active compound in Green Tea and have strong anti-oxidant and anti-inflammatory properties. EGCG protected against cisplatin induced renal dysfunction as measured by serum creatinine and blood urea nitrogen (BUN). EGCG improved cisplatin induced kidney structural damages such as tubular dilatation, cast formation, granulovaculoar degeneration and tubular cell necrosis as evident by PAS staining. Cisplatin induced kidney specific mitochondrial oxidative stress, impaired activities of mitochondrial electron transport chain enzyme complexes, impaired anti-oxidant defense enzyme activities such as glutathione peroxidase (GPX) and manganese superoxide dismutase (MnSOD) in mitochondria, inflammation (tumor necrosis factor α and interleukin 1β), increased accumulation of NF-κB in nuclear fraction, p53 induction, and apoptotic cell death (caspase 3 activity and DNA fragmentation). Treatment of mice with EGCG markedly attenuated cisplatin induced mitochondrial oxidative/nitrative stress, mitochondrial damages to electron transport chain activities and antioxidant defense enzyme activities in mitochondria. These mitochondrial modulations by EGCG led to protection mechanism against cisplatin induced inflammation and apoptotic cell death in mice kidney. As a result, EGCG improved renal function in cisplatin mediated kidney damage. In addition to that, EGCG attenuated cisplatin induced apoptotic cell death and mitochondrial reactive oxygen species (ROS) generation in human kidney tubular cell line HK-2. Thus, our data suggest that EGCG may represent new promising adjunct candidate for

Zataria multiflora ameliorates testicular and spermatological damages induced by cisplatin in mice model

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2017-11-01

Full Text Available Background and objectives: Cisplatin (CP, a highly effective antineoplastic drug, causes testicular damage. Zataria multiflora Boiss. (ZM, a medicinal plant, has antioxidant and anti-inflammatory properties. The aim of this study was to investigate the effects of ZM against cisplatin-induced testicular toxicity. Methods: Thirty-two adult male mice were randomly divided into four groups. The control group received normal saline with oral gavage during 7 days; ZM group received ZM (200 mg/kg during 7 days by gavage; CP group received CP (10 mg/kg i.p. in 5th day of study; ZM + CP group received ZM during 7 days and CP was injected in 5th day. Sperm parameters (including motility, sperm count, sperm viability rate and morphological sperm abnormalities, biochemical (malondialdehyde (MDA, glutathione (GSH and protein carbonyl (PC levels, serum testosterone levels, histological and immunochemistry assays of testis were examined one day after the last receipt of the drug. Results: CP treatment caused significant damage via changed of sperm parameters, increased oxidative stress (increased MDA, PC levels and decreased GSH level, histological changes (degeneration, necrosis, arrest of spermatogenesis, congestion and decrease in thickness of the germinal epithelium, diameter of seminiferous tubules and Johnsen’s Score, decreased serum testosterone level and increased caspase-3 immunoreactivity. ZM preserved spermatogenesis and mitigated the toxic effects of CP on the testis tissue. In addition, pretreatment with ZM significantly reduced caspase-3 immunoreactivity. Conclusion: The findings of this study suggested ZM as a potential antioxidant compound which showed protective effect against cisplatin-induced testicular toxicity.

SIRT1 overexpression decreases cisplatin-induced acetylation of NF-κB p65 subunit and cytotoxicity in renal proximal tubule cells

International Nuclear Information System (INIS)

Jung, Yu Jin; Lee, Jung Eun; Lee, Ae Sin; Kang, Kyung Pyo; Lee, Sik; Park, Sung Kwang; Lee, Sang Yong; Han, Myung Kwan; Kim, Duk Hoon; Kim, Won

2012-01-01

Highlights: ► Cisplatin increases acetylation of NF-κB p65 subunit in HK2 cells. ► SIRT1 overexpression decreases cisplatin-induced p65 acetylation and -cytotoxicity. ► Resveratrol decreased cisplatin-induced cell viability through deacetylation of p65. -- Abstract: As the increased acetylation of p65 is linked to nuclear factor-κB (NF-κB) 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 + )-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-κB and cell injury. To investigate the effect of SIRT1 in on cisplatin-induced acetylation of p65 subunit of NF-κB 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-κB p65 subunit was significantly increased after treatment with cisplatin. Overexpression of SIRT1 ameliorated the increased acetylation of p65 of NF-κB during cisplatin treatment and cisplatin-induced cytotoxicity. Further, treatment of cisplatin-treated HK2 cells with resveratrol, a SIRT1 activator, also decreased acetylation of NF-κB 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-κB through SIRT1 can be a possible target to attenuate cisplatin-induced renal cell damage.

Ameliorative effect of fisetin on cisplatin-induced nephrotoxicity in rats via modulation of NF-κB activation and antioxidant defence.

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Bidya Dhar Sahu

Full Text Available Nephrotoxicity is a dose-dependent side effect of cisplatin limiting its clinical usage in the field of cancer chemotherapy. Fisetin is a bioactive flavonoid with recognized antioxidant and anti-inflammatory properties. In the present study, we investigated the potential renoprotective effect and underlying mechanism of fisetin using rat model of cisplatin-induced nephrotoxicity. The elevation in serum biomarkers of renal damage (blood urea nitrogen and creatinine; degree of histopathological alterations and oxidative stress were significantly restored towards normal in fisetin treated, cisplatin challenged animals. Fisetin treatment also significantly attenuated the cisplatin-induced IκBα degradation and phosphorylation and blocked the NF-κB (p65 nuclear translocation, with subsequent elevation of pro-inflammatory cytokine, TNF-α, protein expression of iNOS and myeloperoxidase activities. Furthermore, fisetin markedly attenuated the translocation of cytochrome c protein from the mitochondria to the cytosol; decreased the expression of pro-apoptotic proteins including Bax, cleaved caspase-3, cleaved caspase-9 and p53; and prevented the decline of anti-apoptotic protein, Bcl-2. The cisplatin-induced mRNA expression of NOX2/gp91phox and NOX4/RENOX and the NADPH oxidase enzyme activity were also significantly lowered by fisetin treatment. Moreover, the evaluated mitochondrial respiratory enzyme activities and mitochondrial antioxidants were restored by fisetin treatment. Estimation of platinum concentration in kidney tissues revealed that fisetin treatment along with cisplatin did not alter the cisplatin uptake in kidney tissues. In conclusion, these findings suggest that fisetin may be used as a promising adjunct candidate for cisplatin use.

Ameliorative Effect of Fisetin on Cisplatin-Induced Nephrotoxicity in Rats via Modulation of NF-κB Activation and Antioxidant Defence

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Sahu, Bidya Dhar; Kalvala, Anil Kumar; Koneru, Meghana; Mahesh Kumar, Jerald; Kuncha, Madhusudana; Rachamalla, Shyam Sunder; Sistla, Ramakrishna

2014-01-01

Nephrotoxicity is a dose-dependent side effect of cisplatin limiting its clinical usage in the field of cancer chemotherapy. Fisetin is a bioactive flavonoid with recognized antioxidant and anti-inflammatory properties. In the present study, we investigated the potential renoprotective effect and underlying mechanism of fisetin using rat model of cisplatin-induced nephrotoxicity. The elevation in serum biomarkers of renal damage (blood urea nitrogen and creatinine); degree of histopathological alterations and oxidative stress were significantly restored towards normal in fisetin treated, cisplatin challenged animals. Fisetin treatment also significantly attenuated the cisplatin-induced IκBα degradation and phosphorylation and blocked the NF-κB (p65) nuclear translocation, with subsequent elevation of pro-inflammatory cytokine, TNF-α, protein expression of iNOS and myeloperoxidase activities. Furthermore, fisetin markedly attenuated the translocation of cytochrome c protein from the mitochondria to the cytosol; decreased the expression of pro-apoptotic proteins including Bax, cleaved caspase-3, cleaved caspase-9 and p53; and prevented the decline of anti-apoptotic protein, Bcl-2. The cisplatin-induced mRNA expression of NOX2/gp91phox and NOX4/RENOX and the NADPH oxidase enzyme activity were also significantly lowered by fisetin treatment. Moreover, the evaluated mitochondrial respiratory enzyme activities and mitochondrial antioxidants were restored by fisetin treatment. Estimation of platinum concentration in kidney tissues revealed that fisetin treatment along with cisplatin did not alter the cisplatin uptake in kidney tissues. In conclusion, these findings suggest that fisetin may be used as a promising adjunct candidate for cisplatin use. PMID:25184746

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

International Nuclear Information System (INIS)

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

2017-01-01

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 100 mg/kg p.o. via inhibiting the oxidative stress/redox status imbalance and may be improving the efflux mechanism. - Highlights: • Synthesis of a novel boswellic acid derivative (IN0523) • Counter oxidative stress induced due to Cisplatin • Protect against urogenital toxicity induced by Cisplatin

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

Energy Technology Data Exchange (ETDEWEB)

Singh, Amarinder [Academy of Scientific & Innovative Research (AcSIR), New Delhi (India); PK-PD-Toxicology and Formulation Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, J& K (India); Arvinda, S [Deptt. of Pathology, Govt. Medical College, Jammu 180001, J& K (India); Singh, Surjeet [PK-PD-Toxicology and Formulation Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, J& K (India); Suri, Jyotsna [Deptt. of Pathology, Govt. Medical College, Jammu 180001, J& K (India); Koul, Surinder [Bio-Organic Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, J& K (India); Mondhe, Dilip M. [Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, J& K (India); Singh, Gurdarshan, E-mail: singh_gd@iiim.ac.in [PK-PD-Toxicology and Formulation Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, J& K (India); Vishwakarma, Ram [Bio-Organic Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, J& K (India)

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 100 mg/kg p.o. via inhibiting the oxidative stress/redox status imbalance and may be improving the efflux mechanism. - Highlights: • Synthesis of a novel boswellic acid derivative (IN0523) • Counter oxidative stress induced due to Cisplatin • Protect against urogenital toxicity induced by Cisplatin.

Study of protective effects of melatonin on cisplatin-induced nephrotoxicity in rabbits

International Nuclear Information System (INIS)

Aslam, J.; Khan, W.; Bakhtiar, S.

2017-01-01

To evaluate the protective effects of melatonin on cisplatin-induced nephrotoxicity in rabbits. Study Design: Laboratory based randomized control trial. Place and Duration of Study: Department of Pharmacology and Therapeutics in collaboration with Clinico Pathologic Laboratory, Army Medical College, Rawalpindi, from Apr to Jun 2015. Material and Methods: Eighteen rabbits were divided into three groups, each consisting of six rabbits. Baseline serum urea, creatinine, sodium and potassium were measured. Rabbits were weighed for dose calculation. A single dose of cisplatin 10mg/kg was given as I/P injection to the toxic group. The protective group received 5 mg/kg I/P melatonin for three days. Rabbits were sacrificed 72 hours after the cisplatin dose and both kidneys were sent for histopathology. Statistical analysis was carried out by using Microsoft Office Excel 2010 and SPSS version 21. Student's t-test and one way ANOVA, followed by 'Post Hoc Tukey' test was used for biochemical parameters, while Chi Square' test was used for histopathological comparison. Results: Moderate nephrotoxicity (grade-II) was seen in the toxic group, with substantial elevations of serum urea and creatinine (p<0.001), and serum sodium and potassium (p<0.01). Melatonin ameliorated the renal injury. Conclusion: The protective effects of melatonin on cisplatin-induced nephrotoxicity were due to its antioxidant properties. (author)

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

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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.

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

Science.gov (United States)

Choi, Yong-Min; Kim, Han-Kyul; 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.

Zingiber officinale Roscoe ameliorates anticancer antibiotic doxorubicin-induced acute cardiotoxicity in rat.

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Ajith, Thekkuttuparambil Ananthanarayanan; Hema, Unnikrishnan; Aswathi, Sreedharan

2016-07-01

Oxidative stress (OS) has been suggested in the cardiotoxicity induced by anticancer antibiotic doxorubicin (DXN). The cardioprotective effects of aqueous ethanol extract of Zingiber officinale was evaluated against DXN-induced acute cardiac damage in rat. The results of the study demonstrated that Z. officinale significantly and dose dependently protected the cardiotoxicity induced by DXN. The activities of serum glutamate oxaloacetate transaminase and serum lactate dehydrogenase activity in the DXN alone treated group of animals were significantly (pofficinale (200 and 400 mg/kg, p.o) plus DXN treated groups. The cardiac malondialdehyde was elevated in the DXN alone treated group and declined significantly in the Z. officinale (400 mg/kg) plus DXN treated group. The results concluded that aqueous ethanol extract of Z. officinale ameliorated DXN-induced cardiotoxicity. The protection can be ascribed to the free radical scavenging activity of Z. officinale. This protective effect may suggest the adjuvant role of Z. officinale against OS induced by cancer chemotherapeutants, which warrant further research. © 2016 Old City Publishing, Inc.

Antiemetic and Myeloprotective Effects of Rhus verniciflua Stoke in a Cisplatin-Induced Rat Model

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Hyo-Seon Kim

2017-01-01

Full Text Available Rhus verniciflua Stoke has been commonly used in traditional medicine to treat gastrointestinal (GI dysfunction diseases. In order to investigate pharmacological properties of Rhus verniciflua Stoke water extract (RVX on cisplatin-induced amnesia, RVX (0, 25, 50, or 100 mg/kg was orally administrated for five consecutive days after a single intraperitoneal injection of cisplatin (6 mg/kg to SD rat. Cisplatin injection significantly increased the kaolin intake (emesis but reduced the normal diet intake (anorexia whereas the RVX treatment significantly improved these abnormal diet behaviors at both the acute and delayed phase. The serotonin concentration and the related gene expressions (5-HT3 receptors and SERT in small intestine tissue were abnormally altered by cisplatin injection, which were significantly attenuated by the RVX treatment. Histological findings of gastrointestinal tracts, as well as the proteins level of proinflammatory cytokines (TNF-α, IL-6, and IL-1β, revealed the beneficial effect of RVX on cisplatin-induced gastrointestinal inflammation. In addition, RVX significantly improved cisplatin-induced myelosuppression, as evidenced by the observation of leukopenia and by histological examinations in bone marrow. Our findings collectively indicated Rhus verniciflua Stoke improved the resistance of rats to chemotherapy-related adverse effects in the gastrointestinal track and bone marrow.

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

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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.

A Role for Tubular Necroptosis in Cisplatin-Induced AKI

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Xu, Yanfang; Ma, Huabin; Shao, Jing; Wu, Jianfeng; Zhou, Linying; Zhang, Zhirong; Wang, Yuze; Huang, Zhe; Ren, Junming; Liu, Suhuan; Chen, Xiangmei

2015-01-01

Cell death and inflammation in the proximal tubules are the hallmarks of cisplatin-induced AKI, but the mechanisms underlying these effects have not been fully elucidated. Here, we investigated whether necroptosis, a type of programmed necrosis, has a role in cisplatin-induced AKI. We found that inhibition of any of the core components of the necroptotic pathway—receptor-interacting protein 1 (RIP1), RIP3, or mixed lineage kinase domain-like protein (MLKL)—by gene knockout or a chemical inhibitor diminished cisplatin-induced proximal tubule damage in mice. Similar results were obtained in cultured proximal tubular cells. Furthermore, necroptosis of cultured cells could be induced by cisplatin or by a combination of cytokines (TNF-α, TNF-related weak inducer of apoptosis, and IFN-γ) that were upregulated in proximal tubules of cisplatin-treated mice. However, cisplatin induced an increase in RIP1 and RIP3 expression in cultured tubular cells in the absence of cytokine release. Correspondingly, overexpression of RIP1 or RIP3 enhanced cisplatin-induced necroptosis in vitro. Notably, inflammatory cytokine upregulation in cisplatin-treated mice was partially diminished in RIP3- or MLKL-deficient mice, suggesting a positive feedback loop involving these genes and inflammatory cytokines that promotes necroptosis progression. Thus, our data demonstrate that necroptosis is a major mechanism of proximal tubular cell death in cisplatin-induced nephrotoxic AKI. PMID:25788533

Amisulpride in the prevention of nausea and vomiting induced by cisplatin-based chemotherapy

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Herrstedt, Jørn; Summers, Yvonne; Daugaard, Gedske

2018-01-01

PURPOSE: The purpose of this study was to investigate the antiemetic effect of the dopamine D2- and dopamine D3-receptor antagonist, amisulpride, in patients receiving cisplatin-based chemotherapy. METHODS: This dose-finding, non-comparative study investigated the antiemetic effect and safety...... of increasing doses (2.5, 7.5 and 20 mg) of amisulpride against acute nausea and vomiting in the period 0-24 h after initiation of cisplatin-based chemotherapy. The 20 mg dose was also investigated in combination with the 5-HT3-receptor antagonist, ondansetron. The primary parameter was complete response (0...... interval: 65-94%) had a CR and 14/23 (61%) had no nausea at all. CONCLUSIONS: Amisulpride has antiemetic effect against cisplatin-induced acute nausea and vomiting. The effect against nausea is of particular interest. Randomised studies are warranted to further explore the effect and safety of amisulpride....

The small-molecule TNF-alpha modulator, UTL-5g, reduces side effects induced by cisplatin and enhances the therapeutic effect of cisplatin in vivo.

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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.

Analysis of spatiotemporal metabolomic dynamics for sensitively monitoring biological alterations in cisplatin-induced acute kidney injury.

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Irie, Miho; Hayakawa, Eisuke; Fujimura, Yoshinori; Honda, Youhei; Setoyama, Daiki; Wariishi, Hiroyuki; Hyodo, Fuminori; Miura, Daisuke

2018-01-29

Clinical application of the major anticancer drug, cisplatin, is limited by severe side effects, especially acute kidney injury (AKI) caused by nephrotoxicity. The detailed metabolic mechanism is still largely unknown. Here, we used an integrated technique combining mass spectrometry imaging (MSI) and liquid chromatography-mass spectrometry (LC-MS) to visualize the diverse spatiotemporal metabolic dynamics in the mouse kidney after cisplatin dosing. Biological responses to cisplatin was more sensitively detected within 24 h as a metabolic alteration, which is much earlier than possible with the conventional clinical chemistry method of blood urea nitrogen (BUN) measurement. Region-specific changes (e.g., medulla and cortex) in metabolites related to DNA damage and energy generation were observed over the 72-h exposure period. Therefore, this metabolomics approach may become a novel strategy for elucidating early renal responses to cisplatin, prior to the detection of kidney damage evaluated by conventional method. Copyright © 2018. Published by Elsevier Inc.

Protective effect and mechanism of action of lupane triterpenes from Cornus walteri in cisplatin-induced nephrotoxicity.

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Lee, Seulah; Jung, Kiwon; Lee, Dahae; Lee, Seoung Rak; Lee, Kang Ro; Kang, Ki Sung; Kim, Ki Hyun

2015-12-01

The present study reports a renoprotective effect and the mechanism of action of lupane triterpenes isolated from Cornus walteri in cisplatin-induced renal toxicity. A phytochemical investigation of the MeOH extract of the stems and stem bark of C. walteri resulted in the isolation and identification of twelve lupane triterpenes. Among these, betulinic acid, 29-oxobetulinic acid, betulin 3-acetate, and lupeol ameliorated cisplatin-induced nephrotoxicity to 80% of the control value at 125 μM. Upregulated phosphorylation of JNK, ERK, and p38 following cisplatin treatment were markedly decreased after co-treatment with betulinic acid, 29-oxobetulinic acid, betulin 3-acetate, and lupeol. In addition, the protein expression level of cleaved caspase-3 and the percentage of apoptotic cells were also significantly reduced after co-treatment with betulinic acid, 29-oxobetulinic acid, betulin 3-acetate, and lupeol. These results show that blocking the MAPK signaling cascade plays a critical role in mediating the renoprotective effect of betulinic acid, 29-oxobetulinic acid, betulin 3-acetate, and lupeol isolated from C. walteri extract. Copyright © 2015 Elsevier Ltd. All rights reserved.

Mechanisms of cisplatin-induced muscle atrophy

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Sakai, Hiroyasu; Sagara, Atsunobu; Arakawa, Kazuhiko; Sugiyama, Ryoto; Hirosaki, Akiko; Takase, Kazuhide; Jo, Ara; Sato, Ken; Chiba, Yoshihiko; Yamazaki, Mitsuaki; Matoba, Motohiro; Narita, Minoru

2014-01-01

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

Mechanisms of cisplatin-induced muscle atrophy

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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.

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

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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.

Andrographolide sulfonate ameliorates lipopolysaccharide-induced acute lung injury in mice by down-regulating MAPK and NF-κB pathways.

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Peng, Shuang; Hang, Nan; Liu, Wen; Guo, Wenjie; Jiang, Chunhong; Yang, Xiaoling; Xu, Qiang; Sun, Yang

2016-05-01

Acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) is a severe, life-threatening medical condition characterized by widespread inflammation in the lungs, and is a significant source of morbidity and mortality in the patient population. New therapies for the treatment of ALI are desperately needed. In the present study, we examined the effect of andrographolide sulfonate, a water-soluble form of andrographolide (trade name: Xi-Yan-Ping Injection), on lipopolysaccharide (LPS)-induced ALI and inflammation. Andrographolide sulfonate was administered by intraperitoneal injection to mice with LPS-induced ALI. LPS-induced airway inflammatory cell recruitment and lung histological alterations were significantly ameliorated by andrographolide sulfonate. Protein levels of pro-inflammatory cytokines in bronchoalveolar lavage fluid (BALF) and serum were reduced by andrographolide sulfonate administration. mRNA levels of pro-inflammatory cytokines in lung tissue were also suppressed. Moreover, andrographolide sulfonate markedly suppressed the activation of mitogen-activated protein kinase (MAPK) as well as p65 subunit of nuclear factor-κB (NF-κB). In summary, these results suggest that andrographolide sulfonate ameliorated LPS-induced ALI in mice by inhibiting NF-κB and MAPK-mediated inflammatory responses. Our study shows that water-soluble andrographolide sulfonate may represent a new therapeutic approach for treating inflammatory lung disorders.

Andrographolide sulfonate ameliorates lipopolysaccharide-induced acute lung injury in mice by down-regulating MAPK and NF-κB pathways

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Shuang Peng

2016-05-01

Full Text Available Acute lung injury (ALI or acute respiratory distress syndrome (ARDS is a severe, life-threatening medical condition characterized by widespread inflammation in the lungs, and is a significant source of morbidity and mortality in the patient population. New therapies for the treatment of ALI are desperately needed. In the present study, we examined the effect of andrographolide sulfonate, a water-soluble form of andrographolide (trade name: Xi-Yan-Ping Injection, on lipopolysaccharide (LPS-induced ALI and inflammation. Andrographolide sulfonate was administered by intraperitoneal injection to mice with LPS-induced ALI. LPS-induced airway inflammatory cell recruitment and lung histological alterations were significantly ameliorated by andrographolide sulfonate. Protein levels of pro-inflammatory cytokines in bronchoalveolar lavage fluid (BALF and serum were reduced by andrographolide sulfonate administration. mRNA levels of pro-inflammatory cytokines in lung tissue were also suppressed. Moreover, andrographolide sulfonate markedly suppressed the activation of mitogen-activated protein kinase (MAPK as well as p65 subunit of nuclear factor-κB (NF-κB. In summary, these results suggest that andrographolide sulfonate ameliorated LPS-induced ALI in mice by inhibiting NF-κB and MAPK-mediated inflammatory responses. Our study shows that water-soluble andrographolide sulfonate may represent a new therapeutic approach for treating inflammatory lung disorders.

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

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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.

Cisplatin-induced hypokalemic paralysis.

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Mohammadianpanah, Mohammad; Omidvari, Shapour; Mosalaei, Ahmad; Ahmadloo, Niloofar

2004-08-01

Profound hypokalemic conditions resulting from cisplatin therapy have been known to produce hypokalemic paralysis in rare cases. We describe such a case of cisplatin-induced hypokalemic paralysis. A 15-year-old Persian girl with ovarian dysgerminoma presented with severe generalized weakness and paraplegia 1 week after the fourth course of cisplatin-based chemotherapy. On physical examination, there was symmetric flaccid paralysis and areflexia in all of the extremities and particularly in the lower limbs. Her serum potassium concentration was 1.7 mmol/L. Metastatic disease was excluded by a comprehensive systemic evaluation. Complete clinical and paraclinical recovery was achieved after short-term administration of potassium supplement. Adverse drug reactions are common with cisplatin, but the drug is only rarely associated with hypokalemic paralysis. Based on the Naranjo causality algorithm, an objective assessment revealed cisplatin to be a probable cause of hypokalemic paralysis in this case. This adverse drug event--whether isolated or secondary to hypomagnesemia--may be deceptive, leading to a fatal mistake in the oncology setting, and should therefore be precisely differentiated from cancer-related complications. This case suggests that cisplatin should be added to the list of agents causing hypokalemic paralysis. Regular serum electrolyte measurement, the early detection of cation deficiency, and appropriate replacement of cations are all recommended.

Hindbrain GLP-1 receptor mediation of cisplatin-induced anorexia and nausea.

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De Jonghe, Bart C; Holland, Ruby A; Olivos, Diana R; Rupprecht, Laura E; Kanoski, Scott E; Hayes, Matthew R

2016-01-01

While chemotherapy-induced nausea and vomiting are clinically controlled in the acute (anorexia, nausea, fatigue, and other illness-type behaviors during the delayed phase (>24 h) of chemotherapy are largely uncontrolled. As the hindbrain glucagon-like peptide-1 (GLP-1) system contributes to energy balance and mediates aversive and stressful stimuli, here we examine the hypothesis that hindbrain GLP-1 signaling mediates aspects of chemotherapy-induced nausea and reductions in feeding behavior in rats. Specifically, hindbrain GLP-1 receptor (GLP-1R) blockade, via 4th intracerebroventricular (ICV) exendin-(9-39) injections, attenuates the anorexia, body weight reduction, and pica (nausea-induced ingestion of kaolin clay) elicited by cisplatin chemotherapy during the delayed phase (48 h) of chemotherapy-induced nausea. Additionally, the present data provide evidence that the central GLP-1-producing preproglucagon neurons in the nucleus tractus solitarius (NTS) of the caudal brainstem are activated by cisplatin during the delayed phase of chemotherapy-induced nausea, as cisplatin led to a significant increase in c-Fos immunoreactivity in NTS GLP-1-immunoreactive neurons. These data support a growing body of literature suggesting that the central GLP-1 system may be a potential pharmaceutical target for adjunct anti-emetics used to treat the delayed-phase of nausea and emesis, anorexia, and body weight loss that accompany chemotherapy treatments. Copyright © 2015 Elsevier Inc. All rights reserved.

Meclofenamic Acid Reduces Reactive Oxygen Species Accumulation and Apoptosis, Inhibits Excessive Autophagy, and Protects Hair Cell-Like HEI-OC1 Cells From Cisplatin-Induced Damage

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He Li

2018-05-01

Full Text Available Hearing loss is the most common sensory disorder in humans, and a significant number of cases is due to the ototoxicity of drugs such as cisplatin that cause hair cell (HC damage. Thus, there is great interest in finding agents and mechanisms that protect HCs from ototoxic drug damage. It has been proposed that epigenetic modifications are related to inner ear development and play a significant role in HC protection and HC regeneration; however, whether the m6A modification and the ethyl ester form of meclofenamic acid (MA2, which is a highly selective inhibitor of FTO (fatmass and obesity-associated enzyme, one of the primary human demethylases, can affect the process of HC apoptosis induced by ototoxic drugs remains largely unexplored. In this study, we took advantage of the HEI-OC1 cell line, which is a cochlear HC-like cell line, to investigate the role of epigenetic modifications in cisplatin-induced cell death. We found that cisplatin injury caused reactive oxygen species accumulation and increased apoptosis in HEI-OC1 cells, and the cisplatin injury was reduced by co-treatment with MA2 compared to the cisplatin-only group. Further investigation showed that MA2 attenuated cisplatin-induced oxidative stress and apoptosis in HEI-OC1 cells. We next found that the cisplatin-induced upregulation of autophagy was significantly inhibited after MA2 treatment, indicating that MA2 inhibited the cisplatin-induced excessive autophagy. Our findings show that MA2 has a protective effect and improves the viability of HEI-OC1 cells after cisplatin treatment, and they provide new insights into potential therapeutic targets for the amelioration of cisplatin-induced ototoxicity.

Nephroprotective effect of Bauhinia variegata (Linn.) whole stem extract against cisplatin-induced nephropathy in rats

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Pani, Saumya R.; Mishra, Satyaranjan; Sahoo, Sabuj; Panda, Prasana K.

2011-01-01

The nephroprotective activity of the ethanolic extract of Bauhinia variegata (Linn.) whole stem against cisplatin-induced nephropathy was investigated by an in vivo method in rats. Acute nephrotoxicity was induced by i.p. injection of cisplatin (7 mg/kg of body weight (b.w.)). Administration of ethanol extract at dose levels of 400 and 200 mg/kg (b.w.) to cisplatin-intoxicated rats for 14 days attenuated the biochemical and histological signs of nephrotoxicity of cisplatin in a dose-dependent fashion. Ethanol extract at 400 mg/kg decreased the serum level of creatinine (0.65 ± 0.09; P<0.001) and urea (32.86 ± 5.88; P<0.001) associated with a significant increase in body weight (7.16 ± 1.10; P<0.001) and urine volume output (11.95 ± 0.79; P<0.05) as compared to the toxic control group. The ethanol extract of B. variegata at 400 mg/kg (b.w.) exhibited significant and comparable nephroprotective potential to that of the standard polyherbal drug cystone. The statistically (one-way-ANOVA followed by Tukey-Kramer multiple comparison) processed results suggested the protective action of B. variegate whole stem against cisplatin-induced nephropathy. PMID:21572659

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

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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.

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

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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

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

International Nuclear Information System (INIS)

El-Naga, Reem N.

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

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

Hydroalcoholic extract of Stevia rebaudiana bert. leaves and stevioside ameliorates lipopolysaccharide induced acute liver injury in rats.

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S, Latha; Chaudhary, Sheetal; R S, Ray

2017-11-01

Oxidative stress and hepatic inflammatory response is primarily implicated in the pathogenesis of LPS induced acute liver injury. Stevioside, a diterpenoidal glycoside isolated from the Stevia rebaudiana leaves, exerts potent anti-oxidant, anti-inflammatory and immunomodulatory activities. The present study was aimed to investigate the hepatoprotective effect of hydroalcoholic extract of Stevia rebaudiana leaves (STE EXT) and its major phytochemical constituent, stevioside (STE) in LPS induced acute liver injury. The hepatoprotective activity of STE EXT (500mg/kg p.o) and STE (250mg/kg p.o) was investigated in lipopolysaccharide (LPS 5mg/kg i.p.) induced acute liver injury in male wistar rats. Our results revealed that both STE EXT and STE treatment ameliorated LPS induced hepatic oxidative stress, evident from altered levels of reduced SOD, Catalase, GSH, MDA, NO. Histopathological observations revealed that both STE EXT and STE attenuated LPS induced structural changes and hepatocellular apoptosis providing additional evidence for its hepatoprotective effect. Further, STE EXT and STE significantly restored the elevated serum and tissue levels of AST and ALT in LPS treated rats. Furthermore, both STE EXT and STE rescued hepatocellular dysfunctions to normal by altering the level of proinflammatory cytokines such as TNF-α, IL-1β and IL-6 exhibiting its anti-inflammatory potential. In conclusion, both STE EXT and STE demonstrated excellent hepatoprotective effects against endotoxemia induced acute liver injury possibly through suppression of hepatic inflammatory response and oxidative stress, attributing to its medicinal importance in treating various liver ailments. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Amelioration of cisplatin-induced nephrotoxicity by ethanolic extract of Bauhinia purpurea: An in vivo study in rats.

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Rana, Md Azmat; Khan, Rahat Ali; Nasiruddin, Mohammad; Khan, Aijaz Ahmed

2016-01-01

Our objective is to study the nephroprotective activity and antioxidant potential of Bauhinia purpurea unripe pods and bark against cisplatin-induced nephrotoxicity. Healthy adult albino rats of either sex (150-200 g) were randomly divided into six groups of six animals each Group I (vehicle control) and Group II (negative control). Group III (BBE200) and Group IV (BBE400) were administered the ethanolic extract of Bauhinia purpurea bark in doses of 200 and 400 mg/kg/day p.o., respectively, and Group V (BPE200) and Group VI (BPE400) were administered the ethanolic extract of Bauhinia purpurea unripe pods at doses of 200 and 400 mg/kg/day p.o., respectively. All the treatments were given for nine days. Cisplatin in a single dose of 6 mg/kg i.p. was given on the 4 th day to all groups, except the vehicle control group. On the 10 th day, blood and urine were collected for biochemical tests and the rats were sacrificed. The kidney was removed for histology and lipid peroxidation-antioxidant test. Cisplatin caused nephrotoxicity as evidenced by elevated blood urea, serum creatinine and urine glucose, and there was decreased creatinine clearance in Group II as compared with Group I. Administration of BBE and BPE at doses of 200 and 400 mg/kg in Group III and Group VI caused a dose-dependant reduction in the rise of blood urea, serum creatinine and urine glucose, and there was a dose-dependant increase in creatinine clearance compared with Group II. There was increased catalase and glutathione and decreased malondialdehyde levels in Group II, while BBE 400 (Group IV) and BPE 400 (Group VI) treatments significantly reversed the changes toward normal values. Histological examination of the kidney revealed protection in Group IV and Group VI compared with Group II. The ethanolic extract of Bauhinia purpurea unripe pods and bark has a nephroprotective activity against cisplatin-induced nephrotoxicity in rats.

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

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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

vivo (forelimb force and muscle volume) outcomes in cachectic animals. Administration of hexarelin or JMV2894 markedly reduced the cisplatin-induced alteration of calcium homeostasis by both common as well as drug-specific mechanisms of action. This effect correlated with muscle function preservation as well as amelioration of various atrophic indexes, thus supporting the functional impact of GHS activity on calcium homeostasis. Our findings provide a direct evidence that a dysregulation of calcium homeostasis plays a key role in cisplatin-induced model of cachexia gaining insight into the etiopathogenesis of this form of muscle wasting. Furthermore, our demonstration that GHS administration efficaciously prevents cisplatin-induced calcium homeostasis alteration contributes to elucidate the mechanism of action through which GHS could potentially ameliorate chemotherapy-associated cachexia. © 2017 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of the Society on Sarcopenia, Cachexia and Wasting Disorders.

An integrated view of cisplatin-induced nephrotoxicity and ototoxicity

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Karasawa, Takatoshi; Steyger, Peter S.

2015-01-01

Cisplatin is one of the most widely-used drugs to treat cancers. However, its nephrotoxic and ototoxic side-effects remain major clinical limitations. Recent studies have improved our understanding of the molecular mechanisms of cisplatin-induced nephrotoxicity and ototoxicity. While cisplatin binding to DNA is the major cytotoxic mechanism in proliferating (cancer) cells, nephrotoxicity and ototoxicity appear to result from toxic levels of reactive oxygen species and protein dysregulation within various cellular compartments. In this review, we discuss molecular mechanisms of cisplatin-induced nephrotoxicity and ototoxicity. We also discuss potential clinical strategies to prevent nephrotoxicity and ototoxicity and their current limitations. PMID:26101797

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

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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

Ghrelin ameliorates acute lung injury induced by oleic acid via inhibition of endoplasmic reticulum stress.

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Tian, Xiuli; Liu, Zhijun; Yu, Ting; Yang, Haitao; Feng, Linlin

2018-03-01

Acute lung injury (ALI) is associated with excessive mortality and lacks appropriate therapy. Ghrelin is a novel peptide that protects the lung against ALI. This study aimed to investigate whether endoplasmic reticulum stress (ERS) mediates the protective effect of ghrelin on ALI. We used a rat oleic acid (OA)-induced ALI model. Pulmonary impairment was detected by hematoxylin and eosin (HE) staining, lung mechanics, wet/dry weight ratio, and arterial blood gas analysis. Plasma and lung content of ghrelin was examined by ELISA, and mRNA expression was measured by quantitative real-time PCR. Protein levels were detected by western blot. Rats with OA treatment showed significant pulmonary injury, edema, inflammatory cellular infiltration, cytokine release, hypoxia and CO 2 retention as compared with controls. Plasma and pulmonary content of ghrelin was reduced in rats with ALI, and mRNA expression was downregulated. Ghrelin (10nmol/kg) treatment ameliorated the above symptoms, but treatment with the ghrelin antagonists D-Lys 3 GHRP-6 (1μmol/kg) and JMV 2959 (6mg/kg) exacerbated the symptoms. ERS induced by OA was prevented by ghrelin and augmented by ghrelin antagonist treatment. The ERS inducer, tunicamycin (Tm) prevented the ameliorative effect of ghrelin on ALI. The decreased ratio of p-Akt and Akt induced by OA was improved by ghrelin treatment, and was further exacerbated by ghrelin antagonists. Ghrelin protects against ALI by inhibiting ERS. These results provide a new target for prevention and therapy of ALI. Copyright © 2017 Elsevier Inc. All rights reserved.

Infliximab Modulates Cisplatin-Induced Hepatotoxicity in Rats

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Medine Cumhur Cüre

2016-10-01

Full Text Available Background: Cisplatin (Cis is one of the most commonly used antineoplastic drugs. It is used as chemotherapy for many solid organ malignancies such as brain, neck, male and female urogenital, vesical and pulmonary cancers. Infliximab blocks tumor necrosis factor alpha (TNF-α. Several studies have reported that infliximab ameliorates cell damage by reducing cytokine levels. Aims: We aimed to investigate whether infliximab has a preventive effect against cisplatin-induced hepatotoxicity and whether it has a synergistic effect when combined with Cis. Study Design: Animal experimentation. Methods: Male Wistar albino rats were divided in three groups as follows: Cis group, infliximab + Cis (CIN group and the control group. Each group comprised 10 animals. Animals in the Cis group received an intraperitoneal single-dose injection of Cis (7 mg/kg. In the CIN group, a single dose of infliximab (7 mg/kg was administered 72 h prior to the Cis injection. After 72 h, a single dose of Cis (7 mg/kg was administered. All rats were sacrificed five days after Cis injection. Results: TNF-α levels in the Cis group were significantly higher (345.5±40.0 pg/mg protein than those of the control (278.7±62.1 pg/mg protein, p=0.003 and CIN groups (239.0±64.2 pg/mg protein, p=0.013. The Cis group was found to have high carbonic anhydrase (CA-II and low carbamoyl phosphate synthetase-1 (CPS-1 levels. Aspartate transaminase (AST and alanine transaminase (ALT levels were lower in the CIN group as compared to the Cis group. Total histological damage was greater in the Cis group as compared to the control and CIN groups. Conclusion: Cis may lead to liver damage by increasing cytokine levels. It may increase oxidative stress-induced tissue damage by increasing carbonic anhydrase II (CA-II enzyme levels and decreasing CPS-1 enzyme levels. Infliximab decreases Cis-induced hepatic damage by blocking TNF-α and it may also protect against liver damage by regulating CPS-1 and

Regulation of apoptosis-inducing factor-mediated, cisplatin-induced apoptosis by Akt

OpenAIRE

Yang, X; Fraser, M; Abedini, M R; Bai, T; Tsang, B K

2008-01-01

Cisplatin is a first-line chemotherapeutic for ovarian cancer, although chemoresistance limits treatment success. Apoptosis, an important determinant of cisplatin sensitivity, occurs via caspase-dependent and -independent mechanisms. Activation of the protein kinase Akt, commonly observed in ovarian tumours, confers resistance to ovarian cancer cells via inhibition of caspase-dependent apoptosis. However, the effect of Akt on cisplatin-induced, caspase-independent apoptosis remains unclear. W...

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 ...

Suppression of Cisplatin-Induced Vomiting by Cannabis sativa in Pigeons: Neurochemical Evidences

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Ihsan Ullah

2018-03-01

Full Text Available Cannabis sativa (CS, family Cannabinaceae has been reported for its anti-emetic activity against cancer chemotherapy-induced emesis in animal models and in clinics. The current study was designed to investigate CS for potential effectiveness to attenuate cisplatin-induced vomiting in healthy pigeons and to study the impact on neurotransmitters involved centrally and peripherally in the act of vomiting. High-performance liquid chromatography system coupled with electrochemical detector was used for the quantification of neurotransmitters 5-hydroxytryptamine (5HT, dopamine (DA and their metabolites; Di-hydroxy Phenyl Acetic acid (Dopac, Homovanillic acid (HVA, and 5-hydroxy indole acetic acid (5HIAA centrally in specific brain areas (area postrema and brain stem while, peripherally in small intestine. Cisplatin (7 mg/kg i.v. induce emesis without lethality across the 24 h observation period. CS hexane fraction (CS-HexFr; 10 mg/kg attenuated cisplatin-induced emesis ∼ 65.85% (P < 0.05; the reference anti-emetic drug, metoclopramide (MCP; 30 mg/kg, produced ∼43.90% reduction (P < 0.05. At acute time point (3rd h, CS-HexFr decreased (P < 0.001 the concentration of 5HT and 5HIAA in the area postrema, brain stem and intestine, while at 18th h (delayed time point CS-HexFr attenuated (P < 0.001 the upsurge of 5HT caused by cisplatin in the brain stem and intestine and dopamine in the area postrema. CS-HexFr treatment alone did not alter the basal neurotransmitters and their metabolites in the brain areas and intestine except 5HIAA and HVA, which were decreased significantly. In conclusion the anti-emetic effect of CS-HexFr is mediated by anti-serotonergic and anti-dopaminergic components in a blended manner at the two different time points, i.e., 3rd and 18th h in pigeons.

Effect of Honey and Royal Jelly against Cisplatin-Induced Nephrotoxicity in Patients with Cancer.

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Osama, Hasnaa; Abdullah, Aya; Gamal, Bassma; Emad, Dina; Sayed, Doha; Hussein, Eman; Mahfouz, Eman; Tharwat, Joy; Sayed, Sally; Medhat, Shrouk; Bahaa, Treza; Abdelrahim, Mohamed E A

2017-07-01

Cisplatin constitutes one of the most potent antineoplastic drugs; however, nephrotoxicity limited its eligibility for optimal clinical use. This study was designed to evaluate the role of honey and royal jelly with antioxidant properties in the protection of cisplatin-induced acute kidney injury in patients with cancer. Patients with cancer assigned for cisplatin chemotherapy were randomly divided into bee honey and royal jelly groups pretreated before the initiation and during cisplatin chemotherapeutic regimen and control group on cisplatin only. Serum creatinine and urea levels were measured before and after the chemotherapeutic cycle and over 2 cycles. Patients on crude bee honey and royal jelly capsules showed lower serum levels of renal injury products (creatinine and urea) compared to those in the control group. The changes in kidney parameters were significantly (p honey group before and after cisplatin treatment. Royal jelly was found to be effective; however, the difference in creatinine and urea levels before and after chemotherapy was not statistically significant. The use of bee honey and royal jelly as natural compounds is effective in reducing cisplatin nephrotoxicity and may offer a promising chance for clinically meaningful prevention. This study has potentially important implications for the treatment of cisplatin kidney side effects and is considered to be the first to investigate this effect of honey and royal jelly in human subjects. However, due to its small sample size, we recommend further investigation using a larger sample size.

Histone deacetylase mediated silencing of AMWAP expression contributes to cisplatin nephrotoxicity

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Ranganathan, Punithavathi; Hamad, Rania; Mohamed, Riyaz; Jayakumar, Calpurnia; Muthusamy, Thangaraju; Ramesh, Ganesan

2015-01-01

Cisplatin-induced acute kidney injury is a serious problem in cancer patients during treatment of solid tumors. Currently, there are no therapies available to treat or prevent cisplatin nephrotoxicity. Since histone deacetylase (HDAC) inhibition augments cisplatin anti-tumor activity, we tested whether HDAC inhibitors can prevent cisplatin-induced nephrotoxicity and determined the underlying mechanism. Cisplatin up-regulated the expression of several HDACs in the kidney. Inhibition of HDAC with clinically used trichostatin A suppressed cisplatin-induced kidney injury, inflammation and epithelial cell apoptosis. Moreover, trichostatin A upregulated the novel anti-inflammatory protein, activated microglia/macrophage WAP domain protein (AMWAP), in epithelial cells which was enhanced with cisplatin treatment. Interestingly, HDAC1 and -2 specific inhibitors are sufficient to potently up-regulate AMWAP in epithelial cells. Administration of recombinant AMWAP or its epithelial cell-specific overexpression reduced cisplatin-induced kidney dysfunction. Moreover, AMWAP treatment suppressed epithelial cell apoptosis, and siRNA-based knockdown of AMWAP expression abolished trichostatin A-mediated suppression of epithelial cell apoptosis in vitro. Thus, HDAC-mediated silencing of AMWAP may contribute to cisplatin nephrotoxicity. Hence, HDAC1 and -2 specific inhibitors or AMWAP could be useful therapeutic agents for the prevention of cisplatin nephrotoxicity. PMID:26509586

Cisplatin and doxorubicin induce distinct mechanisms of ovarian follicle loss; imatinib provides selective protection only against cisplatin.

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Stephanie Morgan

Full Text Available Chemotherapy treatment in premenopausal women has been linked to ovarian follicle loss and premature ovarian failure; the exact mechanism by which this occurs is uncertain. Here, two commonly used chemotherapeutic agents (cisplatin and doxorubicin were added to a mouse ovary culture system, to compare the sequence of events that leads to germ cell loss. The ability of imatinib mesylate to protect the ovary against cisplatin or doxorubicin-induced ovarian damage was also examined.Newborn mouse ovaries were cultured for a total of six days, exposed to a chemotherapeutic agent on the second day: this allowed for the examination of the earliest stages of follicle development. Cleaved PARP and TUNEL were used to assess apoptosis following drug treatment. Imatinib was added to cultures with cisplatin and doxorubicin to determine any protective effect.Histological analysis of ovaries treated with cisplatin showed oocyte-specific damage; in comparison doxorubicin preferentially caused damage to the granulosa cells. Cleaved PARP expression significantly increased for cisplatin (16 fold, p<0.001 and doxorubicin (3 fold, p<0.01. TUNEL staining gave little evidence of primordial follicle damage with either drug. Imatinib had a significant protective effect against cisplatin-induced follicle damage (p<0.01 but not against doxorubicin treatment.Cisplatin and doxorubicin both induced ovarian damage, but in a markedly different pattern, with imatinib protecting the ovary against damage by cisplatin but not doxorubicin. Any treatment designed to block the effects of chemotherapeutic agents on the ovary may need to be specific to the drug(s the patient is exposed to.

A randomized study to assess the efficacy of herbal product to prevent cisplatin-induced nephrotoxicity in a rat model.

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Kucuk, Eyup Veli; Bindayi, Ahmet; Mese, Meral; Gulcu Bulmus, Funda; Parmaksiz, Ergun; Cetinel, Ali Cihangir; Bicik Bahcebasi, Zerrin; Sarica, Kemal

2017-10-03

This study aimed to investigate the protective effect and antioxidant activity of an herbal product that made from multiple plants in a rat model of kidney dysfunction induced by intraperitoneal cisplatin. Twenty-four rats were divided into four different groups namely: Group 1 - control healthy animals without any specific medication, Group 2 - Herbal product only 5 mg/kg, Group 3 - cisplatin only and Group 4 - Herbal product 5 mg/kg + cisplatin. Evaluation of our findings demonstrated a significant (p = 0.017) reduction in Catalase activities and a significant increase (p = 0.001) in renal tissue Malondialdehyde levels in cisplatin- treated rats when compared with the control group. Also, Glutathion and Glutathione peroxidase content revealed significant (p = 0.031) reduction in renal tissues of cisplatintreated rats compared with the control group. Pre-treatment of rats with the herbal product ameliorated these cisplatininduced changes of the antioxidant enzymes. No statistically significant changes were demonstrated in Superoxide dismutase activities in the tissue specimens of any group. This potent antioxidant herbal medicine was found to have potential antioxidant activity, which may in turn to be effective in the protection of kidney tissue resulting from cisplatin application. Therefore, much attention should be given to the possible role of natural dietary antioxidants for protecting the kidney.

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

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Lin, Ji-Fan; Lin, Yi-Chia; Tsai, Te-Fu; Chen, Hung-En; Chou, Kuang-Yu; Hwang, Thomas I-Sheng

2017-01-01

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. 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. 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 cisplatin toward BC cells. These results indicated that cisplatin induced protective autophagy which may contribute to the development of cisplatin resistance and resulted in treatment failure. Mechanistically, upregulation of beclin-1 (BECN1) was detected in cisplatin-treated cells, and knockdown of BECN1 using shRNA attenuated cisplatin-induced autophagy and subsequently enhanced cisplatin-induced apoptosis. Collectively, the study results

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

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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.

Galectin-1-Induced Autophagy Facilitates Cisplatin Resistance of Hepatocellular Carcinoma.

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Yu-Chi Su

Full Text Available Hepatocellular carcinoma (HCC is one of the most common cancers in Taiwan. Although chemotherapy is the primary treatment for HCC patients, drug resistance often leads to clinical failure. Galectin-1 is a beta-galactoside binding lectin which is up-regulated in HCC patients and promotes tumor growth by mediating cancer cell adhesion, migration and proliferation, but its role in chemoresistance of HCC is poorly understood. In this study we found that galectin-1 is able to lead to chemoresistance against cisplatin treatment, and subsequent inhibition has reversed the effect of cell death in HCC cells. Moreover, galectin-1 was found to induce autophagic flux in HCC cells. Inhibition of autophagy by inhibitors or knockdown of Atg5 cancels galectin-1-induced cisplatin resistance in HCC cells. Increase of mitophagy triggered by galectin-1 was found to reduce the mitochondrial potential loss and apoptosis induced by cisplatin treatment. Finally, using an in situ hepatoma mouse model, we clearly demonstrated that inhibition of galectin-1 by thiodigalactoside could significantly augment the anti-HCC effect of cisplatin. Taken together, our findings offer a new insight into the chemoresistance galectin-1 causes against cisplatin treatment, and points to a potential approach to improve the efficacy of cisplatin in the treatment of HCC patients.

Oral administration of Nigella sativa oil ameliorates the effect of cisplatin on membrane enzymes, carbohydrate metabolism and oxidative damage in rat liver

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Zeba Farooqui

Full Text Available Cisplatin (CP is a potent anti-cancer drug widely used against solid tumors. However, it exhibits pronounced adverse effects including hepatotoxicity. Several strategies were attempted to prevent CP hepatotoxicity but were not found suitable for therapeutic application. Nigella sativa has been shown to prevent/reduce the progression of certain type of cardiovascular, kidney and liver diseases. Present study investigates whether N. sativa oil (NSO can prevent CP induced hepatotoxic effects. Rats were divided into four groups viz. control, CP, NSO and CPNSO. Animals in CPNSO and NSO group were administered NSO (2 ml/kg bwt, orally with or without single hepatotoxic dose of CP (6 mg/kg bwt, i.p. respectively. CP hepatotoxicity was recorded by increased serum ALT and AST activities. CP treatment caused oxidant/antioxidant imbalances as reflected by increased lipid peroxidation and decreased enzymatic and non-enzymatic antioxidants. Furthermore, the activities of various carbohydrate metabolism and membrane enzymes were altered by CP treatment. In contrast, NSO administration to CP treated rats, markedly ameliorated the CP elicited deleterious alterations in liver. Histopathological observations showed extensive liver damage in CP treated animals while greatly reduced tissue injury in CPNSO group. In conclusion, NSO appears to protect CP induced hepatotoxicity by improving energy metabolism and strengthening antioxidant defense mechanism. Keywords: Cisplatin, Nigella sativa oil, Carbohydrate metabolism, Antioxidant

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

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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.

A randomized study to assess the efficacy of herbal product to prevent cisplatin-induced nephrotoxicity in a rat model

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Eyup Veli Kucuk

2017-10-01

Full Text Available Objectives: This study aimed to investigate the protective effect and antioxidant activity of an herbal product that made from multiple plants in a rat model of kidney dysfunction induced by intraperitoneal cisplatin. Materials and methods: Twenty-four rats were divided into four different groups namely: Group 1 - control healthy animals without any specific medication, Group 2 - Herbal product only 5 mg/kg, Group 3 - cisplatin only and Group 4 - Herbal product 5 mg/kg + cisplatin. Results: Evaluation of our findings demonstrated a significant (p = 0.017 reduction in Catalase activities and a significant increase (p = 0.001 in renal tissue Malondialdehyde levels in cisplatin- treated rats when compared with the control group. Also, Glutathion and Glutathione peroxidase content revealed significant (p = 0.031 reduction in renal tissues of cisplatintreated rats compared with the control group. Pre-treatment of rats with the herbal product ameliorated these cisplatininduced changes of the antioxidant enzymes. No statistically significant changes were demonstrated in Superoxide dismutase activities in the tissue specimens of any group. Conclusions: This potent antioxidant herbal medicine was found to have potential antioxidant activity, which may in turn to be effective in the protection of kidney tissue resulting from cisplatin application. Therefore, much attention should be given to the possible role of natural dietary antioxidants for protecting the kidney.

Reduced ghrelin secretion in the hypothalamus of rats due to cisplatin-induced anorexia.

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Yakabi, Koji; Sadakane, Chiharu; Noguchi, Masamichi; Ohno, Shino; Ro, Shoki; Chinen, Katsuya; Aoyama, Toru; Sakurada, Tomoya; Takabayashi, Hideaki; Hattori, Tomohisa

2010-08-01

Although chemotherapy with cisplatin is a widely used and effective cancer treatment, the undesirable gastrointestinal side effects associated with it, such as nausea, vomiting, and anorexia, markedly decrease patients' quality of life. To elucidate the mechanism underlying chemotherapy-induced anorexia, focusing on the hypothalamic ghrelin secretion-anorexia association, we measured hypothalamic ghrelin secretion in fasted and cisplatin-treated rats. Hypothalamic ghrelin secretion changes after vagotomy or administration of cisplatin. Cisplatin + rikkunshito, a serotonin 2C receptor antagonist or serotonin 3 receptor antagonist, was investigated. The effects of intracerebroventricular (icv) administration of ghrelin or the serotonin 2C receptor antagonist SB242084 on food intake were also evaluated in cisplatin-treated rats. Hypothalamic ghrelin secretion significantly increased in 24-h-fasted rats compared to freely fed rats and was markedly reduced 24 and 48 h after cisplatin treatment in cisplatin-treated rats compared to saline-treated rats, although their plasma ghrelin levels were comparable. In cisplatin-treated rats, icv ghrelin administration reversed the decrease in food intake, vagotomy partially restored hypothalamic ghrelin secretion, and hypothalamic serotonin 2C receptor mRNA expression increased significantly. Administration of rikkunshito (an endogenous ghrelin enhancer) or a serotonin 2C receptor antagonist reversed the decrease in hypothalamic ghrelin secretion and food intake 24 h after cisplatin treatment. Cisplatin-induced anorexia is mediated through reduced hypothalamic ghrelin secretion. Cerebral serotonin 2C receptor activation partially induces decrease in hypothalamic ghrelin secretion, and rikkunshito suppresses cisplatin-induced anorexia by enhancing this secretion.

Tumour-cell apoptosis after cisplatin treatment is not telomere dependent.

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Jeyapalan, Jessie C; Saretzki, Gabriele; Leake, Alan; Tilby, Michael J; von Zglinicki, Thomas

2006-06-01

Cisplatin is a major chemotherapeutic agent, especially for the treatment of neuroblastoma. Telomeres with their sequence (TTAGGG)n are probable targets for cisplatin intrastrand cross-linking, but the role of telomeres in mediating cisplatin cytotoxicity is not clear. After exposure to cisplatin as single dose or continuous treatment, we found no loss of telomeres in either SHSY5Y neuroblastoma cells (telomere length, approximately 4 kbp), HeLa 229 cells (telomere length, 20 kbp) or in the acute lymphoblastic T cell line 1301 (telomere length, approximately 80 kbp). There was no induction of telomeric single strand breaks, telomeric overhangs were not degraded and telomerase activity was down-regulated only after massive onset of apoptosis. In contrast, cisplatin induced a delayed formation of DNA strand breaks and induced DNA damage foci containing gamma-H2A.X at nontelomeric sites. Interstitial DNA damage appears to be more important than telomere loss or telomeric damage as inducer of the signal pathway towards apoptosis and/or growth arrest in cisplatin-treated tumour cells.

Inhibition of cisplatin-induced vomiting by selective 5-hydroxytryptamine M-receptor antagonism.

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Miner, W. D.; Sanger, G. J.

1986-01-01

MDL 72222, the selective 5-hydroxytryptamine (5-HT) M-receptor antagonist, prevented or reduced cisplatin-induced emesis in ferrets. It is suggested that cisplatin-induced, and possibly other cytotoxic drug-induced vomiting may involve a 5-HT M-receptor mechanism.

Protective effect and mechanism of action of saponins isolated from the seeds of gac (Momordica cochinchinensis Spreng.) against cisplatin-induced damage in LLC-PK1 kidney cells.

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Jung, Kiwon; Lee, Dahae; Yu, Jae Sik; Namgung, Hojin; Kang, Ki Sung; Kim, Ki Hyun

2016-03-01

This study was performed to investigate the renoprotective effect and mechanism of Momordicae Semen, gac seeds, against the cisplatin-induced damage in LLC-PK1 kidney cells. In order to identify the active components, three major saponins were isolated from extract of the gac seed, gypsogenin 3-O-β-d-galactopyranosyl(1→2)-[α-L-rhamnopyranosyl(1→3)]-β-d-glucuronopyranoside (1), quillaic acid 3-O-β-D-galactopyranosyl(1→2)-[α-L-rhamnopyranosyl(1→3)]-β-D-glucuronopyranoside (2), and momordica saponin I (3). Compounds 1 and 2 ameliorated cisplatin-induced nephrotoxicity up to 80% of the control value at both 5 and 25μM. Phosphorylation of MAPKs was decreased along cisplatin treatment after treatment with compounds 1 and 2. These results show that blocking the MAPKs signaling cascade plays a critical role in mediating the renoprotective effect of Momordicae Semen extract and compounds 1 and 2. Copyright © 2016 Elsevier Ltd. All rights reserved.

Dexamethasone Modifies Cystatin C-Based Diagnosis of Acute Kidney Injury During Cisplatin-Based Chemotherapy

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Timothy J. Pianta

2017-03-01

Full Text Available Background/Aims: Plasma cystatin C (pCysC may be superior to serum creatinine (sCr as a surrogate of GFR. However, the performance of pCysC for diagnosing acute kidney injury (AKI after cisplatin-based chemotherapy is potentially affected by accompanying corticosteroid anti-emetic therapy and hydration. Methods: In a prospective observational study pCysC, sCr, urinary kidney injury molecule-1 (KIM-1, and urinary clusterin were measured over 2 weeks in 27 patients given first-cycle chemotherapy. The same variables were measured over 2 weeks in Sprague–Dawley rats given a single intraperitoneal injection of dexamethasone, cisplatin, or both, and in controls. Results: In patients, pCysC increases were greater than sCr 41% vs. 16%, mean paired difference 25% (95% CI: 16–34%], relative increases were ≥ 50% in 9 patients (35% for pCysC compared with 2 (8% for sCr (p = 0.04 and increases in sCr were accompanied by increased KIM-1 and clusterin excretion, but increases in pCysC alone were not. In rats, dexamethasone administration produced dose-dependent increases in pCysC (and augmented cisplatin-induced increases in pCysC, but did not augment histological injury, increases in sCr, or KIM-1 and clusterin excretion. Conclusions: In the presence of dexamethasone, elevation of pCysC does not reliably diagnose AKI after cisplatin-based chemotherapy.

Curcuma longa (curcumin) decreases in vivo cisplatin-induced ototoxicity through heme oxygenase-1 induction.

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Fetoni, Anna R; Eramo, Sara L M; Paciello, Fabiola; Rolesi, Rolando; Podda, Maria Vittoria; Troiani, Diana; Paludetti, Gaetano

2014-06-01

To investigate whether curcumin may have in vivo protective effects against cisplatin ototoxicity by its direct scavenger activity and/or by curcumin-mediated upregulation of HO-1. Cisplatin-induced ototoxicity is a major dose-limiting side effect in anticancer chemotherapy. A protective approach to decrease cisplatin ototoxicity without compromising its therapeutic efficacy remains a critical goal for anticancer therapy. Recent evidences indicate that curcumin exhibits antioxidant, anti-inflammatory, and chemosensitizer activities. In male adult Wistar rats, a curcumin dose of 200 mg/kg, selected from a dose-response curve, was injected 1 hour before cisplatin administration and once daily for the following 3 days. A single dose of cisplatin (16 mg/kg) was administered intraperitoneally. Rats were divided as follows: 1) control, 2) curcumin control, 3) vehicle control, 4) cisplatin, 5) cisplatin+ vehicle, and 6) curcumin+cisplatin. ABRs were measured before and at Days 3 and 5 after cisplatin administration. Rhodamine-phalloidin staining, 4-hydroxy-2-nonenal and heme-oxigenase-1 immunostainings, and Western blot analyses were performed to assess and quantify OHC loss, lipid peroxidation, and the endogenous response to cisplatin-induced damage and to curcumin protection. Curcumin treatment attenuated hearing loss induced by cisplatin, increased OHC survival, decreased 4-HNE expression, and increased HO-1 expression. This preclinical study demonstrates that systemic curcumin attenuates ototoxicity and provides molecular evidence for a role of HO-1 as an additional mediator in attenuating cisplatin-induced damage.

Bardoxolone methyl (BARD) ameliorates aristolochic acid (AA)-induced acute kidney injury through Nrf2 pathway.

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Wu, Juan; Liu, Xinhui; Fan, Jinjin; Chen, Wenfang; Wang, Juan; Zeng, Youjia; Feng, Xiaorang; Yu, Xueqing; Yang, Xiao

2014-04-06

Bardoxolone methyl (BARD) is an antioxidant modulator that acts through induction of the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway. This study aimed to investigate the role of BARD in protecting kidneys from aristolochic acid (AA)-induced acute kidney injury (AKI). Male C57BL/6 mice received intraperitoneal (i.p.) injections of aristolochic acid I (AAI) (5mg/kg/day) for 5 days to produce acute AA nephropathy (AAN) model. BARD (10mg/kg/day, i.p.) was applied for 7 consecutive days, starting 2 days prior to AAI administration. The mice in the AA group showed AKI as evidenced by worsening kidney function evaluated by blood urea nitrogen (BUN) and serum creatinine (SCr) levels, and severe tubulointerstitial injury marked by massive tubule necrosis in kidney tissues. BARD significantly reduced BUN and SCr levels which were elevated by AAI. Additionally, AAI-induced histopathological renal damage was ameliorated by BARD. Furthermore, the expression of Nrf2 was reduced, and its repressor Kelch-like ECH-associated protein 1 (Keap1) was increased significantly, whereas heme oxygenase-1 (HO-1) was upregulated and NAD(P)H quinone oxidoreductase-1 (NQO1) was barely increased in the cytoplasm of tubules in kidneys after treatment with AAI. BARD significantly upregulated renal Nrf2, NQO1 and HO-1 expression and downregulated Keap1 expression compared with those in the AA group. Moreover, it was found that Nrf2 was expressed both in the cytoplasm and nuclear of glomeruli and tubules, whereas NQO1 and HO-1 were localized in the cytoplasm of tubules only. In conclusion, AA-induced acute renal injury was associated with impaired Nrf2 activation and expression of its downstream target genes in renal tissues. BARD prevented renal damage induced by AAI, and this renoprotective effect may be exerted by activating the Nrf2 signaling pathway and increasing expression of the downstream target genes. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

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

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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

Protective effects of edaravone against cisplatin-induced hair cell damage in zebrafish.

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Hong, Seok Jin; Im, Gi Jung; Chang, Jiwon; Chae, Sung Won; Lee, Seung Hoon; Kwon, Soon Young; Jung, Hak Hyun; Chung, Ah Young; Park, Hae Chul; Choi, June

2013-06-01

Edaravone is known to have a potent free radical scavenging effect. The objective of the present study was to evaluate the effects of edaravone on cisplatin-induced ototoxicity in transgenic zebrafish (Brn3C: EGFP). Five day post-fertilization zebrafish larvae were exposed to 1000 μM cisplatin and 50 μM, 100 μM, 250 μM, 500 μM, 750 μM, and 1000 μM concentrations of edaravone for 4h. Hair cells within neuromasts of the supraorbital (SO1 and SO2), otic (O1), and occipital (OC1) lateral lines were analyzed by fluorescence microscopy and confocal microscopy (n=10). Hair cell survival was calculated as a percentage of the hair cells in the control group that were not exposed to cisplatin. Ultrastructural changes were evaluated using scanning electron microscopy and transmission electron microscopy. Edaravone protected cisplatin-induced hair cell loss of neuromasts (edaravone 750 μM: 8.7 ± 1.5 cells, cisplatin 1000 μM only: 3.7 ± 0.9 cells; n=10, pedaravone for 4h. Edaravone attenuated cisplatin-induced hair cell damage in zebrafish. The results of the current study suggest that cisplatin induces apoptosis, and the apoptotic cell death can be prevented by treatment with edaravone in zebrafish. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Involvement of caspase-dependent and -independent apoptotic pathways in cisplatin-induced apoptosis

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Liu, Lei; Zhang, Yingjie; Wang, Xianwang

2009-02-01

Cisplatin, an efficient anticancer agent, can trigger multiple apoptotic pathways in cancer cells. However, the signal transduction pathways in response to cisplatin-based chemotherapy are complicated, and the mechanism is not fully understood. In current study, we showed that, during cisplatin-induced apoptosis of human lung adenocarcinoma cells, both the caspase-dependent and -independent pathways were activated. Herein, we reported that after cisplatin treatment, the activities of caspase-9/-3 were sharply increased; pre-treatment with Z-LEHD-fmk (inhibitor of caspase-9), Z-DEVD-fmk (inhibitor of caspase-3), and Z-VAD-fmk (a pan-caspase inhibitor) increased cell viability and decreased apoptosis, suggesting that caspase-mediated apoptotic pathway was activated following cisplatin treatment. Confocal imaging of the cells transfected with AIF-GFP demonstrated that AIF release occurred about 9 h after cisplatin treatment. The event proceeded progressively over time, coinciding with a nuclear translocation and lasting for more than 2 hours. Down-regulation of AIF by siRNA also significantly increased cell viability and decreased apoptosis, these results suggested that AIF-mediated caspase-independent apoptotic pathway was involved in cispatin-induced apoptosis. In conclusion, the current study demonstrated that both caspase-dependent and -independent apoptotic pathways were involved in cisplatin-induced apoptosis in human lung adenocarcinoma cells.

Cisplatin-Induced Renal Salt Wasting Requiring over 12 Liters of 3% Saline Replacement

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Phuong-Chi Pham

2017-01-01

Full Text Available 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/m2 and etoposide (100 mg/m2 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.

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.

Filipendula ulmaria extracts attenuate cisplatin-induced liver and kidney oxidative stress in rats: In vivo investigation and LC-MS analysis.

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Katanić, Jelena; Matić, Sanja; Pferschy-Wenzig, Eva-Maria; Kretschmer, Nadine; Boroja, Tatjana; Mihailović, Vladimir; Stanković, Vesna; Stanković, Nevena; Mladenović, Milan; Stanić, Snežana; Mihailović, Mirjana; Bauer, Rudolf

2017-01-01

Filipendula ulmaria, known as meadowsweet, is a perennial herb found in wild and cultivated habitats in Europe and Asia. Usage of F. ulmaria in traditional medicine is based on diuretic, astringent, antirheumatic, and anti-inflammatory properties of this plant. Exposure to cisplatin at a dose of 7.5 mg/kg caused significant increase in serum parameters of liver and kidneys function and tissue oxidative stress markers along with some histopathological changes in liver and kidney tissues of experimental rats, as well as high level of genotoxicity. Administration of F. ulmaria extracts in three different concentrations (100, 200, and 400 mg/kg/day) for 10 days resulted in a reduction of oxidative stress in tissues and decrease of serum parameters. Moreover, tested extracts attenuated the genotoxicity of cisplatin in reverse dose-dependent manner. F. ulmaria extracts had no in vitro cytotoxic activity at all applied concentrations (IC 50  > 50 μg/mL). Tested extracts, rich in polyphenolic compounds, attenuate cisplatin-induced liver and kidney oxidative stress, reduce tissue damage, and enhance the antioxidative status of experimental animals during cisplatin application. Therefore, F. ulmaria extracts may be used as supportive agent for the prevention and amelioration of cisplatin side effects. Copyright © 2016 Elsevier Ltd. All rights reserved.

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

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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.

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

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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.

Caveolin-1 sensitizes cisplatin-induced lung cancer cell apoptosis via superoxide anion-dependent mechanism.

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Pongjit, Kanittha; Chanvorachote, Pithi

2011-12-01

Caveolin-1 (Cav-1) expression frequently found in lung cancer was linked with disease prognosis and progression. This study reveals for the first time that Cav-1 sensitizes cisplatin-induced lung carcinoma cell death by the mechanism involving oxidative stress modulation. We established stable Cav-1 overexpressed (H460/Cav-1) cells and investigated their cisplatin susceptibility in comparison with control-transfected cells and found that Cav-1 expression significantly enhanced cisplatin-mediated cell death. Results indicated that the different response to cisplatin between these cells was resulted from different level of superoxide anion induced by cisplatin. Inhibitory study revealed that superoxide anion inhibitor MnTBAP could inhibit cisplatin-mediated toxicity only in H460/Cav-1 cells while had no effect on H460 cells. Further, superoxide anion detected by DHE probe indicated that H460/Cav-1 cells generated significantly higher superoxide anion level in response to cisplatin than that of control cells. The role of Cav-1 in regulating cisplatin sensitivity was confirmed in shRNA-mediated Cav-1 down-regulated (H460/shCav-1) cells and the cells exhibited decreased cisplatin susceptibility and superoxide generation. In summary, these findings reveal novel aspects regarding role of Cav-1 in modulating oxidative stress induced by cisplatin, possibly providing new insights for cancer biology and cisplatin-based chemotherapy.

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

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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.

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

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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.

Chemopreventive Effect of Tadalafil in Cisplatin-Induced ...

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olayemitoyin

mgkg-1 and 5 mgkg-1 of Tadalafil in cisplatin-induced nephrotoxic rats. In this study, twenty-five male ... mitochondria, and reduced nicotinamide adenine dinucletide .... Laboratory Centrifuge (Model SM 112, Surgifriend. Medicals, England) at ...

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

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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

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

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Jiao, Xiaoyan; Cai, Jieru; Yu, Xiaofang; Ding, Xiaoqiang

2017-01-01

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. 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. 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 showed that the tubular β-catenin level was lower in

Inhibition of PKCδ reduces cisplatin-induced nephrotoxicity without blocking chemotherapeutic efficacy in mouse models of cancer

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Pabla, Navjotsingh; Dong, Guie; Jiang, Man; Huang, Shuang; Kumar, M. Vijay; Messing, Robert O.; Dong, Zheng

2011-01-01

Cisplatin is a widely used cancer therapy drug that unfortunately has major side effects in normal tissues, notably nephrotoxicity in kidneys. Despite intensive research, the mechanism of cisplatin-induced nephrotoxicity remains unclear, and renoprotective approaches during cisplatin-based chemotherapy are lacking. Here we have identified PKCδ as a critical regulator of cisplatin nephrotoxicity, which can be effectively targeted for renoprotection during chemotherapy. We showed that early during cisplatin nephrotoxicity, Src interacted with, phosphorylated, and activated PKCδ in mouse kidney lysates. After activation, PKCδ regulated MAPKs, but not p53, to induce renal cell apoptosis. Thus, inhibition of PKCδ pharmacologically or genetically attenuated kidney cell apoptosis and tissue damage, preserving renal function during cisplatin treatment. Conversely, inhibition of PKCδ enhanced cisplatin-induced cell death in multiple cancer cell lines and, remarkably, enhanced the chemotherapeutic effects of cisplatin in several xenograft and syngeneic mouse tumor models while protecting kidneys from nephrotoxicity. Together these results demonstrate a role of PKCδ in cisplatin nephrotoxicity and support targeting PKCδ as an effective strategy for renoprotection during cisplatin-based cancer therapy. PMID:21633170

Cisplatin Induces Cytotoxicity through the Mitogen-Activated Protein Kinase Pathways ana Activating Transcription Factor 3

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Carly St. Germain

2010-07-01

Full Text Available The mechanisms underlying the proapoptotic effect of the chemotherapeutic agent, cisplatin, are largely undefined. Understanding the mechanisms regulating cisplatin cytotoxicity may uncover strategies to enhance the efficacy of this important therapeutic agent. This study evaluates the role of activating transcription factor 3 (ATF3 as a mediator of cisplatin-induced cytotoxicity. Cytotoxic doses of cisplatin and carboplatin treatments consistently induced ATF3 expression in five tumor-derived cell lines. Characterization of this induction revealed a p53, BRCA1, and integrated stress response-independent mechanism, all previously implicated in stress-mediated ATF3 induction. Analysis of mitogenactivated protein kinase (MAPK pathway involvement in ATF3 induction by cisplatin revealed a MAPK-dependent mechanism. Cisplatin treatment combined with specific inhibitors to each MAPK pathway (c-Jun N-terminal kinase, extracellularsignal-regulated kinase, and p38 resulted in decreasedATF3 induction at the protein level. MAPK pathway inhibition led to decreased ATF3 messenger RNA expression and reduced cytotoxic effects of cisplatin as measured by the 3-(4,5-dimethylthiazol-2-ylF2,5-diphenyltetrazolium bromide cell viability assay. In A549 lung carcinoma cells, targeting ATF3 with specific small hairpin RNA also attenuated the cytotoxic effects of cisplatin. Similarly, ATF3-/murine embryonic fibroblasts (MEFs were shown to be less sensitive to cisplatin-induced cytotoxicity compared with ATF3+/+ MEFs. This study identifies cisplatin as a MAPK pathway-dependent inducer of ATF3, whose expression influences cisplatin’s cytotoxic effects.

The renoprotective activity of hesperetin in cisplatin induced nephrotoxicity in rats: Molecular and biochemical evidence.

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Kumar, Mukesh; Dahiya, Vicky; Kasala, Eshvendar Reddy; Bodduluru, Lakshmi Narendra; Lahkar, Mangala

2017-05-01

Nephrotoxicity remain a major life-threatening complication in cancer patients on cisplatin chemotherapy. In this study, we investigated the protective effect and possible cellular mechanism of the hesperetin, a naturally-occurring bioflavonoid against cisplatin-induced renal injury in rats. Hesperetin was administered at a dose of 50mg/kg and 100mg/kg orally for 10days and cisplatin (7.5mg/kg, ip) was administered on the 5th day of experiment. Cisplatin induced nephrotoxicity was evidenced by alteration in the level of markers such as blood urea nitrogen, creatinine, serum albumin and severe histopathological changes in kidney. Cisplatin administration also resulted in significant increase in the tissue oxidative stress and inflammatory cytokines. The level of antioxidants enzymes were decreased significantly in the cisplatin administered rats. Hesperetin treatment (50mg/kg and 100mg/kg) normalized the renal function by attenuation of the cisplatin-induced oxidative stress, lipid peroxidation, and inflammatory cytokines and histopathological alterations. On the basis of these experimental findings our present study postulate that co-administration of hesperetin with cisplatin chemotherapy may be promising preventive approach to limit the major mortal side effect of cisplatin. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Hydrogen-rich saline ameliorates the severity of L-arginine-induced acute pancreatitis in rats

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Chen, Han; Sun, Yan Ping; Li, Yang; Liu, Wen Wu; Xiang, Hong Gang; Fan, Lie Ying; Sun, Qiang; Xu, Xin Yun; Cai, Jian Mei; Ruan, Can Ping; Su, Ning; Yan, Rong Lin; Sun, Xue Jun; Wang, Qiang

2010-01-01

Molecular hydrogen, which reacts with the hydroxyl radical, has been considered as a novel antioxidant. Here, we evaluated the protective effects of hydrogen-rich saline on the L-arginine (L-Arg)-induced acute pancreatitis (AP). AP was induced in Sprague-Dawley rats by giving two intraperitoneal injections of L-Arg, each at concentrations of 250 mg/100 g body weight, with an interval of 1 h. Hydrogen-rich saline (>0.6 mM, 6 ml/kg) or saline (6 ml/kg) was administered, respectively, via tail vein 15 min after each L-Arg administration. Severity of AP was assessed by analysis of serum amylase activity, pancreatic water content and histology. Samples of pancreas were taken for measuring malondialdehyde and myeloperoxidase. Apoptosis in pancreatic acinar cell was determined with terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling technique (TUNEL). Expression of proliferating cell nuclear antigen (PCNA) and nuclear factor kappa B (NF-κB) were detected with immunohistochemistry. Hydrogen-rich saline treatment significantly attenuated the severity of L-Arg-induced AP by ameliorating the increased serum amylase activity, inhibiting neutrophil infiltration, lipid oxidation and pancreatic tissue edema. Moreover, hydrogen-rich saline treatment could promote acinar cell proliferation, inhibit apoptosis and NF-κB activation. These results indicate that hydrogen treatment has a protective effect against AP, and the effect is possibly due to its ability to inhibit oxidative stress, apoptosis, NF-κB activation and to promote acinar cell proliferation.

Mechanical Stress Promotes Cisplatin-Induced Hepatocellular Carcinoma Cell Death

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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

Mechanical Stress Promotes Cisplatin-Induced Hepatocellular Carcinoma Cell Death

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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.

Cisplatin-induced apoptosis inhibits autophagy, which acts as a pro-survival mechanism in human melanoma cells.

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Del Bello, Barbara; Toscano, Marzia; Moretti, Daniele; Maellaro, Emilia

2013-01-01

The interplay between a non-lethal autophagic response and apoptotic cell death is still a matter of debate in cancer cell biology. In the present study performed on human melanoma cells, we investigate the role of basal or stimulated autophagy in cisplatin-induced cytotoxicity, as well as the contribution of cisplatin-induced activation of caspases 3/7 and conventional calpains. The results show that, while down-regulating Beclin-1, Atg14 and LC3-II, cisplatin treatment inhibits the basal autophagic response, impairing a physiological pro-survival response. Consistently, exogenously stimulated autophagy, obtained with trehalose or calpains inhibitors (MDL-28170 and calpeptin), protects from cisplatin-induced apoptosis, and such a protection is reverted by inhibiting autophagy with 3-methyladenine or ATG5 silencing. In addition, during trehalose-stimulated autophagy, the cisplatin-induced activation of calpains is abrogated, suggesting the existence of a feedback loop between the autophagic process and calpains. On the whole, our results demonstrate that in human melanoma cells autophagy may function as a beneficial stress response, hindered by cisplatin-induced death mechanisms. In a therapeutic perspective, these findings suggest that the efficacy of cisplatin-based polychemotherapies for melanoma could be potentiated by inhibitors of autophagy.

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

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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

Protective effect of gallic acid against cisplatin-induced ototoxicity in rats.

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Kilic, Korhan; Sakat, Muhammed Sedat; Akdemir, Fazile Nur Ekinci; Yildirim, Serkan; Saglam, Yavuz Selim; Askin, Seda

2018-04-07

Cisplatin is an antineoplastic agent widely used in the treatment of a variety of cancers. Ototoxicity is one of the main side-effects restricting the use of cisplatin. The purpose of this study was to investigate the protective efficacy of gallic acid, in biochemical, functional and histopathological terms, against ototoxicity induced by cisplatin. Twenty-eight female Sprague Dawley rats were included. Rats were randomly assigned into four groups of seven animals each. Cisplatin group received a single intraperitoneal dose of 15mg/kg cisplatin. Gallic acid group received intraperitoneal gallic acid at 100mg/kg for five consecutive days. Cisplatin+Gallic acid group received intraperitoneal gallic acid at 100mg/kg for five consecutive days and a single intraperitoneal dose of 15mg/kg cisplatin at 3rd day. A control group received 1mL intraperitoneal saline solution for five consecutive days. Prior to drug administration, all rats were exposed to the distortion product otoacoustic emissions test. The test was repeated on the 6th day of the study. All rats were then sacrificed; the cochleas were removed and set aside for biochemical and histopathological analyses. In Cisplatin group, Day 6 signal noise ratio values were significantly lower than those of the other groups. Also, malondialdehyde levels in cochlear tissues were significantly higher, superoxide dismutase and glutathione peroxidase activities were significantly lower compared to the control group. Histopathologic evaluation revealed erosion in the stria vascularis, degeneration and edema in the connective tissue layer in endothelial cells, impairment of outer hair cells and a decrease in the number of these calls. In the Cisplatin+Gallic acid group, this biochemical, histopathological and functional changes were reversed. In the light of our findings, we think that gallic acid may have played a protective role against cisplatin-induced ototoxicity in rats, as indicated by the distortion product otoacoustic

Oridonin effectively reverses the drug resistance of cisplatin involving induction of cell apoptosis and inhibition of MMP expression in human acute myeloid leukemia cells

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Yuan Zhang

2017-03-01

Full Text Available Cisplatin is the first generation platinum-based chemotherapy agent. However, the extensive application of cisplatin inevitably causes drug resistance, which is a major obstacle to cancer chemotherapy. Oridonin is a diterpenoid isolated from Rabdosia rubescens with potent anticancer activity. The aim of our study is to investigate the role of oridonin to reverse the cisplatin-resistance in human acute myeloid leukemia (AML cells. The effect of oridonin on human AML cell proliferation was evaluated by MTT assay, cell migration and invasion were evaluated by transwell migration and invasion assays in cisplatin-resistant human AML cells. Furthermore, cell apoptosis was examined by flow cytometry. The inhibitive effect of oridonin in vivo was determined using xenografted nude mice. In addition, the expressions of MMP2 and MMP9 were detected by Western blot. There was a synergistic antitumor effect between cisplatin and oridonin on cisplatin-resistant human AML cells in vitro and in vivo. In addition, the combination of cisplatin and oridonin synergistically induced cell apoptosis. Furthermore, the combination treatment not only inhibited AML cell migration and invasion, but more significantly, decreased the expressions of MMP2 and MMP9 proteins. Our results suggest that the synergistic effect between both agents is likely to be driven by the inhibition of MMP expression and the resulting increased apoptosis.

Cisplatin as an Anti-Tumor Drug: Cellular Mechanisms of Activity, Drug Resistance and Induced Side Effects

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Florea, Ana-Maria; Büsselberg, Dietrich

2011-01-01

Platinum complexes are clinically used as adjuvant therapy of cancers aiming to induce tumor cell death. Depending on cell type and concentration, cisplatin induces cytotoxicity, e.g., by interference with transcription and/or DNA replication mechanisms. Additionally, cisplatin damages tumors via induction of apoptosis, mediated by the activation of various signal transduction pathways, including calcium signaling, death receptor signaling, and the activation of mitochondrial pathways. Unfortunately, neither cytotoxicity nor apoptosis are exclusively induced in cancer cells, thus, cisplatin might also lead to diverse side-effects such as neuro- and/or renal-toxicity or bone marrow-suppression. Moreover, the binding of cisplatin to proteins and enzymes may modulate its biochemical mechanism of action. While a combination-chemotherapy with cisplatin is a cornerstone for the treatment of multiple cancers, the challenge is that cancer cells could become cisplatin-resistant. Numerous mechanisms of cisplatin resistance were described including changes in cellular uptake, drug efflux, increased detoxification, inhibition of apoptosis and increased DNA repair. To minimize cisplatin resistance, combinatorial therapies were developed and have proven more effective to defeat cancers. Thus, understanding of the biochemical mechanisms triggered by cisplatin in tumor cells may lead to the design of more efficient platinum derivates (or other drugs) and might provide new therapeutic strategies and reduce side effects

Cisplatin as an Anti-Tumor Drug: Cellular Mechanisms of Activity, Drug Resistance and Induced Side Effects

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Florea, Ana-Maria [Department of Neuropathology, Heinrich-Heine University, Düsseldorf (Germany); Büsselberg, Dietrich, E-mail: dib2015@qatar-med.cornell.edu [Weil Cornell Medical College in Qatar, Qatar Foundation-Education City, P.O. Box 24144, Doha (Qatar)

2011-03-15

Platinum complexes are clinically used as adjuvant therapy of cancers aiming to induce tumor cell death. Depending on cell type and concentration, cisplatin induces cytotoxicity, e.g., by interference with transcription and/or DNA replication mechanisms. Additionally, cisplatin damages tumors via induction of apoptosis, mediated by the activation of various signal transduction pathways, including calcium signaling, death receptor signaling, and the activation of mitochondrial pathways. Unfortunately, neither cytotoxicity nor apoptosis are exclusively induced in cancer cells, thus, cisplatin might also lead to diverse side-effects such as neuro- and/or renal-toxicity or bone marrow-suppression. Moreover, the binding of cisplatin to proteins and enzymes may modulate its biochemical mechanism of action. While a combination-chemotherapy with cisplatin is a cornerstone for the treatment of multiple cancers, the challenge is that cancer cells could become cisplatin-resistant. Numerous mechanisms of cisplatin resistance were described including changes in cellular uptake, drug efflux, increased detoxification, inhibition of apoptosis and increased DNA repair. To minimize cisplatin resistance, combinatorial therapies were developed and have proven more effective to defeat cancers. Thus, understanding of the biochemical mechanisms triggered by cisplatin in tumor cells may lead to the design of more efficient platinum derivates (or other drugs) and might provide new therapeutic strategies and reduce side effects.

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

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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

Therapeutic Efficacy of Ginger, Cisplatin and Radiation on Chemically-Induced Cancer in Male Albino Rats

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El-Beih, N.M.; Galal, S.M.; Fahmy, N.M.; Abd El-Azime, M.G.

2015-01-01

This study aimed to investigate the in vivo effect of dietary supplementation with ginger to evaluate its therapeutic effect against lung and kidney cancer and in combination with cisplatin as chemotherapy and radiotherapy in male albino rats. 54 male albino rats were divided into nine groups of 6 animals each, all animals were allowed to food and water ad libitum . Group I was treated with 0.5 ml saline, orlly for 12 consecutive weeks serve as con - trol group Group II injected with N-nitrosodimethylamine (NDMA) and carbon tetrachloride (CCl 4 ); all groups were injected with NDMA + CCl 4 for 6 weeks. Group III were given ginger for 6 consecutive weeks (200 mg/kg, b.wt./day). Group IV animals received cisplatin, group V irradiated with 2 Gy, group VI treated with ginger then irradiated, group VII treated with ginger then injected with cisplatin, group VIII injected with cisplatin then irradiated and group IX treated with ginger and cisplatin then irradiated. Antioxidant status in both kidney and lung tissues were estimated by determining the activity of antioxidant enzyme superoxide dismutase (SOD); as well as the level of reduced glutathione (GSH), Malondialdehyde (MDA) and Nitric oxide (NO). In parallel to histopathological investigations of lung and kidney tissues. In addition, Tumor Necrosis Factor Alpha (TNF-α) level, advanced oxidative protein product (AOPP), urea, creatinine and uric acid. Remarkable disturbances were observed in the levels of all tested parameters in NDMA + CCl 4 group. On the other hand, rats injected with the cancer agents then treated with cisplatin+radiation showed moderate improvements in the studied parameters while, treatment with ginger + cisplatin + radiation ameliorated the levels of the disturbed bio

Epigallocatechin-3-gallate Ameliorates Seawater Aspiration-Induced Acute Lung Injury via Regulating Inflammatory Cytokines and Inhibiting JAK/STAT1 Pathway in Rats

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Liu, Wei; Dong, Mingqing; Bo, Liyan; Li, Congcong; Liu, Qingqing; Li, Yanyan; Ma, Lijie; Xie, Yonghong; Fu, Enqing; Mu, Deguang; Pan, Lei; Jin, Faguang; Li, Zhichao

2014-01-01

Signal transducers and activators of transcriptions 1 (STAT1) play an important role in the inflammation process of acute lung injury (ALI). Epigallocatechin-3-gallate (EGCG) exhibits a specific and strong anti-STAT1 activity. Therefore, our study is to explore whether EGCG pretreatment can ameliorate seawater aspiration-induced ALI and its possible mechanisms. We detected the arterial partial pressure of oxygen, lung wet/dry weight ratios, protein content in bronchoalveolar lavage fluid, and the histopathologic and ultrastructure staining of the lung. The levels of IL-1, TNF-α, and IL-10 and the total and the phosphorylated protein level of STAT1, JAK1, and JAK2 were assessed in vitro and in vivo. The results showed that EGCG pretreatment significantly improved hypoxemia and histopathologic changes, alleviated pulmonary edema and lung vascular leak, reduced the production of TNF-α and IL-1, and increased the production of IL-10 in seawater aspiration-induced ALI rats. EGCG also prevented the seawater aspiration-induced increase of TNF-α and IL-1 and decrease of IL-10 in NR8383 cell line. Moreover, EGCG pretreatment reduced the total and the phosphorylated protein level of STAT1 in vivo and in vitro and reduced the phosphorylated protein level of JAK1 and JAK2. The present study demonstrates that EGCG ameliorates seawater aspiration-induced ALI via regulating inflammatory cytokines and inhibiting JAK/STAT1 pathway in rats. PMID:24692852

Plasmapheresis reverses all side-effects of a cisplatin overdose – a case report and treatment recommendation

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Ploner Ferdinand

2006-01-01

Full Text Available Abstract Background Cisplatin is widely used as an antineoplastic agent since it is effective against a broad spectrum of different tumours. Nevertheless, it has several potential side effects affecting different organ systems and an overdose may lead to life-threatening complications and even death. Case presentation We report on a 46-year old woman with non-small cell lung cancer who accidentally received 225 mg/m2 of cisplatin, which was threefold the dose as scheduled, within a 3-day period. Two days later, the patient presented with hearing loss, severe nausea and vomiting, acute renal failure as well as elevated liver enzymes. In addition, she developed a severe myelodepression. After plasmapheresis on two consecutive days and vigorous supportive treatment, the toxicity-related symptoms improved and the patient recovered without any sequelae. Conclusion To date, no general accepted guidelines for the treatment of cisplatin overdoses are available. Along with the experience from other published cases, our report shows that plasmapheresis is capable of lowering cisplatin plasma and serum levels efficiently. Therefore, plasma exchange performed as soon as possible can ameliorate all side effects of a cisplatin overdose and be a potential tool for clinicians for treatment. However, additional intensive supportive treatment-modalities are necessary to control all occurring side effects.

Hydrogen Inhalation Protects against Ototoxicity Induced by Intravenous Cisplatin in the Guinea Pig

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Anette E. Fransson

2017-09-01

Full Text Available Introduction: Permanent hearing loss and tinnitus as side-effects from treatment with the anticancer drug cisplatin is a clinical problem. Ototoxicity may be reduced by co-administration of an otoprotective agent, but the results in humans have so far been modest.Aim: The present preclinical in vivo study aimed to explore the protective efficacy of hydrogen (H2 inhalation on ototoxicity induced by intravenous cisplatin.Materials and Methods: Albino guinea pigs were divided into four groups. The Cispt (n = 11 and Cispt+H2 (n = 11 groups were given intravenous cisplatin (8 mg/kg b.w., injection rate 0.2 ml/min. Immediately after, the Cispt+H2 group also received gaseous H2 (2% in air, 60 min. The H2 group (n = 5 received only H2 and the Control group (n = 7 received neither cisplatin nor H2. Ototoxicity was assessed by measuring frequency specific ABR thresholds before and 96 h after treatment, loss of inner (IHCs and outer (OHCs hair cells, and by performing densitometry-based immunohistochemistry analysis of cochlear synaptophysin, organic transporter 2 (OCT2, and copper transporter 1 (CTR1 at 12 and 7 mm from the round window. By utilizing metabolomics analysis of perilymph the change of metabolites in the perilymph was assessed.Results: Cisplatin induced electrophysiological threshold shifts, hair cell loss, and reduced synaptophysin immunoreactivity in the synapse area around the IHCs and OHCs. H2 inhalation mitigated all these effects. Cisplatin also reduced the OCT2 intensity in the inner and outer pillar cells and in the stria vascularis as well as the CTR1 intensity in the synapse area around the IHCs, the Deiters' cells, and the stria vascularis. H2 prevented the majority of these effects.Conclusion: H2 inhalation can reduce cisplatin-induced ototoxicity on functional, cellular, and subcellular levels. It is proposed that synaptopathy may serve as a marker for cisplatin ototoxicity. The effect of H2 on the antineoplastic activity of

Protective effect of U74500A on phorbol myristate acetate-induced acute lung injury.

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Chu, Shi-Jye; Chang, Deh-Ming; Wang, David; Lin, Hen-I; Lin, Shih-Hua; Hsu, Kang

2004-08-01

1. The present study was designed to determine whether U74500A could ameliorate acute lung injury (ALI) induced by phorbol myristate acetate (PMA) in our rat isolated lung model compared with any amelioration induced by dimethylthiourea (DMTU), superoxide dismutase (SOD) and catalase. 2. Acute lung injury was induced successfully by PMA during 60 min of observation. At 2 microg/kg, PMA elicited a significant increase in microvascular permeability (measured using the capillary filtration coefficient Kfc), lung weight gain, the lung weight/bodyweight ratio, pulmonary arterial pressure and protein concentration of the bronchoalveolar lavage fluid. 3. Pretreatment with 1.5 mg/kg U74500A significantly attenuated ALI; there was no significant increase in any parameters measured, except for pulmonary arterial pressure. The protective effect of U74500A was approximately the same as that of 600 mg/kg DMTU. However, 6000 U/kg SOD, 50,000 U/kg catalase and 6000 U/kg SOD + 50,000 U/kg catalase had no protective effect. 4. These experimental data suggest that U74500A significantly ameliorates ALI induced by PMA in rats.

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

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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.

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.

Effect of Taurine on Cisplatin -Induced Nephrotoxicity and Hepatoxicity in Male Rat

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Noruzi M.

2010-06-01

Full Text Available Background and Objectives: Cisplatin, Platinum co-ordinate complex is a widely used antineaplastic agent for treatment of metastatic tumors. Taurine is an organic acid and an endogenous antioxidant. In this study we investigated the protective effect of taurine as an endogenous antioxidant against cisplatin induced nephrotoxicity and hepatotexicity.Methods: 24 male albino rats (180-220 grams were divided into 4 groups (n=6: (1: saline-treated group (2: cisplatin-treated group (10mg/kg, ip (3: group that received taurine (400mg/kg, ip 1hr before cisplatin (10mg/kg, ip administration (4: taurine (400mg/kg, ip. The animals were killed 7days after treatment and then blood samples were collected.Results: The results of this study indicated that cisplatin significantly increased CRATININ, URE, ALT, AST levels as compared to control group. Moreover, taurine significantly decreased CRATININ, URE, ALT and AST levels compared to cisplatin group.Conclusion: According to this study taurine prevents the incease of Creatinin, BUN, ALT and AST levels assisted by cisplatin, which may be due to its antioxidant properties.Keywords: Cisplatin; Taurine; Hepatoxicity; Nephrotoxicity; Nephrons.

Ameliorative effect of parsley oil on cisplatin-induced hepato-cardiotoxicity: A biochemical, histopathological, and immunohistochemical study.

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Abdellatief, Suhair A; Galal, Azza A A; Farouk, Sameh M; Abdel-Daim, Mohamed M

2017-02-01

Cisplatin (cis-diamminedichloroplatinum, CDDP) is an effective DNA alkylating agent used in the treatment of different types of tumors; however, its clinical use is associated with hepato-cardiotoxicity. The current study was designed to assess the potential protective effect of parsley oil (PO) against CDDP-induced hepato-cardiotoxicity. For this purpose, 25 adult male rats were assigned into five groups, each containing five animals. Group I (control) was administered saline solution. Group II was administered PO at a dosage of 0.42ml/kg BW. Group III were administered CDDP at a dosage of 5mg/kg BW. Group IV was administered PO in addition to CDDP. Group V was administered saline solution in addition to CDDP, after which they were administered PO for five days. Oral administration of either saline solution or PO was performed each day for 10days, while administration of CDDP was via a single intraperitoneal injection five days following the commencement of the experiment. The recorded results revealed that CDDP induced obvious hepatic and cardiac injuries that were indicated by biochemical, histopathological, and immunohistochemical alterations, including elevation of serum hepatic and cardiac injury markers as well as proinflammatory cytokines. Moreover, CDDP induced an increase in the level of hepatic and cardiac injury biomarkers, decreases in the activities of antioxidant enzymes, a decrease in GSH concentration, and an increase in MDA concentration. CDDP also induced histopathological hepatocellular and myocardial changes, and overexpression of p53 and COX-2 in hepatic and cardiac tissues. Administration of PO either as a preventative medicine or as treatment significantly improved all the observed deleterious effects induced by CDDP in rat liver and heart. Thus, it may be concluded that PO, with its antioxidant, anti-inflammatory, and antiapoptotic activities, can potentially be used in the treatment of CDDP-induced hepatic and cardiac injuries. Copyright �

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

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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.

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

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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.

Efficacy of piroxicam plus cisplatin-loaded PLGA nanoparticles in inducing apoptosis in mesothelioma cells.

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Menale, Ciro; Piccolo, Maria Teresa; Favicchia, Ilaria; Aruta, Maria Grazia; Baldi, Alfonso; Nicolucci, Carla; Barba, Vincenzo; Mita, Damiano Gustavo; Crispi, Stefania; Diano, Nadia

2015-02-01

Combined treatment based on cisplatin-loaded Poly(D,L-lactic-co-glicolic)acid (PLGA) nanoparticles (NP-C) plus the NSAID piroxicam was used as novel treatment for mesothelioma to reduce side effects related to cisplatin toxicity. PLGA nanoparticles were prepared by double emulsion solvent evaporation method. Particle size, drug release profile and in vitro cellular uptake were characterized by TEM, DLS, LC/MS and fluorescence microscopy. MSTO-211H cell line was used to analyse NP-C biological efficacy by FACS and protein analysis. Cisplatin was encapsulated in 197 nm PLGA nanoparticles with 8.2% drug loading efficiency and 47% encapsulation efficiency. Cisplatin delivery from nanoparticles reaches 80% of total encapsulated drug in 14 days following a triphasic trend. PLGA nanoparticles in MSTO-211H cells were localized in the perinuclear space NP-C in combination with piroxicam induced apoptosis using a final cisplatin concentration 1.75 fold less than free drug. Delivered cisplatin cooperated with piroxicam in modulating cell cycle regulators as caspase-3, p53 and p21. Cisplatin loaded PLGA nanoparticles plus piroxicam showed a good efficacy in exerting cytotoxic activity and inducing the same molecular apoptotic effects of the free drugs. Sustained cisplatin release allowed to use less amount of drug, decreasing toxic side effects. This novel approach could represent a new strategy for mesothelioma treatment.

Prevention of cisplatin nephrotoxicity

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Hayati Fatemeh

2016-01-01

Full Text Available Cisplatin has a well-established role in the treatment of broad spectrum of malignancies; however its use is limited because of cisplatin-induced nephrotoxicity (CIN which can be progressive in more than 50% of cases. The most important risk factors for CIN include higher doses of cisplatin, previous cisplatin chemotherapy, underlying kidney damage and concurrent treatment with other potential nephrotoxin agents, such as aminoglycosides, nonsteroidal anti-inflammatory agents, or iodinated contrast media. Different strategies have been offered to diminish or prevent nephrotoxicity of cisplatin. The standard approach for prevention of CIN is the administration of lower doses of cisplatin in combination with full intravenous hydration prior and after cisplatin administration. Cisplatin-induced oxidative stress in the kidney may be prevented by natural antioxidant compounds. The results of this review show that many strategies for prevention of CIN exist, however, attention to the administration of these agent for CIN is necessary.

The protective effect of infliximab on cisplatin-induced intestinal tissue toxicity.

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Aydin, I; Kalkan, Y; Ozer, E; Yucel, A F; Pergel, A; Cure, E; Cure, M C; Sahin, D A

2014-01-01

Cisplatin (CP) is a popular chemotherapeutic agent. However, high doses of CP may lead to severe side effects to the gastrointestinal system. The aim of this study was to investigate the protective effects of infliximab on small intestine injury induced by high doses of CP. The A total of 30 rats were equally divided into three groups, including sham (C), cisplatin (CP), and cisplatin + infliximab (CPI). The CP group was treated with 7 mg/kg intraperitoneal cisplatin, and a laparotomy was performed 5 days later. The CPI group received 7 mg/kg infliximab intraperitoneally, were administered 7 mg/kg cisplatin 4 days later, and a laparotomy was performed 5 days after receiving cisplatin. Histopathological and immunohistochemical analysis of small intestine tissue sections were performed, and superoxide dismutase, malondialdehyde, and TNF-α levels were measured. Histopathological evaluation revealed that the CP group had damage in the epithelium and connective tissue, but this damage was significantly improved in the CPI group (p < 0.05). In addition, these histopathological findings were confirmed by biochemical analyses. These results suggest that infliximab is protective against the adverse effects of CP.

Reduced kidney lipoprotein lipase and renal tubule triglyceride accumulation in cisplatin-mediated acute kidney injury

NARCIS (Netherlands)

Li, Shenyang; Nagothu, K.; Ranganathan, G.; Ali, S.M.; Shank, B.; Gokden, N.; Ayyadevara, S.; Megysi, J.; Olivecrona, G.; Chugh, S.S.; Kersten, A.H.; Portilla, D.

2012-01-01

Peroxisome proliferator-activated receptor-a (PPARa) activation attenuates cisplatin (CP)-mediated acute kidney injury by increasing fatty acid oxidation, but mechanisms leading to reduced renal triglyceride (TG) accumulation could also contribute. Here, we investigated the effects of PPARa and CP

Fentanyl Ameliorates Severe Acute Pancreatitis-Induced Myocardial Injury in Rats by Regulating NF-κB Signaling Pathway.

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Wang, Yayun; Chen, Manhua

2017-07-06

BACKGROUND Acute pancreatitis (AP) is a sudden inflammation of the pancreas. It results in multiple, severe complications, and 15-20% of patients develop severe acute pancreatitis (SAP) with mortality as high as 30%. Consequently, it is imperative to develop an effective therapy for SAP. MATERIAL AND METHODS We used 30 adult male Sprague Dawley (SD) rats. Rats were randomly divided into 3 groups - sham, SAP, and fentanyl+SAP - with 10 rats in each group. An automatic biochemical analyzer was used to analyze the concentration of creatine kinase isoenzyme (CK-MB) and lactate dehydrogenase (LDH). Terminal-deoxynucleotidyl transferase-mediated nick-end labeling (TUNEL) assay was applied to assess the cell apoptosis rate. Pathological changes in pancreas/heart were detected with hematoxylin and eosin (HE) staining. Western immunoblot assay was used to analyze protein levels of interleukin (IL)-1β, IL-6, and IκB. RESULTS Fentanyl pre-treatment inhibits SAP-induced elevation of CK-MB/LDH concentrations in serum. Compared with the sham group, SAP generates a higher brown/yellow staining rate, which is abated by fentanyl. In the pancreas, SAP generated more serious interstitial edema/hemorrhage and fat necrosis than in the sham group, which are attenuated by fentanyl. Likewise, compared to the sham group, SAP generates swelled/disordered myocardial fibers and congested blood vessels in myocardium, which are ameliorated by fentanyl. In the sham group, there was little IL-1β/IL-6, and fentanyl significantly inhibited SAP-induced up-regulation of IL-1β/IL-6 levels. Compared with the sham group, SAP significantly reduced IκB level, which was rescued by fentanyl. CONCLUSIONS Fentanyl effectively alleviates SAP-induced pancreas and heart injuries through regulating the nuclear factor-κB (NF-κB) signaling pathway.

Failure of Elevating Calcium Induces Oxidative Stress Tolerance and Imparts Cisplatin Resistance in Ovarian Cancer Cells

OpenAIRE

Ma, Liwei; Wang, Hongjun; Wang, Chunyan; Su, Jing; Xie, Qi; Xu, Lu; Yu, Yang; Liu, Shibing; Li, Songyan; Xu, Ye; Li, Zhixin

2016-01-01

Cisplatin is a commonly used chemotherapeutic drug, used for the treatment of malignant ovarian cancer, but acquired resistance limits its application. There is therefore an overwhelming need to understand the mechanism of cisplatin resistance in ovarian cancer, that is, ovarian cancer cells are insensitive to cisplatin treatment. Here, we show that failure of elevating calcium and oxidative stress tolerance play key roles in cisplatin resistance in ovarian cancer cell lines. Cisplatin induce...

Xanthohumol ameliorates lipopolysaccharide (LPS-induced acute lung injury via induction of AMPK/GSK3β-Nrf2 signal axis

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Hongming Lv

2017-08-01

Full Text Available Abundant natural flavonoids can induce nuclear factor-erythroid 2 related factor 2 (Nrf2 and/or AMP-activated protein kinase (AMPK activation, which play crucial roles in the amelioration of various inflammation- and oxidative stress-induced diseases, including acute lung injury (ALI. Xanthohumol (Xn, a principal prenylflavonoid, possesses anti-inflammation and anti-oxidant activities. However, whether Xn could protect from LPS-induced ALI through inducing AMPK/Nrf2 activation and its downstream signals, are still poorly elucidated. Accordingly, we focused on exploring the protective effect of Xn in the context of ALI and the involvement of underlying molecular mechanisms. Our findings indicated that Xn effectively alleviated lung injury by reduction of lung W/D ratio and protein levels, neutrophil infiltration, MDA and MPO formation, and SOD and GSH depletion. Meanwhile, Xn significantly lessened histopathological changes, reactive oxygen species (ROS generation, several cytokines secretion, and iNOS and HMGB1 expression, and inhibited Txnip/NLRP3 inflammasome and NF-κB signaling pathway activation. Additionally, Xn evidently decreased t-BHP-stimulated cell apoptosis, ROS generation and GSH depletion but increased various anti-oxidative enzymes expression regulated by Keap1-Nrf2/ARE activation, which may be associated with AMPK and GSK3β phosphorylation. However, Xn-mediated inflammatory cytokines and ROS production, histopathological changes, Txnip/NLRP3 inflammasome and NF-κB signaling pathway in WT mice were remarkably abrogated in Nrf2-/- mice. Our experimental results firstly provided a support that Xn effectively protected LPS-induced ALI against oxidative stress and inflammation damage which are largely dependent upon upregulation of the Nrf2 pathway via activation of AMPK/GSK3β, thereby suppressing LPS-activated Txnip/NLRP3 inflammasome and NF-κB signaling pathway. Keywords: Xanthohumol, Acute lung injury, Oxidative stress

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

DEFF Research Database (Denmark)

Hojman, Pernille; Fjelbye, Jonas; Zerahn, Bo

2014-01-01

, 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 ... as anorexia, impaired muscle strength (22.5% decrease, P wheel running during treatment attenuated body weight...... loss by 50% (P wheel running, nor was glucose tolerance improved. Exercise...

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

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

2016-01-01

Cisplatin (Cis) is used in the treatment of solid tumors and is known to elicit serious side effects. 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. 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. 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, enhanced the activities of some antioxidative enzymes and

Possible mechanism of PNS protection against cisplatin-induced nephrotoxicity in rat models.

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Liu, Xinwen; Huang, Zhenguang; Zou, Xiaoqin; Yang, Yufang; Qiu, Yue; Wen, Yan

2015-01-01

This study investigates the mechanism of the protective effect of Panax notoginsenosides (PNS) against cisplatin-induced nephrotoxicity via the hypoxia inducible factor 1 (HIF-1)/Bcl-2/adenovirus E1B 19 kDa-interacting protein 3 (BNIP3) pathway of autophagy. The rats underwent intraperitoneal injection with a single dose of cisplatin and a subset of rats were also intraperitoneally injected with 31.35 mg/kg PNS once a day. After 24 h exposure to cisplatin, the concentrations of urinary N-acetyl-β-D-glucosaminidase (NAG), blood urea nitrogen (BUN) and serum creatinine (Scr) were determined. The rat renal tissue was examined using H&E-staining, and the mitochondria of renal tubular epithelial cells were observed using transmission electron microscopy. The expressions of microtubule-associated protein-1 light chain (LC)3, autophagy-related gene (Atg)5, Beclin-1 and BNIP3 in rat renal tissue were detected using western blotting. The expression of HIF-1 was detected by immunohistochemistry. The results showed that PNS significantly protected against cisplatin-induced nephrotoxicity, as evidenced by decreasing the concentration of blood BUN and Scr, the attenuation of renal histopathological changes and the mitochondrial damages of renal cells, and the increase of mitochondria autophagosome in renal tubular epithelial cells. Additionally, PNS significantly increased the expression of LC3 and the ratio of LC3II/LC3I in rat renal tissue. Moreover, PNS significantly increased the expression of HIF-1α, BNIP3, Atg5 and Beclin-1 in rat renal tissue. In conclusion, the protective effect of PNS on cisplatin-induced nephrotoxicity was mainly due to its ability to enhancing the mitochondrial autophagy of renal tissue via the HIF-1α/BNIP3 pathway, and here is the first demonstration about it.

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

International Nuclear Information System (INIS)

Zhou, Zhitao; Lu, Xiao; Zhu, Ping; Zhu, Wei; Mu, Xia; Qu, Rongmei; Li, Ming

2012-01-01

Highlights: ► VCC-1 is hypothesized to be associated with carcinogenesis. ► Levels of VCC-1 are increased significantly in HCC. ► Over-expression of VCC-1 could promotes cellular proliferation rate. ► Over-expression of VCC-1 inhibit the cisplatin-provoked apoptosis in HepG2 cells. ► 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.

Protective Effect of Aqueous and Ethanolic Extracts of Portulaca Oleracea Against Cisplatin Induced Nephrotoxicity

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Gholamreza Karimi

2010-04-01

Full Text Available Objective(sPortulaca oleracea L. is a herbaceous weed from portulacaceae family. It can be found in many parts of the world. Modern pharmacological studies have demonstrated that P. oleracea have antioxidant effects. The protective effect of aqueous and ethanolic extract of P. oleracea against cisplatin-induced renal toxicity was studied in rats.Materials and MethodsSingle intraperitoneal injection of 4 mg/kg cisplatin was administrated to rats. After 5 days, blood urea nitrogen (BUN and serum creatinine (Scr concentration were determined. Effect of aqueous and ethanolic extracts, before and after cisplatin injection on BUN and Scr, as well as morphological renal damage, was evaluated. ResultsIt was indicated that treatment with aqueous and ethanolic extracts of P. oleracea in the highest dose (0.8 and 2 g/ kg, 6 and 12 hr before cisplatin injection reduced BUN and Scr. Tubular necrotic damage was not observed either. ConclusionResults suggest that P. oleracea extract may protect against cisplatin-induced renal toxicity and might serve as a novel combination agent with cisplan to limit renal injury.

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

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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.

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

International Nuclear Information System (INIS)

Chen, Yafei; Brott, David; Luo, Wenli; Gangl, Eric; Kamendi, Harriet; Barthlow, Herbert; Lengel, David; Fikes, James; Kinter, Lewis; Valentin, Jean-Pierre; Bialecki, Russell

2013-01-01

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

The response of hypoxic cells in SCCVII murine tumors to treatment with cisplatin and x rays

International Nuclear Information System (INIS)

Yan, R.D.; Durand, R.E.

1991-01-01

Possible mechanisms of enhancement of radiation effects by cisplatin, including radiosensitization of hypoxic cells, drug-induced tumor reoxygenation, and inhibition of repair of sublethal radiation damage, were examined in the murine SCCVII model. Combination radiation/drug treatments were most effective when drug exposure preceded irradiation of animals breathing a reduced oxygen atmosphere, indicating that the primary interaction between the modalities was a cisplatin-induced increase in the oxygenation status of the acutely hypoxic cells in those tumors. Delivering cisplatin prior to or immediately after the first of two 5 Gy fractions was more effective than combinations with a single x-ray exposure, suggesting that proper sequences of the combined modalities may augment natural reoxygenation processes

Abrogation of cisplatin-induced hepatotoxicity in mice by xanthorrhizol is related to its effect on the regulation of gene transcription

International Nuclear Information System (INIS)

Hwan Kim, Seong; Ok Hong, Kyoung; Chung, Won-Yoon; Kwan Hwang, Jae; Park, Kwang-Kyun

2004-01-01

Cisplatin is a widely used anticancer drug, but at high dose, it can produce undesirable side effects such as hepatotoxicity. Because Curcuma xanthorrhiza Roxb. (Zingiberaceae) has been traditionally used to treat liver disorders, the protective effect of xanthorrhizol, which is isolated from C. xanthorrhiza, on cisplatin-induced hepatotoxicity was evaluated in mice. The pretreatment of xanthorrhizol (200 mg/kg/day, po) for 4 days prevented the hepatotoxicity induced by cisplatin (45 mg/kg, ip) with statistical significance. Interestingly, it abrogated cisplatin-induced DNA-binding activity of nuclear factor-kappaB (NF-κB), which consequently affected mRNA expression levels of NF-κB-dependent genes, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2), even in part. It also attenuated the cisplatin-suppressed DNA-binding activity of activator protein 1 (AP-1). Using differential display reverse transcription-polymerase chain reaction (DDRT-PCR), seven upregulated genes including S100 calcium binding protein A9 (S100A9) mRNA and antigenic determinant for rec-A protein mRNA and five downregulated genes including caseinolytic protease X (ClpX) mRNA and ceruloplasmin (CP) mRNA by cisplatin were identified. Although these mRNA expression patterns were not totally consistent with gel shift patterns, altered expression levels by cisplatin were reversed by the pretreatment of xanthorrhizol. In conclusion, the ability of xanthorrhizol to regulate the DNA-binding activities of transcription factors, NF-κB and AP-1, could be one possible mechanism to elucidate the preventive effect of xanthorrhizol on cisplatin-induced hepatotoxicity. Furthermore, genes identified in this study could be helpful to understand the mechanism of cisplatin-induced hepatotoxicity. Finally, the combination treatment of xanthorrhizol and cisplatin may provide more advantage than single treatment of cisplatin in cancer therapy

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.

UPregulated single-stranded DNA-binding protein 1 induces cell chemoresistance to cisplatin in lung cancer cell lines.

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Zhao, Xiang; He, Rong; Liu, Yu; Wu, Yongkai; Kang, Leitao

2017-07-01

Cisplatin and its analogues are widely used as anti-tumor drugs in lung cancer but many cisplatin-resistant lung cancer cases have been identified in recent years. Single-stranded DNA-binding protein 1 (SSDBP1) can effectively induce H69 cell resistance to cisplatin in our previous identification; thus, it is necessary to explore the mechanism underlying the effects of SSDBP1-induced resistance to cisplatin. First, SSDBP1-overexpressed or silent cell line was constructed and used to analyze the effects of SSDBP1 on chemoresistance of lung cancer cells to cisplatin. SSDBP1 expression was assayed by real-time PCR and Western blot. Next, the effects of SSDBP1 on cisplatin sensitivity, proliferation, and apoptosis of lung cancer cell lines were assayed by MTT and flow cytometry, respectively; ABC transporters, apoptosis-related genes, and cell cycle-related genes by real-time PCR, and DNA wound repair by comet assay. Low expression of SSDBP1 was observed in H69 cells, while increased expression in cisplatin-resistant H69 cells. Upregulated expression of SSDBP1 in H69AR cells was identified to promote proliferation and cisplatin resistance and inhibit apoptosis, while downregulation of SSDBP1 to inhibit cisplatin resistance and proliferation and promoted apoptosis. Moreover, SSDBP1 promoted the expression of P2gp, MRP1, Cyclin D1, and CDK4 and inhibited the expression of caspase 3 and caspase 9. Furthermore, SSDBP1 promoted the DNA wound repair. These results indicated that SSDBP1 may induce cell chemoresistance of cisplatin through promoting DNA repair, resistance-related gene expression, cell proliferation, and inhibiting apoptosis.

Hyperbaric oxygen therapy ameliorates acute brain injury after porcine intracerebral hemorrhage at high altitude.

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Zhu, Hai-tao; Bian, Chen; Yuan, Ji-chao; Liao, Xiao-jun; Liu, Wei; Zhu, Gang; Feng, Hua; Lin, Jiang-kai

2015-06-15

Intracerebral hemorrhage (ICH) at high altitude is not well understood to date. This study investigates the effects of high altitude on ICH, and examines the acute neuroprotection of hyperbaric oxygen (HBO) therapy against high-altitude ICH. Minipigs were placed in a hypobaric chamber for 72 h before the operation. ICH was induced by an infusion of autologous arterial blood (3 ml) into the right basal ganglia. Animals in the high-altitude ICH group received HBO therapy (2.5 ATA for 60 min) 30 min after ICH. Blood gas, blood glucose and brain tissue oxygen partial pressure (PbtO2) were monitored continuously for animals from all groups, as were microdialysis products including glucose, lactate, pyruvate and glutamate in perihematomal tissue from 3 to 12 h post-ICH. High-altitude ICH animals showed significantly lower PbtO2, higher lactate/pyruvate ratio (LPR) and glutamate levels than low-altitude ICH animals. More severe neurological deficits, brain edema and neuronal damage were also observed in high-altitude ICH. After HBO therapy, PbtO2 was significantly increased and LPR and glutamate levels were significantly decreased. Brain edema, neurological deficits and neuronal damage were also ameliorated. The data suggested a more serious disturbance of tissue oxygenation and cerebral metabolism in the acute stage after ICH at high altitude. Early HBO treatment reduced acute brain injury, perhaps through a mechanism involving the amelioration of the derangement of cerebral oxygenation and metabolism following high-altitude ICH.

MiR-30c regulates cisplatin-induced apoptosis of renal tubular epithelial cells by targeting Bnip3L and Hspa5.

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Du, Bin; Dai, Xiao-Meng; Li, Shuang; Qi, Guo-Long; Cao, Guang-Xu; Zhong, Ying; Yin, Pei-di; Yang, Xue-Song

2017-08-10

As a common anticancer drug, cisplatin has been widely used for treating tumors in the clinic. However, its side effects, especially its nephrotoxicity, noticeably restrict the application of cisplatin. Therefore, it is imperative to investigate the mechanism of renal injury and explore the corresponding remedies. In this study, we showed the phenotypes of the renal tubules and epithelial cell death as well as elevated cleaved-caspase3- and TUNEL-positive cells in rats intraperitoneally injected with cisplatin. Similar cisplatin-induced cell apoptosis was found in HK-2 and NRK-52E cells exposed to cisplatin as well. In both models of cisplatin-induced apoptosis in vivo and in vitro, quantitative PCR data displayed reductions in miR-30a-e expression levels, indicating that miR-30 might be involved in regulating cisplatin-induced cell apoptosis. This was further confirmed when the effects of cisplatin-induced cell apoptosis were found to be closely correlated with alterations in miR-30c expression, which were manipulated by transfection of either the miR-30c mimic or miR-30c inhibitor in HK-2 and NRK-52E cells. Using bioinformatics tools, including TargetScan and a gene expression database (Gene Expression Omnibus), Adrb1, Bnip3L, Hspa5 and MAP3K12 were predicted to be putative target genes of miR-30c in cisplatin-induced apoptosis. Subsequently, Bnip3L and Hspa5 were confirmed to be the target genes after determining the expression of these putative genes following manipulation of miR-30c expression levels in HK-2 cells. Taken together, our current experiments reveal that miR-30c is certainly involved in regulating the renal tubular cell apoptosis induced by cisplatin, which might supply a new strategy to minimize cisplatin-induced nephrotoxicity.

In vitro toxicity assay of cisplatin on mouse acute lymphoblastic leukaemia and spermatogonial stem cells.

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Shabani, R; Ashtari, K; Behnam, B; Izadyar, F; Asgari, H; Asghari Jafarabadi, M; Ashjari, M; Asadi, E; Koruji, M

2016-06-01

Testicular cancer is the most common cancer affecting men in reproductive age, and cisplatin is one of the major helpful chemotherapeutic agents for treatment of this cancer. In addition, exposure of testes cancer cells to cisplatin could potentially eliminate tumour cells from germ cells in patients. The aim of this study was to evaluate the effect of cisplatin on viability of mouse acute lymphoblastic leukaemia cell line (EL-4) and neonatal mouse spermatogonial cells in vitro. In this study, the isolated spermatogonial stem cells (SSC) and EL-4 were divided into six groups including control (received medium), sham (received DMSO in medium) and experimental groups which received different doses of cisplatin (0.5, 5, 10 and 15 μg ml(-1) ). Cells viability was evaluated with MTT assay. The identity of the cultured cells was confirmed by the expression of specific markers. Our finding showed that viability of both SSC and EL-4 cells was reduced with the dose of 15 μg/ml when compared to the control group (P ≤ 0.05). Also, the differences between the IC50 in doses 10 and 15 μg/ml at different time were significant (P ≤ 0.05). The number of TUNEL-positive cells was increased, and the BAX and caspase-3 expressions were upregulated in EL4 cells for group that received an effective dose of cisplatin). In conclusion, despite the dramatic effects of cisplatin on both cells, spermatogonial stem cells could form colony in culture. © 2015 Blackwell Verlag GmbH.

Protective role of edaravone against cisplatin-induced ototoxicity in an auditory cell line.

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Im, Gi Jung; Chang, Jiwon; Lee, Sehee; Choi, June; Jung, Hak Hyun; Lee, Hyung Min; Ryu, Sung Hoon; Park, Su Kyoung; Kim, Jin Hwan; Kim, Hyung-Jong

2015-12-01

Edaravone is a neuroprotective agent with a potent free radical scavenging and antioxidant actions. In the present study we investigated the influence of edaravone on cisplatin ototoxicity in auditory cells. Cell viability was determined using a 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide cell proliferation assay. Oxidative stress and apoptosis were assessed by reactive oxygen species (ROS) measurement, Hoechst 33258 staining, caspase-3 activity assay, and immunoblotting of PARP. Pretreatment with 100 μM of edaravone prior to application of 15 μM of cisplatin increased cell viability after 48 h of incubation in HEI-OC1 cells (from 51.9% to 64. 6% viability) and also, attenuated the cisplatin-induced increase in reactive oxygen species (ROS) (from 2.3 fold to 1.9 fold). Edaravone also decreased the activation of caspase-3 and reduced levels of cleaved poly-ADP-ribose polymerase (PARP). We propose that edaravone protects against cisplatin-induced ototoxicity by preventing apoptosis, and limiting ROS production in HEI-OC1 cells. Copyright © 2015 Elsevier B.V. All rights reserved.

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

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Xu, Ning; Zhang, Jianjun; Shen, Conghuan; Luo, Yi; Xia, Lei; Xue, Feng; Xia, Qiang

2012-01-01

Highlights: ► miR-199a-5p levels were significantly decreased after cisplatin treatment. ► Cisplatin treatment induced autophagy activation. ► 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.

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

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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.

Reduced expression of bax in small cell lung cancer cells is not sufficient to induce cisplatin-resistance

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Biagosch J

2010-10-01

Full Text Available Abstract Resistance to cisplatin in the course of chemotherapy contributes to the poor prognosis of small cell lung cancer (SCLC. B cell lymphoma-2 is the founding member of a large family of proteins that either promote or inhibit apoptosis. We aimed at investigating if the pro-apoptotic members Bad, Bax, Bim and Bid are involved in cisplatin-resistance. Cisplatin-resistance in the SCLC cell line H1339 was induced by repetitive exposure to cisplatin. Protein expression was quantified by Western Blot and immuno-fluorescence analysis. Protein expression was altered using siRNA interference. Four "cycles" of 0.5 μg/ml cisplatin led to partial cisplatin-resistance in H1339 cells. The expression of Bad, Bim and Bid was comparable in naïve and resistant cells while the expression of Bax was reduced in the resistant clone. But, reducing Bax expression in naïve cells did not lead to altered cisplatin sensitivity neither in H1339 nor in H187 SCLC cells. We conclude that the reduced Bax expression after exposure to cisplatin is not sufficient to induce cis-platin-resistance in SCLC cells.

Pharmacological Protection From Radiation ± Cisplatin-Induced Oral Mucositis

International Nuclear Information System (INIS)

Cotrim, Ana P.; Yoshikawa, Masanobu; Sunshine, Abraham N.; Zheng Changyu; Sowers, Anastasia L.; Thetford, Angela D.; Cook, John A.; Mitchell, James B.; Baum, Bruce J.

2012-01-01

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, ∼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 × 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.

Antioxidant and antigenotoxic role of recombinant human erythropoeitin against alkylating agents: cisplatin and mitomycin C in cultured Vero cells.

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Rjiba-Touati, Karima; Ayed-Boussema, Imen; Soualeh, Nidhal; Achour, Abdellatif; Bacha, Hassen; Abid, Salwa

2013-08-01

Cisplatin (CDDP) and mitomycin C (MMC), two alkylating agents used against various solid tumours, are a common source of acute kidney injury. Thus, strategies for minimizing CDDP and MMC toxicity are of a clinical interest. In this study, we aimed to investigate the protective role of recombinant human erythropoietin (rhEPO) against oxidative stress and genotoxicity induced by CDDP and MMC in cultured Vero cells. Three types of treatments were performed: (i) cells were treated with rhEPO 24 h before exposure to CDDP/MMC (pre-treatment), (ii) cells were treated with rhEPO and CDDP/MMC simultaneously (co-treatment), (iii) cells were treated with rhEPO 24 h after exposure to CDDP/MMC (post-treatment). Our results showed that rhEPO decreased the reactive oxygen species levels, the malondialdehyde levels and ameliorated glutathione (reduced and oxidized glutathione) modulation induced by CDDP and MMC in cultured Vero cells. Furthermore, rhEPO administration prevented alkylating agents-induced DNA damage accessed by comet test. Altogether, our results suggested a protective role of rhEPO, against CDDP- and MMC-induced oxidative stress and genotoxicity, especially in pre-treatment condition.

Mesenchymal stem cells ameliorate rhabdomyolysis-induced acute kidney injury via the activation of M2 macrophages

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2014-01-01

Introduction The mortality of rhabdomyolysis-induced acute kidney injury (AKI) is still high, as there is no effective therapy. It has been shown that bone marrow-derived mesenchymal stem cells (MSCs) can induce M2 macrophages, which mediate MSC protection in other experimental inflammation-related organ injury. This study was designed to investigate the protective effects of macrophage activation in MSC therapy of rhabdomyolysis-induced AKI. Methods MSCs were injected into glycerol-induced rhabdomyolysis mice. Renal injury was evaluated using the serum creatinine, urea nitrogen, renal pathology and acute tubular necrosis score. The distribution of MSCs was detected using two-photon fluorescence confocal imaging. Immunofluorescence of anti-F4/80 and anti-CD206 was performed to determine macrophages and M2 macrophages in the tissues of the kidney, and M2 macrophage infiltration was also evaluated using western blotting analyses. After depletion of macrophages using clodronate liposomes at the phase of kidney repair, renal injury was re-evaluated. RAW 264.7 macrophages were incubated with lipopolysaccharide and co-cultured with MSCs and subsequently visualised using immunofluorescence staining and flow cytometry analysis. Finally, disparate phenotype macrophages, including normal macrophages (M0), lipopolysaccharide-stimulated macrophages (M1), and MSC-co-cultured macrophages (M2), were infused into mice with AKI, which were pre-treated with liposomal clodronate. Results In vivo infusion of MSCs protected AKI mice from renal function impairment and severe tubular injury, which was accompanied by a time-dependent increase in CD206-positive M2 macrophage infiltration. In addition, depleting macrophages with clodronate delayed restoration of AKI. In vitro, macrophages co-cultured with MSCs acquired an anti-inflammatory M2 phenotype, which was characterised by an increased expression of CD206 and the secretory cytokine interleukin (IL)-10. The concentrations of IL-10, IL

Ultrastructural morphology and localisation of cisplatin-induced platinum-DNA adducts in a cisplatin-sensitive and -resistant human small cell lung cancer cell line using electron microscopy

NARCIS (Netherlands)

Meijer, C; van Luyn, MJA; Nienhuis, EF; Blom, N; Mulder, NH; de Vries, EGE

2001-01-01

Ultrastructural morphology (transmission electron microscopy) and localisation of cisplatin-induced platinum (Pt)-DNA adducts (immunoelectron microscopy) were analysed in the human small cell lung cancer cell line GLC(4) and its 40-fold in vitro acquired cisplatin-resistant subline GLC(4)-CDDP,

Can ebselen prevent cisplatin-induced ovarian damage?

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Soyman, Zeynep; Uzun, Hafize; Bayindir, Nihan; Esrefoglu, Mukaddes; Boran, Birtan

2018-06-01

The occurrence of ovarian damage is a major shortcoming in treating tumors with cisplatin (CP). The present study investigates the beneficial effects of ebselen-a seleno-organic compound with antioxidant and antiinflammatory properties-vis-à-vis CP-induced ovarian damage. Twenty-eight adult female rats were divided into four study groups. Group 1 received no treatment. The rats in Groups 2, 3, and 4 were intraperitoneally administered CP (2 mg/kg/day) twice per week, for 5 weeks. Those in Group 2 received 0.3 ml saline (0.9% NaCl) intraperitoneally 60 min before each CP treatment, while those in Group 3 received 0.2 ml dimethyl sulfoxide (DMSO) and 0.3 ml saline intraperitoneally 60 min before each CP treatment. The rats in Group 4 were pretreated with an intraperitoneal injection of 15 mg/kg/day ebselen 60 min before each CP treatment. Ovarian tissue malondialdehyde (MDA), total nitric oxide (NOx), glutathione (GSH), Cu/Zn-superoxide dismutase (Cu/Zn-SOD), and catalase levels, as well as histopathological damage scores (HDSs) and serum antimullerian hormone (AMH) levels, were assessed. Cu/Zn-SOD and GSH levels were significantly higher, and MDA and NOx levels significantly lower, in Group 4 than in Groups 2 and 3. Pretreatment with ebselen significantly improved serum AMH levels, relative to Groups 2 and 3. Additionally, HDS values were significantly lower in Group 4 than in Groups 2 and 3. Our results from using an experimental rat model of CP chemotherapy suggest that ebselen use may ameliorate ovarian damage by preventing oxidative injury.

X-ray analysis of the effect of the 5-HT3 receptor antagonist granisetron on gastrointestinal motility in rats repeatedly treated with the antitumoral drug cisplatin.

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Vera, Gema; López-Pérez, Ana Esther; Martínez-Villaluenga, María; Cabezos, Pablo Antonio; Abalo, Raquel

2014-08-01

Cancer chemotherapy is associated with the development of numerous adverse effects, including nausea, emesis and other alterations in gastrointestinal (GI) motility. The administration of 5-HT3 receptor antagonists has provided a clinical advance in the treatment of chemotherapy-induced vomiting but these drugs lose efficacy throughout chronic treatment. The effects of these drugs in experimental animals under chronic administration are not well known. Our aim was to study, using radiographic methods, the effect of the 5-HT3 receptor antagonist granisetron on GI dysmotility induced in the rat by repeated cisplatin administration. First, invasive methods were used to select a dose of granisetron capable of reducing increased stomach weight due to acute cisplatin administration (6 mg/kg, ip). Second, rats received two intraperitoneal (ip) injections once a week for 4 weeks: granisetron (1 mg/kg, ip) or saline and, thirty min later, saline or cisplatin (2 mg/kg, ip). Body weight gain was measured throughout treatment. Radiological techniques were used to determine the acute (after first dose) and chronic (after last dose) effects of cisplatin and/or granisetron on GI motility. Repeated cisplatin-induced weight loss which granisetron did not prevent. Gastric emptying was delayed after the first cisplatin administration. Granisetron completely prevented this effect. After weekly administration, cisplatin-induced gastric dysmotility was enhanced and granisetron was not capable of completely preventing this effect. Granisetron prevents gastric emptying alterations, but its efficacy decreases throughout antineoplastic treatment. This might be due to the enhanced effect of cisplatin.

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

African Journals Online (AJOL)

JTEkanem

2008-12-14

Dec 14, 2008 ... of reduced glutathione in the liver and kidney over controls (p < 0.05). Cisplatin also caused a ..... Hydroperoxide-induced hepatic toxicity in rats. Food Chem. ... effects of Artemisia absinthium on acetaminophen and CCl. 4. –.

Acute fibrinous and organising pneumonia: a rare histopathological variant of chemotherapy-induced lung injury.

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Gupta, Arjun; Sen, Shiraj; Naina, Harris

2016-04-06

Bleomycin-induced lung injury is the most common chemotherapy-associated lung disease, and is linked with several histopathological patterns. Acute fibrinous and organising pneumonia (AFOP) is a relatively new and rare histological pattern of diffuse lung injury. We report the first known case of bleomycin-induced AFOP. A 36-year-old man with metastatic testicular cancer received three cycles of bleomycin, etoposide and cisplatin, before being transitioned to paclitaxel, ifosfamide and cisplatin. He subsequently presented with exertional dyspnoea, cough and pleuritic chest pain. CT of the chest demonstrated bilateral ground glass opacities with peribronchovascular distribution and pulmonary function tests demonstrated a restrictive pattern of lung disease with impaired diffusion. Transbronchial biopsy revealed intra-alveolar fibrin deposits with organising pneumonia, consisting of intraluminal loose connective tissue consistent with AFOP. The patient received high-dose corticosteroids with symptomatic and radiographic improvement. AFOP should be recognised as a histopathological variant of bleomycin-induced lung injury. 2016 BMJ Publishing Group Ltd.

Squalene Selectively Protects Mouse Bone Marrow Progenitors Against Cisplatin and Carboplatin-Induced Cytotoxicity In Vivo Without Protecting Tumor Growth

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Bikul Das

2008-10-01

Full Text Available Squalene, an isoprenoid antioxidant is a potential cytoprotective agent against chemotherapy-induced toxicity. We have previously published that squalene protects light-density bone marrow cells against cis-diamminedichloroplatinum( II (cisplatin-induced toxicity without protecting tumor cells in vitro. Here, we developed an in vivo mouse model of cisplatin and cis-diammine (cyclobutane-1,1-dicarboxylato platinum(II (carboplatin-induced toxicity to further investigate squalene-mediated LD-BM cytoprotection including the molecular mechanism behind selective cytoprotection. We found that squalene significantly reduced the body weight loss of cisplatin and carboplatin-treated mice. Light-density bone marrow cells from squalene-treated mice exhibited improved formation of hematopoietic colonies (colony-forming unit-granulocyte macrophage. Furthermore, squalene also protected mesenchymal stem cell colonies (colony-forming unit-fibroblast from cisplatin and carboplatin-induced toxicity. Squalene-induced protection was associated with decreased reactive oxygen species and increased levels of glutathione and glutathione peroxidase/glutathione-S-transferase. Importantly, squalene did not protect neuroblastoma, small cell carcinoma, or medulloblastoma xenografts against cisplatin-induced toxicity. These results suggest that squalene is a potential candidate for future development as a cytoprotective agent against chemotherapeutic toxicity.

Evaluation of the protective effect of agmatine against cisplatin nephrotoxicity with 99mTc-DMSA renal scintigraphy and cystatin-C.

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Salihoglu, Yavuz Sami; Elri, Tarik; Gulle, Kanat; Can, Murat; Aras, Mustafa; Ozacmak, Hale Sayan; Cabuk, Mehmet

2016-10-01

The aim of the current study was to investigate whether agmatine (AGM) has a protective effect against cisplatin-induced nephrotoxicity. Thirty-two rats were randomly divided into four groups: (1) Saline (control); (2) Cisplatin (CDDP; 7.5 mg/kg intraperitoneally); (3) Agmatine (AGM; 10 mg/kg intraperitoneally); (4) Cisplatin plus agmatine (CDDP + AGM). Agmatine was given before and two consecutive days after cisplatin injection. All the animals underwent renal scintigraphy with 99mTc-DMSA. The levels of serum creatinine, cystatin C, and blood urea nitrogen (BUN) were measured in addition to examination of the tissue samples with light microscopy. Acute renal injury was assessed with biochemical analyses, scintigraphic imaging, and histopathological evaluation. In the cisplatin group, the levels of BUN, creatinine, and cystatin C were significantly higher than that of the controls. Histopathological examination showed remarkable damage of tubular and glomerular structures. Additionally, cisplatin caused markedly decreased renal 99mTc-DMSA uptake. AGM administration improved renal functions. Serum creatinine, BUN, and cystatin C levels had a tendency to normalize and, scintigraphic and histopathological findings showed significantly less evidence of renal toxicity than those observed in animals receiving cisplatin alone. Our data indicate that AGM has a protective effect against cisplatin-induced nephrotoxicity. Therefore, it may improve the therapeutic index of cisplatin. In addition, the early renal damage induced by cisplatin and protective effects of AGM against cisplatin nephrotoxicity was accurately demonstrated with 99mTc-DMSA renal scintigraphy.

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

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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.

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.

Edaravone alleviates cisplatin-induced neurobehavioral deficits via modulation of oxidative stress and inflammatory mediators in the rat hippocampus.

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Jangra, Ashok; Kwatra, Mohit; Singh, Tavleen; Pant, Rajat; Kushwah, Pawan; Ahmed, Sahabuddin; Dwivedi, Durgesh; Saroha, Babita; Lahkar, Mangala

2016-11-15

Cisplatin is a chemotherapeutic agent used in the treatment of malignant tumors. A major clinical limitation of cisplatin is its potential toxic effects, including neurotoxicity. Edaravone, a potent free radical scavenger, has been reported to have the neuroprotective effect against neurological deficits. The aim of the present study was to determine the neuroprotective effect of edaravone against cisplatin-induced behavioral and biochemical anomalies in male Wistar rats. Our results showed that cisplatin (5mg/kg/week, i.p.) administration for seven weeks caused marked cognitive deficits and motor incoordination in rats. This was accompanied by oxido-nitrosative stress, neuroinflammation, NF-κB activation and down-regulation of Nrf2/HO-1 gene expression level in the hippocampus. Edaravone (10mg/kg/week, i.p.) treatment for seven weeks inhibited the aforementioned neurobehavioral and neurochemical deficits. Furthermore, edaravone was found to up-regulate the gene expression level of Nrf2/HO-1 and prevented the cisplatin-induced NF-κB activation. These findings demonstrated that oxido-nitrosative stress and inflammatory signaling mediators play a key role in the development of cisplatin-induced neurobehavioral deficits which were prevented by edaravone treatment. Copyright © 2016 Elsevier B.V. All rights reserved.

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

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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 < 0.05) and 27.9%, respectively; the reference drug, metoclopramide (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

Therapeutic potency of bee pollen against biochemical autistic features induced through acute and sub-acute neurotoxicity of orally administered propionic acid.

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Al-Salem, Huda S; Bhat, Ramesa Shafi; Al-Ayadhi, Laila; El-Ansary, Afaf

2016-04-23

It is now well documented that postnatal exposure to certain chemicals has been reported to increase the risk of autism spectrum disorder. Propionic acid (PA), as a metabolic product of gut microbiotaandas a commonly used food additive, has been reported to mediate the effects of autism. Results from animal studies may help to identify environmental neurotoxic agents and drugs that can ameliorate neurotoxicity and may thereby aid in the treatment of autism. The present study investigated the ameliorative effects of natural bee pollen against acute and sub-acute brain intoxication induced by (PA) in rats. Twenty-four young male Western Albino ratswere enrolled in the present study. They were classified into four equal groups, eachwith6 rats. The control group received only phosphate buffered saline; the oral buffered PA-treated groups (II and III) received a neurotoxic dose of 750 mg/kg body weight divided in 3 dose of 250 mg/kg body weight/day serving asthe acute group and 750 mg/kg body weight divided in 10 equal dose of 75 mg/kg body weight/day as the sub-acute group. The fourth group received 50 mg bee pollen for 30 days after PA-acute intoxication. The obtained data showed that the PA-treated groups demonstrated multiple signs of brain toxicity, as indicated by a depletion of serotonin (5HT), dopamine and nor-adrenaline, together withan increase in IFN-γ and caspase 3. Bee pollen was effective in ameliorating the neurotoxic effect of PA. All measured parameters demonstrated minimal alteration in comparison with thecontrol animal than did those of acute and sub-acute PA-treated animals. In conclusion, bee pollen demonstrates anti-inflammatory and anti-apoptotic effects while ameliorating the impaired neurochemistry of PA-intoxicated rats.

Hepatitis B virus enhances cisplatin-induced hepatotoxicity via a mechanism involving suppression of glucose-regulated protein of 78 Kda.

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Zhang, Xiaoxue; Zhang, Rui; Yang, HuiOu; Xiang, Qian; Jiang, Qing; He, Qi; Zhang, Ting; Chen, Chen; Zhu, Huifen; Wang, Qiang; Ning, Qin; Li, Yiwu; Lei, Ping; Shen, Guanxin

2016-07-25

Cisplatin is a classical platinum-based chemotherapeutic drug used in the treatment of many cancer types, including hepatocellular carcinoma (HCC). The application of cisplatin is significantly limited by its toxicity, which may be affected by various biological factors. Persistence of Hepatitis B virus (HBV) infection leads to HCC development and may be associated with higher incidence of severe hepatitis during chemotherapy. However, whether HBV alters the susceptibility of hepatocytes to cisplatin remains poorly understood. Here, we demonstrate that HBV transfection enhanced cisplatin-induced hepatotoxicity via a mechanism involving suppression of glucose-regulated protein of 78 KDa (Grp78), a major stress-induced chaperone that localizes to the endoplasmic reticulum. Silencing Grp78 gene increased the susceptibility of HepG2 to cisplatin by activating caspase-3. Grp78 expression was down-regulated by HBV infection both in vitro and in liver tissues of patients. We compared the cisplatin sensitivity of hepatoma cells either expressing (HepG2.2.15 cells) or not expressing the entire Hepatitis B Virus genome (HepG2). HepG2.2.15 cells showed increased sensitivity to cisplatin and a higher apoptosis rate. Overexpression of Grp78 counteracted the increase of sensitivity of HepG2.215 cells to cisplatin. Furthermore, we found that HBV disrupted Grp78 synthesis in response to cisplatin stimulation, which may trigger severe and prolonged endoplasmic reticulum (ER) stress that can induce cellular apoptosis. Our findings provide new information into the effect of HBV in the modulation of Grp78 expression, and, consequently on cisplatin-induced hepatotoxicity during viral infection. Copyright © 2016. Published by Elsevier Ireland Ltd.

Mechanism of gastrointestinal abnormal motor activity induced by cisplatin in conscious dogs.

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Ando, Hiroyuki; Mochiki, Erito; Ohno, Tetsuro; Yanai, Mitsuhiro; Toyomasu, Yoshitaka; Ogata, Kyoichi; Tabe, Yuichi; Aihara, Ryuusuke; Nakabayashi, Toshihiro; Asao, Takayuki; Kuwano, Hiroyuki

2014-11-14

To investigate whether 5-hydroxytryptamine (serotonin; 5-HT) is involved in mediating abnormal motor activity in dogs after cisplatin administration. After the dogs had been given a 2-wk recovery period, all of them were administered cisplatin, and the motor activity was recorded using strain gauge force transducers. Blood and intestinal fluid samples were collected to measure 5-HT for 24 h. To determine whether 5-HT in plasma or that in intestinal fluids is more closely related to abnormal motor activity we injected 5-HT into the bloodstream and the intestinal tract of the dogs. Cisplatin given intravenously produced abnormal motor activity that lasted up to 5 h. From 3 to 4 h after cisplatin administration, normal intact dogs exhibited retropropagation of motor activity accompanied by emesis. The concentration of 5-HT in plasma reached the peak at 4 h, and that in intestinal fluids reached the peak at 3 h. In normal intact dogs with resection of the vagus nerve that were administered kytril, cisplatin given intravenously did not produce abnormal motor activity. Intestinal serotonin administration did not produce abnormal motor activity, but intravenous serotonin administration did. After the intravenous administration of cisplatin, abnormal motor activity was produced in the involved vagus nerve and in the involved serotonergic neurons via another pathway. This study was the first to determine the relationship between 5-HT and emesis-induced motor activity.

Radiochemotherapy including cisplatin alone versus cisplatin + 5-fluorouracil for locally advanced unresectable stage IV squamous cell carcinoma of the head and neck

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Tribius, Silke; Kilic, Yasemin [Dept. of Radiation Oncology, Univ. Medical Center Hamburg-Eppendorf, Hamburg (Germany); Kronemann, Stefanie [Dept. of Radiation Oncology, Univ. Hospital Schleswig-Holstein, Campus Luebeck (Germany); Schroeder, Ursula [Dept. of Head and Neck Surgery, Univ. Hospital Schleswig-Holstein, Campus Luebeck (Germany); Hakim, Samer [Dept. of Oro-Maxillo-Facial Surgery, Univ. Hospital Schleswig-Holstein, Campus Luebeck (Germany); Schild, Steven E. [Dept. of Radiation Oncology, Mayo Clinic, Scottsdale, AZ (United States); Rades, Dirk [Dept. of Radiation Oncology, Univ. Medical Center Hamburg-Eppendorf, Hamburg (Germany); Dept. of Radiation Oncology, Univ. Hospital Schleswig-Holstein, Campus Luebeck (Germany)

2009-10-15

Background and purpose: the optimal radiochemotherapy regimen for advanced head-and-neck cancer is still debated. This nonrandomized study compares two cisplatin-based radiochemotherapy regimens in 128 patients with locally advanced unresectable stage IV squamous cell carcinoma of the head and neck (SCCHN). Patients and methods: concurrent chemotherapy consisted of either two courses cisplatin (20 mg/m{sup 2}/d1-5 + 29-33; n = 54) or two courses cisplatin (20 mg/m{sup 2}/d1-5 + 29-33) + 5-fluorouracil (5-FU; 600 mg/m{sup 2}/d1-5 + 29-33; n = 74). Results: at least one grade 3 toxicity occurred in 25 of 54 patients (46%) receiving cisplatin alone and in 52 of 74 patients (70%) receiving cisplatin + 5-FU. The latter regimen was particularly associated with increased rates of mucositis (p = 0.027) and acute skin toxicity (p = 0.001). Seven of 54 (13%) and 20 of 74 patients (27%) received only one chemotherapy course due to treatment-related acute toxicity. Late toxicity in terms of xerostomia, neck fibrosis, skin toxicity, and lymphedema was not significantly different. The 2-year locoregional control rates were 67% after cisplatin alone and 52% after cisplatin + 5-FU (p = 0.35). The metastases-free survival rates were 79% and 69%, respectively (p = 0.65), and the overall survival rates 70% and 51%, respectively (p = 0.10). On multivariate analysis, outcome was significantly associated with performance status, T-category, N-category, hemoglobin level prior to radiotherapy, and radiotherapy break > 1 week. Conclusion: two courses of fractionated cisplatin (20 mg/m{sup 2}/day) alone appear preferable, as this regimen resulted in similar outcome and late toxicity as two courses of cisplatin + 5-FU, but in significantly less acute toxicity. (orig.)

Real-time monitoring of cisplatin-induced cell death.

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Hamed Alborzinia

Full Text Available Since the discovery of cisplatin more than 40 years ago and its clinical introduction in the 1970s an enormous amount of research has gone into elucidating the mechanism of action of cisplatin on tumor cells. With a novel cell biosensor chip system allowing continuous monitoring of respiration, glycolysis, and impedance we followed cisplatin treatment of different cancer cell lines in real-time. Our measurements reveal a first effect on respiration, in all cisplatin treated cell lines, followed with a significant delay by interference with glycolysis in HT-29, HCT-116, HepG2, and MCF-7 cells but not in the cisplatin-resistant cell line MDA-MB-231. Most strikingly, cell death started in all cisplatin-sensitive cell lines within 8 to 11 h of treatment, indicating a clear time frame from exposure, first response to cisplatin lesions, to cell fate decision. The time points of most significant changes were selected for more detailed analysis of cisplatin response in the breast cancer cell line MCF-7. Phosphorylation of selected signal transduction mediators connected with cellular proliferation, as well as changes in gene expression, were analyzed in samples obtained directly from sensor chips at the time points when changes in glycolysis and impedance occurred. Our online cell biosensor measurements reveal for the first time the time scale of metabolic response until onset of cell death under cisplatin treatment, which is in good agreement with models of p53-mediated cell fate decision.

The small-molecule TNF-α inhibitor, UTL-5g, delays deaths and increases survival rates for mice treated with high doses of cisplatin.

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Shaw, Jiajiu; Media, Joseph; Chen, Ben; Valeriote, Fredrick

2013-09-01

UTL-5g is a novel small-molecule chemoprotector that lowers hepatotoxicity, nephrotoxicity, and myelotoxicity induced by cisplatin through TNF-α inhibition among other factors. The objective of this study was to investigate whether UTL-5g can reduce the overall acute toxicity of cisplatin and increase cisplatin tolerability in mice. BDF1 female mice were treated individually with UTL-5g (suspended in Ora-Plus) by oral gavage at 60 mg/kg, 30 min before i.p. injection of cisplatin at 10, 15, and 20 mg/kg, respectively, on Day 0. Starting from Day 1, individual mice were again treated daily by the same dose of UTL-5g for 4 consecutive days. Survivals and body weights were monitored. UTL-5g treatment increased the survival rate and delayed the time to death for mice treated with 150 % of the maximum tolerated dose (MTD) of cisplatin (15 mg/kg). Likewise, at 200 % of the MTD of cisplatin (20 mg/kg), treatment of UTL-5g increased the survival rate and delayed the time to death. Treatment of UTL-5g did not have a significant effect on weight loss induced by cisplatin, indicating that body weight may not be a sensitive-enough measure for chemoprotection of UTL-5g against cisplatin. In summary, UTL-5g delayed deaths and increased survival rates of mice treated by high doses of cisplatin, indicating that UTL-5g is capable of reducing the overall acute toxicity of cisplatin and increased cisplatin tolerability in mice; this is in line with the specific chemoprotective effects of UTL-5g previously reported. Further investigation of UTL-5g in combination with cisplatin is warranted.

A novel and selective poly (ADP-ribose polymerase inhibitor ameliorates chemotherapy-induced painful neuropathy.

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Lauren E Ta

Full Text Available Chemotherapy-induced neuropathy is the principle dose limiting factor requiring discontinuation of many chemotherapeutic agents, including cisplatin and oxaliplatin. About 30 to 40% of patients receiving chemotherapy develop pain and sensory changes. Given that poly (ADP-ribose polymerase (PARP inhibition has been shown to provide neuroprotection, the current study was developed to test whether the novel PARP inhibitor compound 4a (analog of ABT-888 would attenuate pain in cisplatin and oxaliplatin-induced neuropathy in mice.An established chemotherapy-induced painful neuropathy model of two weekly cycles of 10 intraperitoneal (i.p. injections separated by 5 days rest was used to examine the therapeutic potential of the PARP inhibitor compound 4a. Behavioral testing using von Frey, paw radiant heat, cold plate, and exploratory behaviors were taken at baseline, and followed by testing at 3, 6, and 8 weeks from the beginning of drug treatment.Cisplatin-treated mice developed heat hyperalgesia and mechanical allodynia while oxaliplatin-treated mice exhibited cold hyperalgesia and mechanical allodynia. Co-administration of 50 mg/kg or 25 mg/kg compound 4a with platinum regimen, attenuated cisplatin-induced heat hyperalgesia and mechanical allodynia in a dose dependent manner. Similarly, co-administration of 50 mg/kg compound 4a attenuated oxaliplatin-induced cold hyperalgesia and mechanical allodynia. These data indicate that administration of a novel PARP inhibitor may have important applications as a therapeutic agent for human chemotherapy-induced painful neuropathy.

A novel and selective poly (ADP-ribose) polymerase inhibitor ameliorates chemotherapy-induced painful neuropathy.

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Ta, Lauren E; Schmelzer, James D; Bieber, Allan J; Loprinzi, Charles L; Sieck, Gary C; Brederson, Jill D; Low, Philip A; Windebank, Anthony J

2013-01-01

Chemotherapy-induced neuropathy is the principle dose limiting factor requiring discontinuation of many chemotherapeutic agents, including cisplatin and oxaliplatin. About 30 to 40% of patients receiving chemotherapy develop pain and sensory changes. Given that poly (ADP-ribose) polymerase (PARP) inhibition has been shown to provide neuroprotection, the current study was developed to test whether the novel PARP inhibitor compound 4a (analog of ABT-888) would attenuate pain in cisplatin and oxaliplatin-induced neuropathy in mice. An established chemotherapy-induced painful neuropathy model of two weekly cycles of 10 intraperitoneal (i.p.) injections separated by 5 days rest was used to examine the therapeutic potential of the PARP inhibitor compound 4a. Behavioral testing using von Frey, paw radiant heat, cold plate, and exploratory behaviors were taken at baseline, and followed by testing at 3, 6, and 8 weeks from the beginning of drug treatment. Cisplatin-treated mice developed heat hyperalgesia and mechanical allodynia while oxaliplatin-treated mice exhibited cold hyperalgesia and mechanical allodynia. Co-administration of 50 mg/kg or 25 mg/kg compound 4a with platinum regimen, attenuated cisplatin-induced heat hyperalgesia and mechanical allodynia in a dose dependent manner. Similarly, co-administration of 50 mg/kg compound 4a attenuated oxaliplatin-induced cold hyperalgesia and mechanical allodynia. These data indicate that administration of a novel PARP inhibitor may have important applications as a therapeutic agent for human chemotherapy-induced painful neuropathy.

Ameliorative influence of Urtica dioica L against cisplatin-induced toxicity in mice bearing Ehrlich ascites carcinoma.

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Özkol, Halil; Musa, Davut; Tuluce, Yasin; Koyuncu, Ismail

2012-07-01

Cisplatin (CP) is a widely used cytotoxic agent against cancer, and high doses of CP have been known to cause nephrotoxicity and hepatotoxicity. Some reports claim that antioxidants can reduce CP-induced toxicity. This study investigated the hepatoprotective, nephroprotective, and antioxidant activity of Urtica dioica L methanolic extract (UDME) against CP toxicity in Erhlich ascites tumor (EAT)-bearing mice. Levels of serum hepatic enzymes, renal function markers, and oxidant/antioxidant parameters of liver tissue were measured. Mice were inoculated with EAT on day 0 and treated with nothing else for 24 hours. After a single dose of CP administration on day 1, the extract was given at the doses of 50, 100, 200, and 400 mg/kg body weight daily during 6 days. Almost all doses of UDME performed a significant (P < 0.05) preventive role against CP toxicity by decreasing aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, blood urea nitrogen, creatinine, lipid peroxidation, protein oxidation levels, and myeloperoxidase activity, as well as increasing reduced glutathione content, superoxide dismutase, catalase, glutathione S-transferase, and glutathione peroxidase activities. This suggests that UDME has a protective capacity and antioxidant activity against CP toxicity in EAT-bearing mice, probably by promoting antioxidative defense systems.

A H2S Donor GYY4137 Exacerbates Cisplatin-Induced Nephrotoxicity in Mice

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Mi Liu

2016-01-01

Full Text Available Accumulating evidence demonstrated that hydrogen sulfide (H2S is highly involved in inflammation, oxidative stress, and apoptosis and contributes to the pathogenesis of kidney diseases. However, the role of H2S in cisplatin nephrotoxicity is still debatable. Here we investigated the effect of GYY4137, a novel slow-releasing H2S donor, on cisplatin nephrotoxicity in mice. Male C57BL/6 mice were pretreated with GYY4137 for 72 h prior to cisplatin injection. After cisplatin treatment for 72 h, mice developed obvious renal dysfunction and kidney injury as evidenced by elevated blood urea nitrogen (BUN and histological damage. Consistently, these mice also showed increased proinflammatory cytokines such as TNF-α, IL-6, and IL-1β in circulation and/or kidney tissues. Meanwhile, circulating thiobarbituric aid-reactive substances (TBARS and renal apoptotic indices including caspase-3, Bak, and Bax were all elevated. However, application of GYY4137 further aggravated renal dysfunction and kidney structural injury in line with promoted inflammation, oxidative stress, and apoptotic response following cisplatin treatment. Taken together, our results suggested that GYY4137 exacerbated cisplatin-induced nephrotoxicity in mice possibly through promoting inflammation, oxidative stress, and apoptotic response.

Role of annexin A5 in cisplatin-induced toxicity in renal cells: molecular mechanism of apoptosis.

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Jeong, Jin-Joo; Park, Nahee; Kwon, Yeo-Jung; Ye, Dong-Jin; Moon, Aree; Chun, Young-Jin

2014-01-24

Annexin A5 belongs to a large family of calcium-binding and phospholipid-binding proteins and may act as an endogenous regulator of various pathophysiological processes. There is increasing evidence that annexin A5 is related to cytotoxicity, but the precise function of this protein has yet to be elucidated. In this study, we aimed to verify the function of annexin A5 in the apoptosis of renal epithelial cells. Real-time PCR and Western blot analysis, together with immunofluorescence analysis, showed that the expression of annexin A5 significantly increased in the presence of cisplatin in both human and rat renal epithelial cells. With regard to the mechanism of cisplatin-induced apoptosis, apoptosis-inducing factor (AIF) release into the cytosol was observed, and the underlying mechanism was identified as voltage-dependent anion channel (VDAC) oligomerization. Mitochondrial membrane potential (Δψm) was found to be greatly disrupted in cisplatin-treated cells. Moreover, cisplatin strongly induced translocation of annexin A5 into mitochondria. To understand the functional significance of annexin A5 in renal cell death, we used a siRNA-mediated approach to knock down annexin A5. Annexin A5 depletion by siRNA led to decreased annexin A5 translocation into mitochondria and significantly reduced VDAC oligomerization and AIF release. Annexin A5 siRNA also increased cell viability compared with the control. Moreover, expression of annexin A5 was induced by other nephrotoxicants such as CdCl2 and bacitracin. Taken together, our data suggest that annexin A5 may play a crucial role in cisplatin-induced toxicity by mediating the mitochondrial apoptotic pathway via the induction and oligomerization of VDAC.

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

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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

Andrographolide Ameliorates Beta-Naphthoflavone-Induced CYP1A Enzyme Activity and Lipid Peroxidation in Hamsters with Acute Opisthorchiasis.

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Udomsuk, Latiporn; Chatuphonprasert, Waranya; Jarukamjorn, Kanokwan; Sithithaworn, Paiboon

2016-01-01

Opisthorchis viverrini (OV) infection generates oxidative stress/free radicals and is considered as a primary cause ofcholangiocarcinoma since it primarily triggers sclerosing cholangitis. In this study, the impacts of andrographolide on acute opisthorchaisis in β-naphthoflavone (BNF)-exposed hamsters were investigated. Ethoxyresorufin O-deethylase (EROD) and methoxyresorufin O-demethylase (MROD) activities and Thiobarbituric acid reaction substances (TBARS) assay of andrographolide in acute opisthorchiasis in the BNF-exposed hamsters were assessed. The results showed that andrographolide ameliorated the hepatic CYP1A1 and CYP1A2 activities by decreases of the specific enzymatic reactions of EROD and MROD, respectively, in the BNF-exposed hamsters. Moreover, andrographolide lowered the formation of malondialdehyde in the livers and brains of the hamsters. These observations revealed the promising chemo-protective and antioxidant activities of andrographolide via suppression of the specific EROD and MROD reactions and lipid peroxidation against acute opisthorchiasis in the BNF-exposed hamsters.

D-Methionine attenuated cisplatin-induced vestibulotoxicity through altering ATPase activities and oxidative stress in guinea pigs

International Nuclear Information System (INIS)

Cheng, P.-W.; Liu, S.-H.; Young, Y.-H.; Lin-Shiau, Shoei-Yn

2006-01-01

Cisplatin has been used as a chemotherapeutic agent to treat many kinds of malignancies. Its damage to the vestibulo-ocular reflex (VOR) system has been reported. However, the underlying biochemical change in the inner ear or central vestibular nervous system is not fully understood. In this study, we attempted to examine whether cisplatin-induced vestibulotoxicity and D-methionine protection were correlated with the changes of ATPase activities and oxidative stress of ampullary tissue of vestibules as well as cerebellar cortex (the inhibitory center of VOR system) of guinea pigs. By means of a caloric test coupled with electronystagmographic recordings, we found that cisplatin exposure caused a dose-dependent (1, 3, or 5 mg/kg) vestibular dysfunction as revealed by a decrease of slow phase velocity (SPV). In addition, cisplatin significantly inhibited the Na + , K + -ATPase and Ca 2+ -ATPase activities in the ampullary tissue with a good dose-response relationship but not those of cerebellar cortex. Regression analysis indicated that a decrease of SPV was well correlated with the reduction of Na + , K + -ATPase and Ca 2+ -ATPase activities of the ampullary tissue. D-Methionine (300 mg/kg) reduced both abnormalities of SPV and ATPase activities in a correlated manner. Moreover, cisplatin exposure led to a significant dose-dependent increase of lipid peroxidation and nitric oxide concentrations of the vestibules, which could be significantly suppressed by D-methionine. However, cisplatin did not alter the levels of lipid peroxidation and nitric oxide of the cerebellum. In conclusion, cisplatin inhibited ATPase activities and increased oxidative stress in guinea pig vestibular labyrinths. D-Methionine attenuated cisplatin-induced vestibulotoxicity associated with ionic disturbance through its antioxidative property

Activation of PPARα by Wy-14643 ameliorates systemic lipopolysaccharide-induced acute lung injury

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Yoo, Seong Ho; Abdelmegeed, Mohamed A.; Song, Byoung-Joon

2013-01-01

Highlights: •Activation of PPARα attenuated LPS-mediated acute lung injury. •Pretreatment with Wy-14643 decreased the levels of IFN-γ and IL-6 in ALI. •Nitrosative stress and lipid peroxidation were downregulated by PPARα activation. •PPARα agonists may be potential therapeutic targets for acute lung injury. -- Abstract: Acute lung injury (ALI) is a major cause of mortality and morbidity worldwide. The activation of peroxisome proliferator-activated receptor-α (PPARα) by its ligands, which include Wy-14643, has been implicated as a potential anti-inflammatory therapy. To address the beneficial efficacy of Wy-14643 for ALI along with systemic inflammation, the in vivo role of PPARα activation was investigated in a mouse model of lipopolysaccharide (LPS)-induced ALI. Using age-matched Ppara-null and wild-type mice, we demonstrate that the activation of PPARα by Wy-14643 attenuated LPS-mediated ALI. This was evidenced histologically by the significant alleviation of inflammatory manifestations and apoptosis observed in the lung tissues of wild-type mice, but not in the corresponding Ppara-null mice. This protective effect probably resulted from the inhibition of LPS-induced increases in pro-inflammatory cytokines and nitroxidative stress levels. These results suggest that the pharmacological activation of PPARα might have a therapeutic effect on LPS-induced ALI

Activation of PPARα by Wy-14643 ameliorates systemic lipopolysaccharide-induced acute lung injury

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Yoo, Seong Ho, E-mail: yoosh@snu.ac.kr [Seoul National University Hospital, Biomedical Research Institute and Institute of Forensic Medicine, Seoul National University College of Medicine, Seoul (Korea, Republic of); Abdelmegeed, Mohamed A. [Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD (United States); Song, Byoung-Joon, E-mail: bj.song@nih.gov [Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD (United States)

2013-07-05

Highlights: •Activation of PPARα attenuated LPS-mediated acute lung injury. •Pretreatment with Wy-14643 decreased the levels of IFN-γ and IL-6 in ALI. •Nitrosative stress and lipid peroxidation were downregulated by PPARα activation. •PPARα agonists may be potential therapeutic targets for acute lung injury. -- Abstract: Acute lung injury (ALI) is a major cause of mortality and morbidity worldwide. The activation of peroxisome proliferator-activated receptor-α (PPARα) by its ligands, which include Wy-14643, has been implicated as a potential anti-inflammatory therapy. To address the beneficial efficacy of Wy-14643 for ALI along with systemic inflammation, the in vivo role of PPARα activation was investigated in a mouse model of lipopolysaccharide (LPS)-induced ALI. Using age-matched Ppara-null and wild-type mice, we demonstrate that the activation of PPARα by Wy-14643 attenuated LPS-mediated ALI. This was evidenced histologically by the significant alleviation of inflammatory manifestations and apoptosis observed in the lung tissues of wild-type mice, but not in the corresponding Ppara-null mice. This protective effect probably resulted from the inhibition of LPS-induced increases in pro-inflammatory cytokines and nitroxidative stress levels. These results suggest that the pharmacological activation of PPARα might have a therapeutic effect on LPS-induced ALI.

Plant-Derived Agents for Counteracting Cisplatin-Induced Nephrotoxicity

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Ojha, Shreesh; Venkataraman, Balaji; Kurdi, Amani; Mahgoub, Eglal; Sadek, Bassem; Rajesh, Mohanraj

2016-01-01

Cisplatin (CSP) is a chemotherapeutic agent commonly used to treat a variety of malignancies. The major setback with CSP treatment is that its clinical efficacy is compromised by its induction of organ toxicity, particular to the kidneys and ears. Despite the significant strides that have been made in understanding the mechanisms underlying CSP-induced renal toxicity, advances in developing renoprotective strategies are still lacking. In addition, the renoprotective approaches described in th...

Induced hypernatraemia is protective in acute lung injury.

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Bihari, Shailesh; Dixon, Dani-Louise; Lawrence, Mark D; Bersten, Andrew D

2016-06-15

Sucrose induced hyperosmolarity is lung protective but the safety of administering hyperosmolar sucrose in patients is unknown. Hypertonic saline is commonly used to produce hyperosmolarity aimed at reducing intra cranial pressure in patients with intracranial pathology. Therefore we studied the protective effects of 20% saline in a lipopolysaccharide lung injury rat model. 20% saline was also compared with other commonly used fluids. Following lipopolysaccharide-induced acute lung injury, male Sprague Dawley rats received either 20% hypertonic saline, 0.9% saline, 4% albumin, 20% albumin, 5% glucose or 20% albumin with 5% glucose, i.v. During 2h of non-injurious mechanical ventilation parameters of acute lung injury were assessed. Hypertonic saline resulted in hypernatraemia (160 (1) mmol/l, mean (SD)) maintained through 2h of ventilation, and in amelioration of lung oedema, myeloperoxidase, bronchoalveolar cell infiltrate, total soluble protein and inflammatory cytokines, and lung histological injury score, compared with positive control and all other fluids (p ≤ 0.001). Lung physiology was maintained (conserved PaO2, elastance), associated with preservation of alveolar surfactant (p ≤ 0.0001). Independent of fluid or sodium load, induced hypernatraemia is lung protective in lipopolysaccharide-induced acute lung injury. Copyright © 2016 Elsevier B.V. All rights reserved.

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

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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.

Glutamate Receptors in the Central Nucleus of the Amygdala Mediate Cisplatin-Induced Malaise and Energy Balance Dysregulation through Direct Hindbrain Projections.

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Alhadeff, Amber L; Holland, Ruby A; Nelson, Alexandra; Grill, Harvey J; De Jonghe, Bart C

2015-08-05

Cisplatin chemotherapy is used commonly to treat a variety of cancers despite severe side effects such as nausea, vomiting, and anorexia that compromise quality of life and limit treatment adherence. The neural mechanisms mediating these side effects remain elusive despite decades of clinical use. Recent data highlight the dorsal vagal complex (DVC), lateral parabrachial nucleus (lPBN), and central nucleus of the amygdala (CeA) as potential sites of action in mediating the side effects of cisplatin. Here, results from immunohistochemical studies in rats identified a population of cisplatin-activated DVC neurons that project to the lPBN and a population of cisplatin-activated lPBN calcitonin gene-related peptide (CGRP, a marker for glutamatergic neurons in the lPBN) neurons that project to the CeA, outlining a neuroanatomical circuit that is activated by cisplatin. CeA gene expressions of AMPA and NMDA glutamate receptor subunits were markedly increased after cisplatin treatment, suggesting that CeA glutamate receptor signaling plays a role in mediating cisplatin side effects. Consistent with gene expression results, behavioral/pharmacological data showed that CeA AMPA/kainate receptor blockade attenuates cisplatin-induced pica (a proxy for nausea/behavioral malaise in nonvomiting laboratory rodents) and that CeA NMDA receptor blockade attenuates cisplatin-induced anorexia and body weight loss in addition to pica, demonstrating that glutamate receptor signaling in the CeA is critical for the energy balance dysregulation caused by cisplatin treatment. Together, these data highlight a novel circuit and CGRP/glutamatergic mechanism through which cisplatin-induced malaise and energy balance dysregulation are mediated. To treat cancer effectively, patients must follow prescribed chemotherapy treatments without interruption, yet most cancer treatments produce side effects that devastate quality of life (e.g., nausea, vomiting, anorexia, weight loss). Although hundreds of

Glutamate Receptors in the Central Nucleus of the Amygdala Mediate Cisplatin-Induced Malaise and Energy Balance Dysregulation through Direct Hindbrain Projections

Science.gov (United States)

Alhadeff, Amber L.; Holland, Ruby A.; Nelson, Alexandra; Grill, Harvey J.

2015-01-01

Cisplatin chemotherapy is used commonly to treat a variety of cancers despite severe side effects such as nausea, vomiting, and anorexia that compromise quality of life and limit treatment adherence. The neural mechanisms mediating these side effects remain elusive despite decades of clinical use. Recent data highlight the dorsal vagal complex (DVC), lateral parabrachial nucleus (lPBN), and central nucleus of the amygdala (CeA) as potential sites of action in mediating the side effects of cisplatin. Here, results from immunohistochemical studies in rats identified a population of cisplatin-activated DVC neurons that project to the lPBN and a population of cisplatin-activated lPBN calcitonin gene-related peptide (CGRP, a marker for glutamatergic neurons in the lPBN) neurons that project to the CeA, outlining a neuroanatomical circuit that is activated by cisplatin. CeA gene expressions of AMPA and NMDA glutamate receptor subunits were markedly increased after cisplatin treatment, suggesting that CeA glutamate receptor signaling plays a role in mediating cisplatin side effects. Consistent with gene expression results, behavioral/pharmacological data showed that CeA AMPA/kainate receptor blockade attenuates cisplatin-induced pica (a proxy for nausea/behavioral malaise in nonvomiting laboratory rodents) and that CeA NMDA receptor blockade attenuates cisplatin-induced anorexia and body weight loss in addition to pica, demonstrating that glutamate receptor signaling in the CeA is critical for the energy balance dysregulation caused by cisplatin treatment. Together, these data highlight a novel circuit and CGRP/glutamatergic mechanism through which cisplatin-induced malaise and energy balance dysregulation are mediated. SIGNIFICANCE STATEMENT To treat cancer effectively, patients must follow prescribed chemotherapy treatments without interruption, yet most cancer treatments produce side effects that devastate quality of life (e.g., nausea, vomiting, anorexia, weight loss

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 ...

Hederagenin Induces Apoptosis in Cisplatin-Resistant Head and Neck Cancer Cells by Inhibiting the Nrf2-ARE Antioxidant Pathway.

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Kim, Eun Hye; Baek, Seungho; Shin, Daiha; Lee, Jaewang; Roh, Jong-Lyel

2017-01-01

Acquired resistance to cisplatin is the most common reason for the failure of cisplatin chemotherapy. Hederagenin, triterpenoids extracted from ivy leaves, exhibits antitumor activity in various types of cancer. However, the therapeutic potential of hederagenin in head and neck cancer (HNC) has remained unclear. Therefore, we examined the effects of hederagenin in cisplatin-resistant HNC cells and characterized its molecular mechanisms of action in this context. We evaluated the effects of hederagenin treatment on cell viability, apoptosis, reactive oxygen species (ROS) production, glutathione levels, mitochondrial membrane potential (Δ Ψ m), and protein and mRNA expression in HNC cells. The antitumor effect of hederagenin in mouse tumor xenograft models was also analyzed. Hederagenin selectively induced cell death in both cisplatin-sensitive and cisplatin-resistant HNC cells by promoting changes in Δ Ψ m and inducing apoptosis. Hederagenin inhibited the Nrf2-antioxidant response element (ARE) pathway and activated p53 in HNC cells, thereby enhancing ROS production and promoting glutathione depletion. These effects were reversed by the antioxidant trolox. Hederagenin activated intrinsic apoptotic pathways via cleaved PARP, cleaved caspase-3, and Bax. The selective inhibitory effects of hederagenin were confirmed in cisplatin-resistant HNC xenograft models. These data suggest that hederagenin induces cell death in resistant HNC cells via the Nrf2-ARE antioxidant pathway.

Aprepitant plus granisetron and dexamethasone for prevention of chemotherapy-induced nausea and vomiting in patients with gastric cancer treated with S-1 plus cisplatin.

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Oyama, Katsunobu; Fushida, Sachio; Kaji, Masahide; Takeda, Toshiya; Kinami, Shinichi; Hirono, Yasuo; Yoshimoto, Katsuhiro; Yabushita, Kazuhisa; Hirosawa, Hisashi; Takai, Yuki; Nakano, Tatsuo; Kimura, Hironobu; Yasui, Toshiaki; Tsuneda, Atsushi; Tsukada, Tomoya; Kinoshita, Jun; Fujimura, Takashi; Ohta, Tetsuo

2013-11-01

We aimed to evaluate the efficacy of a new combination antiemetic therapy comprising aprepitant, granisetron, and dexamethasone in gastric cancer patients undergoing chemotherapy with cisplatin and S-1. Gastric cancer patients scheduled to receive their first course of chemotherapy with cisplatin (60 mg/m(2)) and S-1 (80 mg/m(2)) were treated with a new combination antiemetic therapy aprepitant, granisetron, and dexamethasone on day 1; aprepitant and dexamethasone on days 2 and 3; and dexamethasone on day 4. The patients reported vomiting, nausea, use of rescue therapy, and change in the amount of diet intake, and completed the Functional Living Index-Emesis (FLIE) questionnaire. The primary endpoint was complete response (CR; no emesis and use of no rescue antiemetics) during the overall study phase (0-120 h after cisplatin administration). The secondary endpoints included complete protection (CP; CR plus no significant nausea); change in the amount of diet intake; and the impact of chemotherapy-induced nausea and vomiting (CINV) on daily life during the overall, acute (0-24 h), and delayed (24-120 h) phases. Fifty-three patients were included. CR was achieved in 88.7, 98.1, and 88.7% of patients in the overall, acute, and delayed phases, respectively. The corresponding rates of CP were 67.9, 96.2, and 67.9%. Approximately half of the patients had some degree of anorexia. FLIE results indicated that 79.5% of patients reported "minimal or no impact of CINV on daily life". Addition of aprepitant to standard antiemetic therapy was effective in gastric cancer patients undergoing treatment with cisplatin and S-1.

Effects of a histamine H4 receptor antagonist on cisplatin-induced anorexia in mice.

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Yamamoto, Kouichi; Okui, Rikuya; Yamatodani, Atsushi

2018-04-12

Cancer chemotherapy often induces gastrointestinal symptoms such as anorexia, nausea, and vomiting. Antiemetic agents are effective in inhibiting nausea and vomiting, but patients still experience anorexia. We previously reported that chemotherapeutic agent-induced anorexia is associated with an increase of inflammatory cytokines. Other studies also reported that antagonism of the histamine H 4 receptor is anti-inflammatory. In this study, we investigated the involvement of the H 4 receptor in the development of chemotherapy-induced anorexia in mice. Cisplatin-induced anorexia occurred within 24 h of its administration and continued for 3 days. The early phase (day 1), but not the delayed phase (days 2 and 3), of anorexia was inhibited by the daily injection of a 5-HT 3 receptor antagonist (granisetron). However, a corticosteroid (dexamethasone) or selective H 4 receptor antagonist (JNJ7777120) abolished the delayed phases of anorexia. Cisplatin significantly increased TNF-α mRNA expression in the hypothalamus and spleen, and the period of expression increase paralleled the onset period of anorexia. In addition, pretreatment with JNJ7777120 completely inhibited the increased expression. These results suggest that TNF-α mRNA expression via H 4 receptors may contribute to the development of cisplatin-induced anorexia, and that H 4 receptor antagonists are potentially useful treatments. Copyright © 2018 Elsevier B.V. All rights reserved.

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

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Rainey, Robert N.; Ng, Sum-yan; Llamas, Juan; van der Horst, Gijsbertus T. J.

2016-01-01

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. SIGNIFICANCE STATEMENT The utility of cisplatin in chemotherapy remains limited due to serious side effects, including

Evaluation of the Role of Ginger, Cisplatin and Radiation in the Treatment of Chemically- Induced Cancer in Male Albino Rats

International Nuclear Information System (INIS)

Mohamed, Sh.M.G.

2015-01-01

This study aimed to investigate the effect of dietary supplementation with ginger to evaluate its therapeutic effect against lung and kidney cancer and in combination with cisplatin as chemotherapy and radiotherapy in male Wistar albino rats (Rattus norvegicus). Studies involve investigating the therapeutic role of ginger for better restoration of certain haematological parameters: (white blood cells count, red blood cells count, haemoglobin content, hematocrit value and platelets count ) Besides biochemical parameters (serum tumor necrosis factor alpha (TNF-α) level, advanced oxidative protein product (AOPP), urea, creatinine and uric acid ). Tissue parameters in both kidney and lung tissues: were estimated by determining the activity of antioxidant enzyme superoxide dismutase (SOD); as well as by determining the levels of reduced glutathione (GSH), Malondialdehyde (MDA) and Nitric oxide (NO) and histopathological changes of kidney and lung tissues. Cancer induced a significant decrease in WBCs, RBCs, Hb, Hct value and platelets count with a significant increase in the serum tumor necrosis factor alpha (TNF-α) level, advanced oxidative protein product (AOPP), urea, creatinine and uric acid. Besides, it produced high levels of lung and kidney Malondialdehyde (MDA) and Nitric oxide (NO) with significant decrease in reduced glutathione (GSH) and superoxide dismutase (SOD). Ginger + cisplatin + radiation manifested good amelioration against NDMA + CCl 4 group in the studied haematological and biochemical parameters. In histological investigation showed that rat groups treated with ginger alone showed no deviation from control group. While rats injected with NDMA + CCl 4 showed sever degenerative changes. On the other hand, groups injected with NDMA + CCl4 and treated with ginger + cisplatin + radiation group showed an even more remarkable effect showing histopathological lung and kidney profiles close to those of the control group when compared with NDMA + CCl 4

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

International Nuclear Information System (INIS)

Li, Qing; Guo, Dong; Dong, Zhongqi; Zhang, Wei; Zhang, Lei; Huang, Shiew-Mei; Polli, James E.; Shu, Yan

2013-01-01

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 3 ) receptor antagonists, such as ondansetron, should be investigated in patients. - Highlights: • Nephrotoxicity significantly limits clinical use of the chemotherapeutic cisplatin

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

Herbal medicines for the treatment of cancer chemotherapy-induced side effects

OpenAIRE

Ohnishi, Shunsuke; Takeda, Hiroshi

2015-01-01

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 o...

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

Protective effects of vitamins E, B and C and L-carnitine in the prevention of cisplatin-induced ototoxicity in rats.

Science.gov (United States)

Tokgöz, S Alicura; Vuralkan, E; Sonbay, N D; Çalişkan, M; Saka, C; Beşalti, Ö; Akin, İ

2012-05-01

This experimental study aimed to investigate the effects of vitamins E, B and C and L-carnitine in preventing cisplatin-induced ototoxicity. Twenty-five adult, male, Wistar albino rats were randomly allocated to receive intraperitoneal cisplatin either alone or preceded by vitamins B, E or C or L-carnitine. Auditory brainstem response (i.e. hearing thresholds and wave I-IV intervals) and distortion product otoacoustic emissions (i.e. signal-to-noise ratios) were recorded before and 72 hours after cisplatin administration. The following statistically significant differences were seen: control group pre- vs post-treatment wave I-IV interval values (p vitamin E and B groups' I-IV interval values (p vitamin E vs vitamin B and C and L-carnitine groups' hearing thresholds (p vitamin B vs vitamin C and L-carnitine groups' hearing thresholds (p vitamin B and L-carnitine groups (2000 and 3000 Hz; p Vitamins B, E and C and L-carnitine appear to reduce cisplatin-induced ototoxicity in rats. The use of such additional treatments to decrease cisplatin-induced ototoxicity in humans is still under discussion.

Hederagenin Induces Apoptosis in Cisplatin-Resistant Head and Neck Cancer Cells by Inhibiting the Nrf2-ARE Antioxidant Pathway

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Eun Hye Kim

2017-01-01

Full Text Available Acquired resistance to cisplatin is the most common reason for the failure of cisplatin chemotherapy. Hederagenin, triterpenoids extracted from ivy leaves, exhibits antitumor activity in various types of cancer. However, the therapeutic potential of hederagenin in head and neck cancer (HNC has remained unclear. Therefore, we examined the effects of hederagenin in cisplatin-resistant HNC cells and characterized its molecular mechanisms of action in this context. We evaluated the effects of hederagenin treatment on cell viability, apoptosis, reactive oxygen species (ROS production, glutathione levels, mitochondrial membrane potential (ΔΨm, and protein and mRNA expression in HNC cells. The antitumor effect of hederagenin in mouse tumor xenograft models was also analyzed. Hederagenin selectively induced cell death in both cisplatin-sensitive and cisplatin-resistant HNC cells by promoting changes in ΔΨm and inducing apoptosis. Hederagenin inhibited the Nrf2-antioxidant response element (ARE pathway and activated p53 in HNC cells, thereby enhancing ROS production and promoting glutathione depletion. These effects were reversed by the antioxidant trolox. Hederagenin activated intrinsic apoptotic pathways via cleaved PARP, cleaved caspase-3, and Bax. The selective inhibitory effects of hederagenin were confirmed in cisplatin-resistant HNC xenograft models. These data suggest that hederagenin induces cell death in resistant HNC cells via the Nrf2-ARE antioxidant pathway.

Acute cold hypersensitivity characteristically induced by oxaliplatin is caused by the enhanced responsiveness of TRPA1 in mice

Directory of Open Access Journals (Sweden)

Zhao Meng

2012-07-01

Full Text Available Abstract Background Oxaliplatin, a platinum-based chemotherapeutic agent, causes an unusual acute peripheral neuropathy. Oxaliplatin-induced acute peripheral neuropathy appears in almost all patients rapidly after infusion, and is triggered or exacerbated by cold, while its mechanisms are poorly understood. In this study, the involvement of thermosensitive transient receptor potential channels (TRPA1, TRPM8 and TRPV1 in oxaliplatin-induced acute hypersensitivity was investigated in mice. Results A single intraperitoneal administration of oxaliplatin (1–10 mg/kg induced cold but not mechanical hypersensitivity within 2 h in a dose-dependent manner. Infusion of the oxaliplatin metabolite, oxalate (1.7 mg/kg, also induced acute cold hypersensitivity, while another platinum-based chemotherapeutic agent, cisplatin (5 mg/kg, or the non-platinum-containing chemotherapeutic agent, paclitaxel (6 mg/kg failed to induce mechanical or cold hypersensitivity. The oxaliplatin-induced acute cold hypersensitivity was abolished by the TRPA1 antagonist HC-030031 (100 mg/kg and by TRPA1 deficiency. The nocifensive behaviors evoked by intraplantar injections of allyl-isothiocyanate (AITC; TRPA1 agonist were significantly enhanced in mice treated for 2 h with oxaliplatin (1–10 mg/kg in a dose-dependent manner, while capsaicin (TRPV1 agonist-evoked nocifensive behaviors were not affected. Menthol (TRPM8/TRPA1 agonist-evoked nocifensive-like behaviors were also enhanced by oxaliplatin pretreatment, which were inhibited by TRPA1 deficiency. Similarly, oxalate enhanced, but neither cisplatin nor paclitaxel affected AITC-evoked nocifensive behaviors. Pretreatment of cultured mouse dorsal root ganglia (DRG neurons with oxaliplatin (30–300 μM for 1, 2, or 4 h significantly increased the number of AITC-sensitive neurons in a concentration-dependent manner whereas there was no change in the number of menthol- or capsaicin-sensitive neurons

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,

Cetuximab enhances cisplatin-induced endoplasmic reticulum stress-associated apoptosis in laryngeal squamous cell carcinoma cells by inhibiting expression of TXNDC5.

Science.gov (United States)

Peng, Fusen; Zhang, Hailin; Du, Youhong; Tan, Pingqing

2018-03-01

Cisplatin and cetuximab, an anti‑epidermal growth factor receptor (EGFR) monoclonal humanized antibody, have been used for treatment of laryngeal squamous cell carcinoma (LSCC). It has been demonstrated that cisplatin and inhibition of EGFR signaling may induce endoplasmic reticulum (ER) stress‑associated apoptosis. However, ER protein thioredoxin domain‑containing protein 5 (TXNDC5) reportedly protects cells from ER stress‑associated apoptosis. The present study investigated the interaction between cisplatin, cetuximab and TXNDC5 on ER stress‑associated apoptosis in LSCC cells. AMC‑HN‑8 human LSCC cells with or without TXNDC5 overexpression or knockdown were treated with cisplatin (5, 10, 20 and 40 µM) and/or cetuximab (10, 50, 100 and 150 µg/ml), for 12, 24, 36 and 48 h. Cisplatin and cetuximab concentration‑ and time‑dependently increased and decreased the expression of TXNDC5 in AMC‑HN‑8 cells, respectively. Knockdown of TXNDC5 markedly augmented cisplatin‑induced levels of CCAAT/enhancer‑binding protein homologous protein (CHOP), caspase‑3 activity and apoptosis; while overexpression of TXNDC5 largely eliminated cetuximab‑induced levels of CHOP, caspase‑3 activity and apoptosis. Cisplatin and cetuximab demonstrated a combinatorial effect on increasing the levels of CHOP, caspase‑3 activity and apoptosis, which was largely eliminated by overexpression of TXNDC5 or a reactive oxygen species (ROS) scavenger/antagonist. In addition, promoter/luciferase reporter assays revealed that cisplatin and cetuximab regulated the expression of TXNDC5 at the gene transcription/promoter level. In conclusion, the findings suggested that ER stress‑associated apoptosis is a major mechanism underlying the apoptotic effect of cisplatin and cetuximab on LSCC cells; cetuximab enhanced cisplatin‑induced ER stress‑associated apoptosis in LSCC cells largely by inhibiting the expression of TXNDC5 and thereby increasing ROS production

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

A randomized, double-blind, multicentre study comparing daily 2 and 5 mg of tropisetron for the control of nausea and vomiting induced by low-dose cisplatin- or non-cisplatin-containing chemotherapy

NARCIS (Netherlands)

Wymenga, ANM; vanderGraaf, WTA; Wils, JA; vanHeukelom, LS; vanderLinden, GHM; DullemondWestland, AC; Nooy, M; vanderHeul, C; deBruijn, KM; deVries, EGE

Background: This study compares efficacy safety and tolerability of 2 and 5 mg tropisetron in prevention of nausea and vomiting induced by low-dose cisplatin- or non-cisplatin-containing chemotherapy. Patients and methods: 152 chemotherapy-naive cancer patients were randomized in a double-blind

Resveratrol influences platinum pharmacokinetics: A novel mechanism in protection against cisplatin-induced nephrotoxicity.

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Darwish, Mostafa A; Abo-Youssef, Amira M; Khalaf, Marwa M; Abo-Saif, Ali A; Saleh, Ibrahim G; Abdelghany, Tamer M

2018-06-15

Cisplatin (CP) is a widely used drug in treatment of solid tumors. However, the use of CP was hampered by its serious side effects especially nephrotoxicity. This study aims to investigate the effect of resveratrol (RES) on CP-induced nephrotoxicity, particularly, the effect of RES on CP pharmacokinetics (PKs). Male white albino rats were divided to four group's six rats each. The first group received (1%) tween 80 in normal saline and served as control. The second group received RES (30 mg kg -1 ) per day for 14 consecutive day's i.p. The third and fourth groups were given a single i.p. injection of CP (6 mg kg -1 ) with or without pre-treatment of RES (30 mg kg -1 per day for 14 consecutive days), respectively. Following administration of CP, plasma, urine and kidney platinum concentration were monitored to study PKs of CP. Five days after the CP injection, rats were killed; blood samples were collected; kidneys were dissected; and biochemical, immunohistochemical, and histological examinations were performed. Our results revealed that CP treatment significantly deteriorated kidney functions with subsequent alteration in redox balance of the kidney. On the other hand, RES successfully ameliorated CP-induced kidney injury and recovered normal kidney tissue redox status. Importantly, while RES pre-treatment did not significantly alter the plasma CP level, it dramatically decreased the urine concentration of CP and lowered its accumulation into the kidneys. Moreover, it increased CP plasma half-life (t 1/2 ) with subsequent decrease in its elimination rate constant, indicating an important role of PKs modulation in RES protection against CP-induced renal damage. Taken together, RES may protect the kidney tissue from the deleterious effects of CP through constringe of CP renal accumulation and enhancement of CP-induced oxidative stress. Copyright © 2018 Elsevier B.V. All rights reserved.

Leukocytoclastic vasculitis complicating cisplatin + radiation treatment for laryngeal cancer: a case report.

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Quintanilha, Júlia Coelho França; Visacri, Marília Berlofa; Amaral, Laís Sampaio; Lima, Carmen Silvia Passos; Cintra, Maria Letícia; Moriel, Patricia

2017-12-06

Leukocytoclastic vasculitis is typically mediated by deposition of immune complexes and is related to many causes, including medication. To the best of our knowledge, leukocytoclastic vasculitis related to cisplatin has not yet been described in the scientific literature. We report a rare case of leukocytoclastic vasculitis after the first cycle of high-dose cisplatin chemotherapy in a patient with larynx carcinoma. A 48-year-old Caucasian man with larynx carcinoma received a high-dose of cisplatin monochemotherapy (100 mg/m 2 every 21 days), along with 70 Gy of radiotherapy divided into 35 sessions, as a therapeutic schedule. Twelve days after the first chemotherapy administration and after 8 sessions of radiotherapy (total of 16 Gy), the patient presented with acute onset of palpable purpura in the lower limbs. The patient was hospitalized for 10 days, and during this period, he underwent several examinations to rule out infectious, autoimmune, and neoplastic disorders. A skin biopsy showed leukocytoclastic vasculitis with a positive pattern for IgM and C3, as detected through direct immunofluorescence. Twenty-five days after cisplatin administration, the chemotherapy regimen was changed to carboplatin AUC 5, and the episodes of purpura ceased, reinforcing the hypothesis of an adverse reaction to cisplatin. Cisplatin can induce leukocytoclastic vasculitis and clinicians should be aware of this potential effect for better case management and diagnosis.

Gamma-aminobutyric acid aggravates nephrotoxicity induced by cisplatin in female rats.

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Peysepar, Elham; Soltani, Nepton; Nematbakhsh, Mehdi; Eshraghi-Jazi, Fatemeh; Talebi, Ardeshir

2016-01-01

Cisplatin (CP) is a major antineoplastic drug for treatment of solid tumors. CP-induced nephrotoxicity may be gender-related. This is while gamma-aminobutyric acid (GABA) is an inhibitory neurotransmitter in the central nervous system that has renoprotective impacts on acute renal injury. This study was designed to investigate the protective role of GABA against CP-induced nephrotoxicity in male and female rats. Sixty Wistar male and female rats were used in eight experimental groups. Both genders received GABA (50 μg/kg/day; i. p.) for 14 days and CP (2.5 mg/kg/day; i. p.) was added from day 8 to the end of the study, and they were compared with the control groups. At the end of the study, all animals were sacrificed and the serum levels of blood urea nitrogen (BUN), creatinine (Cr), nitrite, malondialdehyde (MDA), and magnesium (Mg) were measured. The kidney tissue damage was also determined via staining. CP significantly increased the serum levels of Cr and BUN, kidney weight, and kidney tissue damage score in both genders (PGABA did not attenuate these markers in males; even these biomarkers were intensified in females. Serum level of Mg, and testis and uterus weights did not alter in the groups. However, the groups were significantly different in terms of nitrite and MDA levels. It seems that GABA did not improve nephrotoxicity induced by CP-treated rats, and it exacerbated renal damage in female rats.

Emblica extract prevents cisplatin-induced apoptosis in dermal papilla fibroblasts

OpenAIRE

Sudjit Luanpitpong; Varisa Pongrakhananon; Ubonthip Nimmannit; Pithi Chanvorachote

2008-01-01

Cisplatin is a widely prescribed anticancer agent that causes hair loss in patients. Since the dermal papilla (DP) fibroblasts are known to be a key mediator in controlling hair growth and loss, understanding the effect and underlying mechanism of cisplatin on these cells may lead to new strategy for hair loss protection in chemotherapy patients. Less is known regarding the effect of cisplatin on DP fibroblasts. We thus treated DP cells with cisplatin (0-250 mmol/L) and found that cisplatin i...

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

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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 (potolith dysfunction. D-Met attenuated the reduced ATPase activities and increased oxidative stress induced by cisplatin toxicity in the otolith organs. Copyright © 2015 Elsevier Inc. All rights reserved.

Beneficial Effects of Bioactive Compounds in Mulberry Fruits against Cisplatin-Induced Nephrotoxicity

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Dahae Lee

2018-04-01

Full Text Available Mulberry, the fruit of white mulberry tree (Morus alba L., Moraceae, is commonly used in traditional Chinese medicines as a sedative, tonic, laxative, and emetic. In our continuing research of the bioactive metabolites from mulberry, chemical analysis of the fruits led to the isolation of five compounds, 1–5. The compounds were identified as butyl pyroglutamate (1, quercetin 3-O-β-d-glucoside (2, kaempferol 3-O-β-d-rutinoside (3, rutin (4, and 2-phenylethyl d-rutinoside (5 by spectroscopic data analysis, comparing their nuclear magnetic resonance (NMR data with those in published literature, and liquid chromatography–mass spectrometry analysis. The isolated compounds 1–5 were evaluated for their effects on anticancer drug-induced side effects by cell-based assays. Compound 1 exerted the highest protective effect against cisplatin-induced kidney cell damage. This effect was found to be mediated through the attenuation of phosphorylation of c-Jun N-terminal kinase, extracellular signal-regulated kinase, p38, mitogen-activated protein kinase, and caspase-3 in cisplatin-induced kidney cell damage.

Delivery of Placenta-Derived Mesenchymal Stem Cells Ameliorates Ischemia Induced Limb Injury by Immunomodulation

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Bo Zhang

2014-11-01

Full Text Available Background: Peripheral artery disease (PAD is a major health burden in the world. Stem cell-based therapy has emerged as an attractive treatment option in regenerative medicine. In this study, we sought to test the hypothesis that stem cell-based therapy can ameliorate ischemia induced limb injury. Methods: We isolated mesenchymal stem cells derived from human placentas (PMSCs and intramuscularly transplanted them into injured hind limbs. Treatment with PMSCs reduced acute muscle fibers apoptosis induced by ischemia. Results: PMSC treatment significantly enhanced regeneration of the injured hind limb by reducing fibrosis and enhancing running capacity when the animals were subjected to treadmill training. Mechanistically, injected PMSCs can modulate acute inflammatory responses by reducing neutrophil and macrophage infiltration following limb ischemia. ELISA assays further confirmed that PMSC treatment can also reduce pro-inflammatory cytokines, TNF-α and IL-6, and enhance anti-inflammatory cytokine, IL-10 at the injury sites. Conclusion: Taken together, our results demonstrated that PMSCs can be a potential effective therapy for treatment of PAD via immunomodulation.

Cisplatin-Induced Conditioned Taste Aversion: Attenuation by Dexamethasone but not Zacopride or GR38032F

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1992-01-01

SR2-1 Cisplatin-induced conditioned taste aversion: ateuto by dexamethasone but not zacopride or GR38032F Nm I- Paul C Mele, John R. McDonough, David...to 5-H1’, receptor blockade. 5-HT., receptor antagonists; Zacopridc: GR38032F; Desamethasone: Cisplatin: Taste aversion (conditioned) I. Introductlon...intake) was used as the area known as the chemoreceptor trigger zone (Borri- index of the CTA. son, 1974). Moreover. the findings that rats, ferrets

Fentanyl induces autophagy via activation of the ROS/MAPK pathway and reduces the sensitivity of cisplatin in lung cancer cells.

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Yao, Jiaqi; Ma, Chi; Gao, Wei; Liang, Jinxiao; Liu, Chang; Yang, Hongfang; Yan, Qiu; Wen, Qingping

2016-12-01

Cancer pain is the most common complication of lung carcinoma. Opioid agonist fentanyl is widely used for relieving pain in cancer patients, and cisplatin (DDP)‑based chemotherapy is commonly used for the treatment of advanced lung cancer; these two drugs are always used together in lung carcinoma patients. However, the mechanisms and related biological pathways by which fentanyl influences cisplatin sensitivity are relatively poorly reported. Here, we found that fentanyl reduces the sensitivity of cisplatin in human lung cancer cells and induces autophagy. Fentanyl induced reactive oxygen species (ROS) generation and JNK activation. N-acetyl‑L‑cysteine is a ROS scavenger and antioxidant, and the inhibition of JNK with SP600125 prevented fentanyl‑induced autophagy. We also found that 3-methyladenine (3-MA; an autophagy inhibitor) increased the sensitivity of DDP and weakened the inhibition of fentanyl. In conclusion, fentanyl reduces the sensitivity of cisplatin in lung cancer cells through the ROS-JNK-autophagy pathway, whereas the autophagy inhibitor 3-MA may weaken this effect.

Slit2 ameliorates renal inflammation and fibrosis after hypoxia-and lipopolysaccharide-induced epithelial cells injury in vitro

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Zhou, Xiangjun [Department of Urology, Taihe Hospital, Hubei University of Medicine, Hubei (China); Yao, Qisheng, E-mail: yymcyqs@126.com [Department of Urology, Taihe Hospital, Hubei University of Medicine, Hubei (China); Sun, Xinbo; Gong, Xiaoxin; Yang, Yong; Chen, Congbo [Department of Urology, Taihe Hospital, Hubei University of Medicine, Hubei (China); Shan, Guang [Department of Urology, Renmin Hospital of Wuhan University, Hubei (China)

2017-03-01

Hypoxic acute kidney injury (AKI) is often incompletely repaired and leads to chronic kidney disease (CKD), which is characterized by tubulointerstitial inflammation and fibrosis. The Slit2 family of secreted glycoproteins is expressed in the kidney, it has been shown to exert an anti-inflammatory activity and prevent ischemic renal injury in vivo. However, whether Slit2 reduces renal fibrosis and inflammation after hypoxic and inflammatory epithelial cells injury in vitro remains unknown. In this study, we aimed to evaluate whether Slit2 ameliorated fibrosis and inflammation in two renal epithelial cells line challenged with hypoxia and lipopolysaccharide (LPS). Renal epithelial cells were treated with hypoxia and LPS to induce cell injury. Hoechst staining and Western blot analysis was conducted to examine epithelial cells injury. Immunofluorescence staining and Western blot analysis was performed to evaluate tubulointerstitial fibrosis. Real-time polymerase chain reaction (PCR) tested the inflammatory factor interleukin (IL)−1β and tumor necrosis factor (TNF)-α, and Western blot analysis determined the hypoxia-inducible factor (HIF)−1α, Toll-like receptor 4 (TLR4) and nuclear factor (NF)-κB. Results revealed that hypoxia induced epithelial cells apoptosis, inflammatory factor IL-1β and TNF-α release and tubulointerstitial fibrosis. LPS could exacerbate hypoxia -induced epithelial cells apoptosis, IL-1β and TNF-α release and fibrosis. Slit2 reduced the expression of fibronectin, the rate of epithelial cell apoptosis, and the expression of inflammatory factor. Slit2 could also inhibit the expression of TLR4 and NF-κB, but not the expression of HIF-1α. Therefore, Slit2 attenuated inflammation and fibrosis after LPS- and hypoxia-induced epithelial cells injury via the TLR4/NF-κB signaling pathway, but not depending on the HIF-1α signaling pathway. - Highlights: • Slit2 ameliorates inflammation after hypoxia-and LPS-induced epithelial cells injury

Edaravone ameliorates compression-induced damage in rat nucleus pulposus cells.

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Lin, Hui; Ma, Xuan; Wang, Bai-Chuan; Zhao, Lei; Liu, Jian-Xiang; Pu, Fei-Fei; Hu, Yi-Qiang; Hu, Hong-Zhi; Shao, Zeng-Wu

2017-11-15

Edaravone is a strong free radical scavenger most used for treating acute ischemic stroke. In this study we investigated the protective effects and underlying mechanisms of edaravone on compression-induced damage in rat nucleus pulposus (NP) cells. Cell viability was determined using MTT assay methods. NP cell apoptosis was measured by Hoechst 33,258 staining and Annexin V/PI double staining. Intracellular reactive oxygen species (ROS), mitochondrial membrane potential (MMP), and intracellular calcium ([Ca 2+ ] i ) were determined by fluorescent probes DCFH-DA, JC-1 and Fluo-3/AM, respectively. Apoptosis-related proteins (cleaved caspase-3, cytosolic cytochrome c, Bax and Bcl-2) and extracellular matrix proteins (aggrecan and collagen II) were analyzed by western blot. Edaravone attenuated the compression-induced decrease in viability of NP cells in a dose-dependent manner. 33,258 and Annexin V/PI double staining showed that edaravone protected NP cells from compression-induced apoptosis. Further studies confirmed that edaravone protected NP cells against compression-induced mitochondrial pathway of apoptosis by inhibiting overproduction of ROS, collapse of MMP and overload of [Ca 2+ ] i . In addition, edaravone promoted the expression of aggrecan and collagen II in compression-treated NP cells. These results strongly indicate that edaravone ameliorates compression-induced damage in rat nucleus pulposus cells. Edaravone could be a potential new drug for treatment of IDD. Copyright © 2017 Elsevier Inc. All rights reserved.

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...... ascites tumour cells (ELA). Loss of KCl and cell shrinkage are hallmarks in apoptosis and has been shown in EATC. However, we find no reduction in cell volume and only a minor loss of K(+) which is accompanied by net uptake of Na(+) following 18 hours cisplatin exposure in ELA. Glutathione and taurine...

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

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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.

Ameliorative potential of gemfibrozil and silymarin on experimentally induced nephrotoxicity in rats

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A.M. Kabel

2013-12-01

Conclusion: The combination of gemfibrozil and silymarin has protective effects against cisplatin-induced nephrotoxicity in rats better than each of these drugs alone due to anti-inflammatory and antioxidant properties of the used drugs.

Metformin induces an intracellular reductive state that protects oesophageal squamous cell carcinoma cells against cisplatin but not copper-bis(thiosemicarbazones)

International Nuclear Information System (INIS)

Damelin, Leonard Howard; Jivan, Rupal; Veale, Robin Bruce; Rousseau, Amanda Louise; Mavri-Damelin, Demetra

2014-01-01

Oesophageal squamous cell carcinoma (OSCC) is a highly aggressive carcinoma with a poor survival rate. One of the most commonly used chemotherapeutic drugs, cisplatin, displays varied and often poor efficacy in vivo. Therefore, alternative, cost-effective and more efficacious treatments are required. Metformin has been previously shown to reduce proliferative rates in various carcinoma cell lines. We report for the first time, the effect of metformin on OSCC cell proliferation and show that it antagonises cisplatin-induced but not copper-bis(thiosemicarbazone)-induced cytotoxicity in OSCC cells. Cell proliferation and stage of the cell cycle were quantified by trypan blue counts and flow cytometry, respectively. All cytotoxicity measurements were made using the tetrazolium based MTT assay. Metabolic alterations to cells were determined as follows: glycolysis via a lactate dehydrogenase assay, reducing equivalents by MTT reduction and reduced intracellular thiols by monobromobimane-thiol fluorescence, and glutathione depletion using buthionine sulfoximine. Inductively coupled plasma mass spectrometry was used to quantify cisplatin-DNA adduct formation. Metformin was found to reduce cell proliferation significantly in all OSCC cell lines, with an accumulation of cells in G0/G1 phase of the cell cycle. However, metformin significantly protected OSCC cells against cisplatin toxicity. Our results indicate that a major mechanism of metformin-induced cisplatin resistance results from a significant increase in glycolysis, intracellular NAD(P)H levels with a concomitant increase in reduced intracellular thiols, leading to decreased cisplatin-DNA adduct formation. The glutathione synthesis inhibitor buthionine sulfoximine significantly ablated the protective effect of metformin. We subsequently show that the copper-bis(thiosemicarbazones), Cu-ATSM and Cu-GTSM, which are trapped in cells under reducing conditions, cause significant OSCC cytotoxicity, both alone and in

Protective mechanism of Korean Red Ginseng in cisplatin-induced ototoxicity through attenuation of nuclear factor-κB and caspase-1 activation.

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Kim, Su-Jin; Kwak, Hyun Jeong; Kim, Dae-Seung; Choi, Hyun-Myung; Sim, Jung-Eun; Kim, Sung-Hoon; Um, Jae-Young; Hong, Seung-Heon

2015-07-01

Cisplatin is an effective anti-cancer drug; however, one of its side effects is irreversible sensorineural hearing damage. Korean Red Ginseng (KRG) has been used clinically for the treatment of various diseases; however, the underlying mechanism of KRG treatment of ototoxicity has not been studied extensively. The present study aimed to further investigate the mechanism of KRG on cisplatin-induced toxicity in auditory HEI-OC1 cells in vitro, as well as in vivo. The pharmacological effects of KRG on cisplatin-induced changes in the hearing threshold of mice were determined, as well as the effect on the impairment of hair cell arrays. In addition, in order to elucidate the protective mechanisms of KRG, the regulatory effects of KRG on cisplatin-induced apoptosis-associated gene levels and nuclear factor-κB (NF-κB) activation were investigated in auditory cells. The results revealed that KRG prevented cisplatin-induced alterations in the hearing threshold of mice as well as the destruction of hair cell arrays in rat organ of Corti primary explants. In addition, KRG inhibited cisplatin-mediated cell toxicity, reactive oxygen species generation, interleukin-6 production, cytochrome c release and activation of caspases-3 in the HEI-OC1 auditory cell line. Furthermore, the results demonstrated that KRG inhibited the activation of NF-κB and caspase-1. In conclusion, these results provided a model for the pharmacological mechanism of KRG and provided evidence for potential therapies against ototoxicity.

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

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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

Edaravone attenuates lipopolysaccharide-induced acute respiratory distress syndrome associated early pulmonary fibrosis via amelioration of oxidative stress and transforming growth factor-β1/Smad3 signaling.

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Wang, Xida; Lai, Rongde; Su, Xiangfen; Chen, Guibin; Liang, Zijing

2018-01-01

Pulmonary fibrosis is responsible for the both short-term and long-term outcomes in patients with acute respiratory distress syndrome (ARDS). There is still no effective cure to improve prognosis. The purpose of this study was to investigate whether edaravone, a free radical scavenger, have anti-fibrosis effects in the rat model of ARDS associated early pulmonary fibrosis by lipopolysaccharide (LPS) administration. Rats were subjected to intravenous injection of LPS, and edaravone was given intraperitoneally after LPS administration daily for 7 consecutive days. LPS treatment rapidly increased lung histopathology abnormalities, coefficient of lung, hydroxyproline and collagen I levels, stimulated myofibroblast differentiation and induced expression of TGF-β1 and activation of TGF-β1/Smad3 signaling as early as day 7 after LPS injection. Moreover, LPS intoxication significantly increased the contents of malondialdehyde (MDA), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), whereas it dramatically decreased superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX) activities from day 1 after LPS treatment. On the contrary, edaravone treatment ameliorated LPS-induced myofibroblast differentiation and pulmonary fibrosis, simultaneously, and attenuated LPS-stimulated oxidative stress and activation of TGF-β1/Smad3 signaling. Collectively, edaravone may attenuate ARDS associated early pulmonary fibrosis through amelioration of oxidative stress and TGF-β1/Smad3 signaling pathway. Edaravone may be a promising drug candidate for the treatment of ARDS-related pulmonary fibrosis in early period. Copyright © 2017 Elsevier Inc. All rights reserved.

Dihydroartemisinin potentiates the anticancer effect of cisplatin via mTOR inhibition in cisplatin-resistant ovarian cancer cells: involvement of apoptosis and autophagy

International Nuclear Information System (INIS)

Feng, Xue; Li, Ling; Jiang, Hong; Jiang, Keping; Jin, Ye; Zheng, Jianhua

2014-01-01

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

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.

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.

Evidence for different mechanisms of ‘unhooking’ for melphalan and cisplatin-induced DNA interstrand cross-links in vitro and in clinical acquired resistant tumour samples

International Nuclear Information System (INIS)

Spanswick, Victoria J; Hartley, John A; Lowe, Helen L; Newton, Claire; Bingham, John P; Bagnobianchi, Alessia; Kiakos, Konstantinos; Craddock, Charles; Ledermann, Jonathan A; Hochhauser, Daniel

2012-01-01

DNA interstrand cross-links (ICLs) are critical lesions produced by several cancer chemotherapy agents including platinum drugs and nitrogen mustards. We have previously shown in haematological (multiple myeloma) and solid tumours (ovarian cancer) that clinical sensitivity to such agents can result from a defect in DNA ICL processing leading to their persistence. Conversely, enhanced repair can result in clinical acquired resistance following chemotherapy. The repair of ICLs is complex but it is assumed that the ‘unhooking’ step is common to all ICLs. Using a modification of the single cell gel electrophoresis (Comet) assay we measured the formation and unhooking of melphalan and cisplatin-induced ICLs in cell lines and clinical samples. DNA damage response in the form of γ-H2AX foci formation and the formation of RAD51 foci as a marker of homologous recombination were also determined. Real-time PCR of 84 genes involved in DNA damage signalling pathways was also examined pre- and post-treatment. Plasma cells from multiple myeloma patients known to be clinically resistant to melphalan showed significant unhooking of melphalan-induced ICLs at 48 hours, but did not unhook cisplatin-induced ICLs. In ovarian cancer cells obtained from patients following platinum-based chemotherapy, unhooking of cisplatin-induced ICLs was observed at 48 hours, but no unhooking of melphalan-induced ICLs. In vitro, A549 cells were proficient at unhooking both melphalan and cisplatin-induced ICLs. γ-H2AX foci formation closely followed the formation of ICLs for both drugs, and rapidly declined following the peak of formation. RPMI8226 cells unhooked melphalan, but not cisplatin-induced ICLs. In these cells, although cross-links form with cisplatin, the γ-H2AX response is weak. In A549 cells, addition of 3nM gemcitabine resulted in complete inhibition of cisplatin-induced ICL unhooking but no effect on repair of melphalan ICLs. The RAD51 foci response was both drug and cell line

The p53-reactivating small-molecule RITA enhances cisplatin-induced cytotoxicity and apoptosis in head and neck cancer.

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Roh, Jong-Lyel; Ko, Jung Ho; Moon, Soo Jin; Ryu, Chang Hwan; Choi, Jun Young; Koch, Wayne M

2012-12-01

We evaluated whether the restoration of p53 function by the p53-reactivating small molecule RITA (reactivation of p53 and induction of tumor cell apoptosis enhances cisplatin-induced cytotoxicity and apoptosis in head-and-neck cancer (HNC). RITA induced prominent accumulation and reactivation of p53 in a wild-type TP53-bearing HNC cell line. RITA showed maximal growth suppression in tumor cells showing MDM2-dependent p53 degradation. RITA promoted apoptosis in association with upregulation of p21, BAX, and cleaved caspase-3; notably, the apoptotic response was blocked by pifithrin-α, demonstrating its p53 dependence. With increasing concentrations, RITA strongly induced apoptosis rather than G2-phase arrest. In combination therapy, RITA enhanced cisplatin-induced growth inhibition and apoptosis of HNC cells invitro and in vivo. Our data suggest that the restoration of p53 tumor-suppressive function by RITA enhances the cytotoxicity and apoptosis of cisplatin, an action that may offer an attractive strategy for treating HNC. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Cisplatin induces expression of drug resistance-related genes through c-jun N-terminal kinase pathway in human lung cancer cells.

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Xu, Li; Fu, Yingya; Li, Youlun; Han, Xiaoli

2017-08-01

Change of multidrug resistance-related genes (e.g., lung resistance protein, LRP) and overexpression of anti-apoptotic genes (Bcl-2, Bcl-Xl, XIAP, Survivin) are responsible for cisplatin resistance. In our study, we investigated the mechanism by which cisplatin induces LRP, Bcl-2, Bcl-xL, XIAP, and Survivin expression in human lung adenocarcinoma A549 cells and human H446 small cell lung cancer cells at mRNA and protein levels. In our study, cell proliferation was assessed with CCK-8 assays, and cell apoptosis was assessed with flow cytometric analysis and Annexin-V/PI staining. qPCR was used to complete RNA experiments. Protein expression was assessed with Western blotting. Cisplatin increased Bcl-2, LRP, and Survivin expression, but decreased Bcl-xL and XIAP expression in a dose-dependent manner. Preincubation with JNK-specific inhibitor, SP600125, significantly inhibited these genes' expression at mRNA and protein levels, enhanced chemosensitivity of lung cancer cells to cisplatin, and promoted cisplatin-induced apoptosis. Our data suggest that the JNK signaling pathway plays an important role in cisplatin resistance. Lung resistance protein (LRP) and anti-apoptotic genes (Bcl-2, Bcl-Xl, XIAP, Survivin) are involved in the process. The results reminded us of a novel therapy target for lung cancer treatment.

Detecting acute neurotoxicity during platinum chemotherapy by neurophysiological assessment of motor nerve hyperexcitability

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Hill, Andrew; Bergin, Peter; Hanning, Fritha; Thompson, Paul; Findlay, Michael; Damianovich, Dragan; McKeage, Mark J

2010-01-01

Platinum-based drugs, such as cisplatin and oxaliplatin, are well-known for inducing chronic sensory neuropathies but their acute and motor neurotoxicities are less well characterised. Use was made of nerve conduction studies and needle electromyography (EMG) to assess motor nerve excitability in cancer patients during their first treatment cycle with platinum-based chemotherapy in this study. Twenty-nine adult cancer patients had a neurophysiological assessment either before oxaliplatin plus capecitabine, on days 2 to 4 or 14 to 20 after oxaliplatin plus capecitabine, or on days 2 to 4 after carboplatin plus paclitaxel or cisplatin, undertaken by a neurophysiologist who was blinded to patient and treatment details. Patients completed a symptom questionnaire at the end of the treatment cycle. Abnormal spontaneous high frequency motor fibre action potentials were detected in 100% of patients (n = 6) and 72% of muscles (n = 22) on days 2 to 4 post-oxaliplatin, and in 25% of patients (n = 8) and 13% of muscles (n = 32) on days 14 to 20 post-oxaliplatin, but in none of the patients (n = 14) or muscles (n = 56) tested prior to oxaliplatin or on days 2 to 4 after carboplatin plus paclitaxel or cisplatin. Repetitive compound motor action potentials were less sensitive and less specific than spontaneous high frequency motor fibre action potentials for detection of acute oxaliplatin-induced motor nerve hyperexcitability but were present in 71% of patients (n = 7) and 32% of muscles (n = 32) on days 2 to 4 after oxaliplatin treatment. Acute neurotoxicity symptoms, most commonly cold-induced paraesthesiae and jaw or throat tightness, were reported by all patients treated with oxaliplatin (n = 22) and none of those treated with carboplatin plus paclitaxel or cisplatin (n = 6). Abnormal spontaneous high frequency motor fibre activity is a sensitive and specific endpoint of acute oxaliplatin-induced motor nerve hyperexcitability, detectable on EMG on days 2 to 4 post

Detecting acute neurotoxicity during platinum chemotherapy by neurophysiological assessment of motor nerve hyperexcitability

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Hill Andrew

2010-08-01

Full Text Available Abstract Background Platinum-based drugs, such as cisplatin and oxaliplatin, are well-known for inducing chronic sensory neuropathies but their acute and motor neurotoxicities are less well characterised. Use was made of nerve conduction studies and needle electromyography (EMG to assess motor nerve excitability in cancer patients during their first treatment cycle with platinum-based chemotherapy in this study. Methods Twenty-nine adult cancer patients had a neurophysiological assessment either before oxaliplatin plus capecitabine, on days 2 to 4 or 14 to 20 after oxaliplatin plus capecitabine, or on days 2 to 4 after carboplatin plus paclitaxel or cisplatin, undertaken by a neurophysiologist who was blinded to patient and treatment details. Patients completed a symptom questionnaire at the end of the treatment cycle. Results Abnormal spontaneous high frequency motor fibre action potentials were detected in 100% of patients (n = 6 and 72% of muscles (n = 22 on days 2 to 4 post-oxaliplatin, and in 25% of patients (n = 8 and 13% of muscles (n = 32 on days 14 to 20 post-oxaliplatin, but in none of the patients (n = 14 or muscles (n = 56 tested prior to oxaliplatin or on days 2 to 4 after carboplatin plus paclitaxel or cisplatin. Repetitive compound motor action potentials were less sensitive and less specific than spontaneous high frequency motor fibre action potentials for detection of acute oxaliplatin-induced motor nerve hyperexcitability but were present in 71% of patients (n = 7 and 32% of muscles (n = 32 on days 2 to 4 after oxaliplatin treatment. Acute neurotoxicity symptoms, most commonly cold-induced paraesthesiae and jaw or throat tightness, were reported by all patients treated with oxaliplatin (n = 22 and none of those treated with carboplatin plus paclitaxel or cisplatin (n = 6. Conclusions Abnormal spontaneous high frequency motor fibre activity is a sensitive and specific endpoint of acute oxaliplatin-induced motor nerve

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

cancer cell death, and determine how NHE1 regulates this process. Cisplatin treatment elicited apoptosis, ATM phosphorylation, upregulation of p53, Noxa (PMAIP1), and PUMA (BBC3), and cleavage of caspase-9, -7, fodrin, and PARP-1 in MCF-7 cells. Inducible ΔNErbB2 expression strongly reduced cisplatin...

Honey feeding protects kidney against cisplatin nephrotoxicity through suppression of inflammation.

Science.gov (United States)

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.

Qingfei Xiaoyan Wan, a traditional Chinese medicine formula, ameliorates Pseudomonas aeruginosa–induced acute lung inflammation by regulation of PI3K/AKT and Ras/MAPK pathways

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Yuanyuan Hou

2016-05-01

Full Text Available Gram-negative pathogen–induced nosocomial infections and resistance are a most serious menace to global public health. Qingfei Xiaoyan Wan (QF, a traditional Chinese medicine (TCM formula, has been used clinically in China for the treatment of upper respiratory tract infections, acute or chronic bronchitis and pulmonary infection. In this study, the effects of QF on Pseudomonas aeruginosa–induced acute pneumonia in mice were evaluated. The mechanisms by which four typical anti-inflammatory ingredients from QF, arctigenin (ATG, cholic acid (CLA, chlorogenic acid (CGA and sinapic acid (SPA, regulate anti-inflammatory signaling pathways and related targets were investigated using molecular biology and molecular docking techniques. The results showed that pretreatment with QF significantly inhibits the release of cytokines (TNF-α and IL-6 and chemokines (IL-8 and RANTES, reduces leukocytes recruitment into inflamed tissues and ameliorates pulmonary edema and necrosis. In addition, ATG was identified as the primary anti-inflammatory agent with action on the PI3K/AKT and Ras/MAPK pathways. CLA and CGA enhanced the actions of ATG and exhibited synergistic NF-κB inactivation effects possibly via the Ras/MAPK signaling pathway. Moreover, CLA is speculated to target FGFR and MEK firstly. Overall, QF regulated the PI3K/AKT and Ras/MAPK pathways to inhibit pathogenic bacterial infections effectively.

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

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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.

Inhibition of glycogen synthase kinase 3beta ameliorates triptolide-induced acute cardiac injury by desensitizing mitochondrial permeability transition

International Nuclear Information System (INIS)

Wang, Wenwen; Yang, Yanqin; Xiong, Zhewen; Kong, Jiamin; Fu, Xinlu; Shen, Feihai; Huang, Zhiying

2016-01-01

Triptolide (TP), a diterpene triepoxide, is a major active component of Tripterygium wilfordii extracts, which are prepared as tablets and has been used clinically for the treatment of inflammation and autoimmune disorders. However, TP's therapeutic potential is limited by severe adverse effects. In a previous study, we reported that TP induced mitochondria dependent apoptosis in cardiomyocytes. Glycogen synthase kinase-3β (GSK-3β) is a multifunctional serine/threonine kinase that plays important roles in the necrosis and apoptosis of cardiomyocytes. Our study aimed to investigate the role of GSK-3β in TP-induced cardiotoxicity. Inhibition of GSK-3β activity by SB 216763, a potent and selective GSK-3 inhibitor, prominently ameliorated the detrimental effects in C57BL/6J mice with TP administration, which was associated with a correction of GSK-3β overactivity. Consistently, in TP-treated H9c2 cells, SB 216763 treatment counteracted GSK-3β overactivity, improved cell viability, and prevented apoptosis by modulating the expression of Bcl-2 family proteins. Mechanistically, GSK-3β interacted with and phosphorylated cyclophilin F (Cyp-F), a key regulator of mitochondrial permeability transition pore (mPTP). GSK-3β inhibition prevented the phosphorylation and activation of Cyp-F, and desensitized mPTP. Our findings suggest that pharmacological targeting of GSK-3β could represent a promising therapeutic strategy for protecting against cardiotoxicity induced by TP. - Highlights: • GSK-3β inhibition ameliorates TP-induced cardiotoxicity in vitro and in vivo. • GSK-3β controls Cyp-F activation, and regulates mPTP and apoptosis in H9c2 cells. • The protective effect is attributed to GSK-3β activity rather than to protein level. • GSK-3β may be a promising target against TP-induced cardiotoxicity.

Inhibition of glycogen synthase kinase 3beta ameliorates triptolide-induced acute cardiac injury by desensitizing mitochondrial permeability transition

Energy Technology Data Exchange (ETDEWEB)

Wang, Wenwen; Yang, Yanqin; Xiong, Zhewen; Kong, Jiamin [School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006 (China); Fu, Xinlu [Laboratory Animals Center, Sun Yat-sen University, Guangzhou 510006 (China); Shen, Feihai, E-mail: shenfh3@mail.sysu.edu.cn [School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006 (China); Huang, Zhiying, E-mail: hzhiying@mail.sysu.edu.cn [School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006 (China)

2016-12-15

Triptolide (TP), a diterpene triepoxide, is a major active component of Tripterygium wilfordii extracts, which are prepared as tablets and has been used clinically for the treatment of inflammation and autoimmune disorders. However, TP's therapeutic potential is limited by severe adverse effects. In a previous study, we reported that TP induced mitochondria dependent apoptosis in cardiomyocytes. Glycogen synthase kinase-3β (GSK-3β) is a multifunctional serine/threonine kinase that plays important roles in the necrosis and apoptosis of cardiomyocytes. Our study aimed to investigate the role of GSK-3β in TP-induced cardiotoxicity. Inhibition of GSK-3β activity by SB 216763, a potent and selective GSK-3 inhibitor, prominently ameliorated the detrimental effects in C57BL/6J mice with TP administration, which was associated with a correction of GSK-3β overactivity. Consistently, in TP-treated H9c2 cells, SB 216763 treatment counteracted GSK-3β overactivity, improved cell viability, and prevented apoptosis by modulating the expression of Bcl-2 family proteins. Mechanistically, GSK-3β interacted with and phosphorylated cyclophilin F (Cyp-F), a key regulator of mitochondrial permeability transition pore (mPTP). GSK-3β inhibition prevented the phosphorylation and activation of Cyp-F, and desensitized mPTP. Our findings suggest that pharmacological targeting of GSK-3β could represent a promising therapeutic strategy for protecting against cardiotoxicity induced by TP. - Highlights: • GSK-3β inhibition ameliorates TP-induced cardiotoxicity in vitro and in vivo. • GSK-3β controls Cyp-F activation, and regulates mPTP and apoptosis in H9c2 cells. • The protective effect is attributed to GSK-3β activity rather than to protein level. • GSK-3β may be a promising target against TP-induced cardiotoxicity.

Evidence for different mechanisms of ‘unhooking’ for melphalan and cisplatin-induced DNA interstrand cross-links in vitro and in clinical acquired resistant tumour samples

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Spanswick Victoria J

2012-09-01

Full Text Available Abstract Background DNA interstrand cross-links (ICLs are critical lesions produced by several cancer chemotherapy agents including platinum drugs and nitrogen mustards. We have previously shown in haematological (multiple myeloma and solid tumours (ovarian cancer that clinical sensitivity to such agents can result from a defect in DNA ICL processing leading to their persistence. Conversely, enhanced repair can result in clinical acquired resistance following chemotherapy. The repair of ICLs is complex but it is assumed that the ‘unhooking’ step is common to all ICLs. Methods Using a modification of the single cell gel electrophoresis (Comet assay we measured the formation and unhooking of melphalan and cisplatin-induced ICLs in cell lines and clinical samples. DNA damage response in the form of γ-H2AX foci formation and the formation of RAD51 foci as a marker of homologous recombination were also determined. Real-time PCR of 84 genes involved in DNA damage signalling pathways was also examined pre- and post-treatment. Results Plasma cells from multiple myeloma patients known to be clinically resistant to melphalan showed significant unhooking of melphalan-induced ICLs at 48 hours, but did not unhook cisplatin-induced ICLs. In ovarian cancer cells obtained from patients following platinum-based chemotherapy, unhooking of cisplatin-induced ICLs was observed at 48 hours, but no unhooking of melphalan-induced ICLs. In vitro, A549 cells were proficient at unhooking both melphalan and cisplatin-induced ICLs. γ-H2AX foci formation closely followed the formation of ICLs for both drugs, and rapidly declined following the peak of formation. RPMI8226 cells unhooked melphalan, but not cisplatin-induced ICLs. In these cells, although cross-links form with cisplatin, the γ-H2AX response is weak. In A549 cells, addition of 3nM gemcitabine resulted in complete inhibition of cisplatin-induced ICL unhooking but no effect on repair of melphalan ICLs. The

Sodium selenosulfate at an innocuous dose markedly prevents cisplatin-induced gastrointestinal toxicity

Energy Technology Data Exchange (ETDEWEB)

Li, Jun; Sun, Kang [School of Tea and Food Science, Anhui Agricultural University, Hefei 230036, Anhui (China); Ni, Lijuan; Wang, Xufang [School of Chemistry and Materials of Science, University of Science and Technology of China, Hefei 230052, Anhui (China); Wang, Dongxu [School of Tea and Food Science, Anhui Agricultural University, Hefei 230036, Anhui (China); Zhang, Jinsong, E-mail: zjs@ahau.edu.cn [School of Tea and Food Science, Anhui Agricultural University, Hefei 230036, Anhui (China)

2012-02-01

Our previous studies in mice revealed that two weeks short-term toxicity of sodium selenosulfate was significantly lower than that of sodium selenite, but selenium repletion efficacy of both compounds was equivalent. In addition, we showed that sodium selenosulfate reduced nephrotoxicity of cisplatin (CDDP) without compromising its anticancer activity, thus leading to a dramatic increase of cancer cure rate from 25% to 75%. Hydration has been used in clinical practice to reduce CDDP-induced nephrotoxicity, but it cannot mitigate CDDP-induced gastrointestinal toxicity. The present work investigated whether sodium selenosulfate is a potential preventive agent for the gastrointestinal toxicity. In tumor-bearing mice, sodium selenosulfate was administered at a dose of 9.5 μmol/kg daily for 11 days, CDDP alone resulted in diarrhea by 88% on day 12, whereas the co-administration of CDDP and sodium selenosulfate dramatically reduced diarrhea to 6% (p < 0.0001). Such a prominent protective effect promoted us to evaluate the safety potential of long-term sodium selenosulfate application. Mice were administered with sodium selenosulfate or sodium selenite for 55 days at the doses of 12.7 and 19 μmol/kg. The low-dose sodium selenite caused growth suppression and hepatotoxicity which were aggravated by the high-dose, leading to 40% mortality rate, but no toxic symptoms were observed in the two sodium selenosulfate groups. Altogether these results clearly show that sodium selenosulfate at an innocuous dose can markedly prevent CDDP-induced gastrointestinal toxicity. -- Highlights: ►Cisplatin resulted in diarrhea in mice by 88%. ►i.p. selenosulfate at 9.5 μmol/kg daily for 11 days reduced diarrhea to 6%. ►i.p. selenosulfate at 19 μmol/kg daily for 55 days was not toxic. ►i.p. selenite at 19 μmol/kg daily for 55 days was lethal. ►Innocuous dose of selenosulfate greatly prevents cisplatin-induced diarrhea.

Sodium selenosulfate at an innocuous dose markedly prevents cisplatin-induced gastrointestinal toxicity

International Nuclear Information System (INIS)

Li, Jun; Sun, Kang; Ni, Lijuan; Wang, Xufang; Wang, Dongxu; Zhang, Jinsong

2012-01-01

Our previous studies in mice revealed that two weeks short-term toxicity of sodium selenosulfate was significantly lower than that of sodium selenite, but selenium repletion efficacy of both compounds was equivalent. In addition, we showed that sodium selenosulfate reduced nephrotoxicity of cisplatin (CDDP) without compromising its anticancer activity, thus leading to a dramatic increase of cancer cure rate from 25% to 75%. Hydration has been used in clinical practice to reduce CDDP-induced nephrotoxicity, but it cannot mitigate CDDP-induced gastrointestinal toxicity. The present work investigated whether sodium selenosulfate is a potential preventive agent for the gastrointestinal toxicity. In tumor-bearing mice, sodium selenosulfate was administered at a dose of 9.5 μmol/kg daily for 11 days, CDDP alone resulted in diarrhea by 88% on day 12, whereas the co-administration of CDDP and sodium selenosulfate dramatically reduced diarrhea to 6% (p < 0.0001). Such a prominent protective effect promoted us to evaluate the safety potential of long-term sodium selenosulfate application. Mice were administered with sodium selenosulfate or sodium selenite for 55 days at the doses of 12.7 and 19 μmol/kg. The low-dose sodium selenite caused growth suppression and hepatotoxicity which were aggravated by the high-dose, leading to 40% mortality rate, but no toxic symptoms were observed in the two sodium selenosulfate groups. Altogether these results clearly show that sodium selenosulfate at an innocuous dose can markedly prevent CDDP-induced gastrointestinal toxicity. -- Highlights: ►Cisplatin resulted in diarrhea in mice by 88%. ►i.p. selenosulfate at 9.5 μmol/kg daily for 11 days reduced diarrhea to 6%. ►i.p. selenosulfate at 19 μmol/kg daily for 55 days was not toxic. ►i.p. selenite at 19 μmol/kg daily for 55 days was lethal. ►Innocuous dose of selenosulfate greatly prevents cisplatin-induced diarrhea.

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

[Decursin reduces reactive oxygen species and inhibits cisplatin-induced apoptosis in rat renal tubular epithelial cells].

Science.gov (United States)

Li, Cuiqiong; Li, Jianchun; Fan, Junming; Meng, Lifeng; Cao, Ling

2017-10-01

Objective To study the mechanism underlying the inhibitory effect of decursin on the apoptosis of rat renal tubular epithelial cells NRK-52E induced by cisplatin. Methods First, CCK-8 assay was used to detect the effects of 0, 10, 20, 40, 80, 100, 150, 200 μmol/L decursin and 0, 5, 10, 20, 30, 40, 50 μg/mL cispatin treatment for 24 hours on cell proliferation in NRK-52E cells via determining the half inhibitory concentration (IC 50 ). Then, NRK-52E cells were stimulated with 20 μg/mL cisplatin combined with 10, 50, 100 μmol/L decursin, and cell activity was detected by CCK-8 assay. The cells were divided into normal control group, 20 μg/mL cisplatin stimulation group, and 10, 50, 100 μmol/L decursin treated groups. Cell morphological changes was observed under inverted microscope, morphological changes of nucleus was detected by DAPI staining, cell apoptosis was detected by flow cytometry, the level of intracellular ROS was detected by DCFH-DA staining, and the apoptosis marker proteins cleaved-caspase-3 and cleaved-PARP were examined by Western blot analysis. Results Compared with the normal control group, cisplatin significantly inhibited the activity of the cells, and IC 50 was about 20 μg/mL; compared with the model group, in the decursin pretreatment groups, the level of intracellular ROS decreased remarkably, the expressions of cleaved-casspase-3 and cleaved-PARP proteins were reduced, and cell apoptosis was depressed. Conclusion Decursin can decrease the intracellular ROS level and inhibit the apoptosis of NRK-52E cells induced by cisplatin.

Human agonistic TRAIL receptor antibodies Mapatumumab and Lexatumumab induce apoptosis in malignant mesothelioma and act synergistically with cisplatin

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Felley-Bosco Emanuela

2007-10-01

Full Text Available Abstract Background The incidence of malignant pleural mesothelioma (MPM is associated with exposure to asbestos, and projections suggest that the yearly number of deaths in Western Europe due to MPM will increase until 2020. Despite progress in chemo- and in multimodality therapy, MPM remains a disease with a poor prognosis. Inducing apoptosis by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL or agonistic monoclonal antibodies which target TRAIL-receptor 1 (TRAIL-R1 or TRAIL-R2 has been thought to be a promising cancer therapy. Results We have compared the sensitivity of 13 MPM cell lines or primary cultures to TRAIL and two fully human agonistic monoclonal antibodies directed to TRAIL-R1 (Mapatumumab and TRAIL-R2 (Lexatumumab and examined sensitization of the MPM cell lines to cisplatin-induced by the TRAIL-receptor antibodies. We found that sensitivity of MPM cells to TRAIL, Mapatumumab and Lexatumumab varies largely and is independent of TRAIL-receptor expression. TRAIL-R2 contributes more than TRAIL-R1 to death-receptor mediated apoptosis in MPM cells that express both receptors. The combination of cisplatin with Mapatumumab or Lexatumumab synergistically inhibited the cell growth and enhanced apoptotic death. Furthermore, pre-treatment with cisplatin followed by Mapatumumab or Lexatumumab resulted in significant higher cytotoxic effects as compared to the reverse sequence. Combination-induced cell growth inhibition was significantly abrogated by pre-treatment of the cells with the antioxidant N-acetylcysteine. Conclusion Our results suggest that the sequential administration of cisplatin followed by Mapatumumab or Lexatumumab deserves investigation in the treatment of patients with MPM.

The dimethylthiourea-induced attenuation of cisplatin nephrotoxicity is associated with the augmented induction of heat shock proteins

International Nuclear Information System (INIS)

Tsuji, Takayuki; Kato, Akihiko; Yasuda, Hideo; Miyaji, Takehiko; Luo, Jinghui; Sakao, Yukitoshi; Ito, Hideaki; Fujigaki, Yoshihide; Hishida, Akira

2009-01-01

Dimethylthiourea (DMTU), a potent hydroxyl radical scavenger, affords protection against cisplatin (CDDP)-induced acute renal failure (ARF). Since the suppression of oxidative stress and the enhancement of heat shock proteins (HSPs) are both reported to protect against CDDP-induced renal damage, we tested whether increased HSP expression is involved in the underlying mechanisms of the DMTU-induced renal protection. We examined the effect of DMTU treatment on the expression of HSPs in the kidney until day 5 following a single injection of CDDP (5 mg/kg BW). DMTU significantly inhibited the CDDP-induced increments of serum creatinine, the number of 8-hydroxyl-2'-deoxyguanosine (8-OHdG)- and terminal deoxynucleotidyl transferase nick-end labeling (TUNEL)-positive tubular cells, and tubular damage score (p < 0.05). CDDP significantly increased renal abundances of HO-1, HSP60, HSP72 and HSP90 at days 1, 3, and 5. DMTU significantly augmented only the expression of HSP60 expression mainly in the cytoplasm of the proximal tubular cells at days 1 and 3 in CDDP-induced ARF. DMTU also inhibited the CDDP-induced increment of Bax, a pro-apoptotic protein, in the fraction of organelles/membranes at day 3. The findings suggest that DMTU may afford protection against CDDP-induced ARF, partially through the early induction of cytoplasmic HSP60, thereby preventing the Bax-mediated apoptosis in renal tubular cells

Cisplatin ototoxicity involves cytokines and STAT6 signaling network

Institute of Scientific and Technical Information of China (English)

Hyung-Jin Kim; Jeong-Dug Sul; Channy Park; Sang-Young Chung; Sung-Kyun Moon; David J Lim; Hong-Seob So; Raekil Park; Gi-Su Oh; Jeong-Han Lee; Ah-Ra Lyu; Hye-Min Ji; Sang-Heon Lee; Jeho Song; Sung-Joo Park; Yong-Ouk You

2011-01-01

We herein investigated the role of the STAT signaling cascade in the production of pro-inflammatory cytokines and cisplatin ototoxicity. A significant hearing impairment caused by cisplatin injection was observed in Balb/c (wild type,WT) and STAT4-/-,but not in STAT6-/- mice. Moreover,the expression levels of the protein and mRNA of proinflammatory cytokines,including TNF-α,IL-1β,and IL-6,were markedly increased in the serum and cochlea of WT and STAT4+,but not STAT6-/- mice. Organotypic culture revealed that the shape of stereocilia bundles and arrays of sensory hair cell layers in the organ of Corti from STAT6-/- mice were intact after treatment with cisplatin,whereas those from WT and STAT4-/- mice were highly distorted and disarrayed after the treatment. Cisplatin induced the phosphorylation of STAT6 in HEI-OC1 auditory cells,and the knockdown of STAT6 by STAT6-specific siRNA significantly protected HEI-OC1 auditory cells from cisplatin-induced cell death and inhibited pro-inflammatory cytokine production. We further demonstrated that IL-4 and IL-13 induced by cisplatin modulated the phosphorylation of STAT6 by binding with IL-4 receptor alpha and IL-13Rα1. These findings suggest that STAT6 signaling plays a pivotal role in cisplatin-mediated pro-inflammatory cytokine production and ototoxicity.

USP22 Induces Cisplatin Resistance in Lung Adenocarcinoma by Regulating γH2AX-Mediated DNA Damage Repair and Ku70/Bax-Mediated Apoptosis

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Aman Wang

2017-05-01

Full Text Available Resistance to platinum-based chemotherapy is one of the most important reasons for treatment failure in advanced non-small cell lung cancer, but the underlying mechanism is extremely complex and unclear. The present study aimed to investigate the correlation of ubiquitin-specific peptidase 22 (USP22 with acquired resistance to cisplatin in lung adenocarcinoma. In this study, we found that overexpression of USP22 could lead to cisplatin resistance in A549 cells. USP22 and its downstream proteins γH2AX and Sirt1 levels are upregulated in the cisplatin- resistant A549/CDDP cell line. USP22 enhances DNA damage repair and induce cisplatin resistance by promoting the phosphorylation of histone H2AX via deubiquitinating histone H2A. In addition, USP22 decreases the acetylation of Ku70 by stabilizing Sirt1, thus inhibiting Bax-mediated apoptosis and inducing cisplatin resistance. The cisplatin sensitivity in cisplatin-resistant A549/CDDP cells was restored by USP22 inhibition in vivo and vitro. In summary, our findings reveal the dual mechanism of USP22 involvement in cisplatin resistance that USP22 can regulate γH2AX-mediated DNA damage repair and Ku70/Bax-mediated apoptosis. USP22 is a potential target in cisplatin-resistant lung adenocarcinoma and should be considered in future therapeutic practice.

Melatonin Role in Ameliorating Radiation-induced Skin Damage: From Theory to Practice (A Review of Literature

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Abbaszadeh A.

2017-06-01

Full Text Available Normal skin is composed of epidermis and dermis. Skin is susceptible to radiation damage because it is a continuously renewing organ containing rapidly proliferating mature cells. Radiation burn is a damage to the skin or other biological tissues caused by exposure to radiofrequency energy or ionizing radiation. Acute skin reaction is the most frequently occurring side effect of radiation therapy. Generally, any chemical/ biological agent given before or at the time of irradiation to prevent or ameliorate damage to normal tissues is called a radioprotector. Melatonin is a highly lipophilic substance that easily penetrates organic membranes and therefore is able to protect important intracellular structures including mitochondria and DNA against oxidative damage directly at the sites where such a kind of damage would occur. Melatonin leads to an increase in the molecular level of some important antioxidative enzymes such as superoxide, dismotase and glutation-peroxidase, and also a reduction in synthetic activity of nitric oxide. There is a large body of evidence which proves the efficacy of Melatonin in ameliorating UV and X ray-induced skin damage. We propose that, in the future, Melatonin would improve the therapeutic ratio in radiation oncology and ameliorate skin damage more effectively when administered in optimal and non-toxic doses

Cisplatin-induced caspase activation mediates PTEN cleavage in ovarian cancer cells: a potential mechanism of chemoresistance

International Nuclear Information System (INIS)

Singh, Mohan; Chaudhry, Parvesh; Fabi, Francois; Asselin, Eric

2013-01-01

The phosphatase and tensin homolog deleted on chromosome 10 (PTEN) tumor suppressor protein is a central negative regulator of the PI3K/AKT signaling cascade and suppresses cell survival as well as cell proliferation. PTEN is found to be either inactivated or mutated in various human malignancies. In the present study, we have investigated the regulation of PTEN during cisplatin induced apoptosis in A2780, A270-CP (cisplatin resistant), OVCAR-3 and SKOV3 ovarian cancer cell lines. Cells were treated with 10μM of cisplatin for 24h. Transcript and protein levels were analysed by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) and western blotting, respectively. Immunofluorescence microscopy was used to assess the intracellular localization of PTEN. Proteasome inhibitor and various caspases inhibitors were used to find the mechanism of PTEN degradation. PTEN protein levels were found to be decreased significantly in A2780 cells; however, there was no change in PTEN protein levels in A2780-CP, OVCAR-3 and SKOV3 cells with cisplatin treatment. The decrease in PTEN protein was accompanied with an increase in the levels of AKT phosphorylation (pAKT) in A2780 cells and a decrease of BCL-2. Cisplatin treatment induced the activation/cleavage of caspase-3, -6, -7, -8, -9 in all cell lines tested in this study except the resistant variant A2780-CP cells. In A2780 cells, restoration of PTEN levels was achieved upon pre-treatment with Z-DEVD-FMK (broad range caspases inhibitor) and not with MG132 (proteasome inhibitor) and by overexpression of BCL-2, suggesting that caspases and BCL-2 are involved in the decrease of PTEN protein levels in A2780 cells. The decrease in pro-apoptotic PTEN protein levels and increase in survival factor pAKT in A2780 ovarian cancer cells suggest that cisplatin treatment could further exacerbate drug resistance in A2780 ovarian cancer cells

Cisplatin-induced caspase activation mediates PTEN cleavage in ovarian cancer cells: a potential mechanism of chemoresistance.

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Singh, Mohan; Chaudhry, Parvesh; Fabi, Francois; Asselin, Eric

2013-05-10

The phosphatase and tensin homolog deleted on chromosome 10 (PTEN) tumor suppressor protein is a central negative regulator of the PI3K/AKT signaling cascade and suppresses cell survival as well as cell proliferation. PTEN is found to be either inactivated or mutated in various human malignancies. In the present study, we have investigated the regulation of PTEN during cisplatin induced apoptosis in A2780, A270-CP (cisplatin resistant), OVCAR-3 and SKOV3 ovarian cancer cell lines. Cells were treated with 10μM of cisplatin for 24h. Transcript and protein levels were analysed by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) and western blotting, respectively. Immunofluorescence microscopy was used to assess the intracellular localization of PTEN. Proteasome inhibitor and various caspases inhibitors were used to find the mechanism of PTEN degradation. PTEN protein levels were found to be decreased significantly in A2780 cells; however, there was no change in PTEN protein levels in A2780-CP, OVCAR-3 and SKOV3 cells with cisplatin treatment. The decrease in PTEN protein was accompanied with an increase in the levels of AKT phosphorylation (pAKT) in A2780 cells and a decrease of BCL-2. Cisplatin treatment induced the activation/cleavage of caspase-3, -6, -7, -8, -9 in all cell lines tested in this study except the resistant variant A2780-CP cells. In A2780 cells, restoration of PTEN levels was achieved upon pre-treatment with Z-DEVD-FMK (broad range caspases inhibitor) and not with MG132 (proteasome inhibitor) and by overexpression of BCL-2, suggesting that caspases and BCL-2 are involved in the decrease of PTEN protein levels in A2780 cells. The decrease in pro-apoptotic PTEN protein levels and increase in survival factor pAKT in A2780 ovarian cancer cells suggest that cisplatin treatment could further exacerbate drug resistance in A2780 ovarian cancer cells.

Effect of biologically active fraction of Nardostachys jatamansi on cerulein-induced acute pancreatitis

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Bae, Gi-Sang; Kim, Min-Sun; Park, Kyoung-Chel; Koo, Bon Soon; Jo, Il-Joo; Choi, Sun Bok; Lee, Dong-Sung; Kim, Youn-Chul; Kim, Tae-Hyeon; Seo, Sang-Wan; Shin, Yong Kook; Song, Ho-Joon; Park, Sung-Joo

2012-01-01

AIM: To determine if the fraction of Nardostachys jatamansi (NJ) has the potential to ameliorate the severity of acute pancreatitis (AP). METHODS: Mice were administered the biologically active fraction of NJ, i.e., the 4th fraction (NJ4), intraperitoneally, and then injected with the stable cholecystokinin analogue cerulein hourly for 6 h. Six hours after the last cerulein injection, the pancreas, lung, and blood were harvested for morphological examination, measurement of cytokine expression, and examination of neutrophil infiltration. RESULTS: NJ4 administration attenuated the severity of AP and lung injury associated with AP. It also reduced cytokine production and neutrophil infiltration and resulted in the in vivo up-regulation of heme oxygenase-1 (HO-1). Furthermore, NJ4 and its biologically active fraction, NJ4-2 inhibited the cerulein-induced death of acinar cells by inducing HO-1 in isolated pancreatic acinar cells. CONCLUSION: These results suggest that NJ4 may be a candidate fraction offering protection in AP and NJ4 might ameliorate the severity of pancreatitis by inducing HO-1 expression. PMID:22783046

Significance of downregulation of renal organic cation transporter (SLC47A1 in cisplatin-induced proximal tubular injury

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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

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

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Tanida, Satoshi; Mizoshita, Tsutomu; Ozeki, Keiji; Tsukamoto, Hironobu; Kamiya, Takeshi; Kataoka, Hiromi; Sakamuro, Daitoku; Joh, Takashi

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...

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

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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.

Phytoceramide Shows Neuroprotection and Ameliorates Scopolamine-Induced Memory Impairment

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Seikwan Oh

2011-10-01

Full Text Available The function and the role phytoceramide (PCER and phytosphingosine (PSO in the central nervous system has not been well studied. This study was aimed at investigating the possible roles of PCER and PSO in glutamate-induced neurotoxicity in cultured neuronal cells and memory function in mice. Phytoceramide showed neuro-protective activity in the glutamate-induced toxicity in cultured cortical neuronal cells. Neither phytosphingosine nor tetraacetylphytosphingosine (TAPS showed neuroproective effects in neuronal cells. PCER (50 mg/kg, p.o. recovered the scopolamine-induced reduction in step-through latency in the passive avoidance test; however, PSO did not modulate memory function on this task. The ameliorating effects of PCER on spatial memory were confirmed by the Morris water maze test. In conclusion, through behavioral and neurochemical experimental results, it was demonstrated that central administration of PCER produces amelioration of memory impairment. These results suggest that PCER plays an important role in neuroprotection and memory enhancement and PCER could be a potential new therapeutic agent for the treatment of neurodegenerative diseases such as Alzheimer’s disease.

1α,25-Dihydroxyvitamin D3 Ameliorates Seawater Aspiration-Induced Acute Lung Injury via NF-κB and RhoA/Rho Kinase Pathways

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Liu, Wei; Wang, Li; Luo, Ying; Li, Zhichao; Jin, Faguang

2014-01-01

Introduction Inflammation and pulmonary edema are involved in the pathogenesis of seawater aspiration-induced acute lung injury (ALI). Although several studies have reported that 1α,25-Dihydroxyvitamin D3 (calcitriol) suppresses inflammation, it has not been confirmed to be effective in seawater aspiration-induced ALI. Thus, we investigated the effect of calcitriol on seawater aspiration-induced ALI and explored the probable mechanism. Methods Male SD rats receiving different doses of calcitriol or not, underwent seawater instillation. Then lung samples were collected at 4 h for analysis. In addition, A549 cells and rat pulmonary microvascular endothelial cells (RPMVECs) were cultured with calcitriol or not and then stimulated with 25% seawater for 40 min. After these treatments, cells samples were collected for analysis. Results Results from real-time PCR showed that seawater stimulation up-regulated the expression of vitamin D receptor in lung tissues, A549 cells and RPMVECs. Seawater stimulation also activates NF-κB and RhoA/Rho kinase pathways. However, we found that pretreatment with calcitriol significantly inhibited the activation of NF-κB and RhoA/Rho kinase pathways. Meanwhile, treatment of calcitriol also improved lung histopathologic changes, reduced inflammation, lung edema and vascular leakage. Conclusions These results demonstrated that NF-κB and RhoA/Rho kinase pathways are critical in the development of lung inflammation and pulmonary edema and that treatment with calcitriol could ameliorate seawater aspiration-induced ALI, which was probably through the inhibition of NF-κB and RhoA/Rho kinase pathways. PMID:25118599

Case report: An unusual case of cisplatin induced paralytic ileus

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Rosdiana Abd Rahim

2017-12-01

Full Text Available Background: Ileus is a failure of normal intestinal motility in the absence of mechanical obstruction. Ileus is thought to result from an imbalance between sympathetic and parasympathetic motor activity, resulting in intestinal atony. Few anti-cancer therapies reported to be associated with paralytic ileus, such as vincristine, vinblastine and paclitaxel. It is thought as a consequences of autonomic neuropathy. Here we present a paralytic ileus experience during cisplatin therapy. Case presentation: We present a case of 57 years old gentleman with diagnosis of metastatic nasopharyngeal carcinoma to lung and multiple bones who develop paralytic ileus following chemotherapy cisplatin and fluorouracil. The patient complained of abdominal discomfort with bloating and not tolerating Ryle tube feeding started 3 days after completion of cycle 2 cisplatin & fluorouracil infusion chemotherapy. No vomiting and still passing out small amount of stool everyday. Physical examination revealed abdominal distension, lower abdominal tenderness, sluggish bowel sound and empty rectum. The blood investigations for electrolyte, renal and hepatic function, and amylase were normal. Abdominal computerized tomography showed diffuse dilatation of small and large bowels extending to the rectum, without any obstructive pathology which was consistent with paralytic ileus. He was hospitalized and treated with nasogastric decompression and partial parenteral nutrition started. The symptoms improved after few days of decompression. Conclusion: Peripheral neuropathy due to cisplatin has been well described, however paralytic ileus has not previously been reported in medical literature. From patient self-reported outcome study, however, this complication was not that uncommon, and was reported by 0.76% of patients receiving cisplatin, especially people who are male, 60 years old and more, have been taking the drug for more than 1 month, also take medication dexamethasone. The

Renoprotective mechanisms of chlorogenic acid in cisplatin-induced kidney injury

International Nuclear Information System (INIS)

Domitrović, Robert; Cvijanović, Olga; Šušnić, Vesna; Katalinić, Nataša

2014-01-01

Highlights: • Chlorogenic acid attenuated cisplatin-induced renal oxidative stress by reducing the expression of 4-HNE, HO-1 and CYP2E1. • The inhibition of inflammatory response was achieved through the reduction of TNF-α and COX-2 expression. • The expression of p53, Bax, active caspase-3 and LC3B was suppressed, suggesting the inhibition of apoptosis and autophagy. • Attenuation of Mrp1 and Mrp2 expression and the increase in Oct2 expression indicated reduced burden of tubular cells. • The recovery of kidneys form cisplatin injury was accompanied by the suppression of cyclin D1 and augmented PCNA expression. - Abstract: The aim of this study was to investigate the renoprotective activity of chlorogenic acid (CA) in a murine model of cisplatin (CP)-induced kidney injury. Male BALB/cN mice were gavaged daily with CA at 3, 10 and 30 mg/kg for two successive days, 48 h after intraperitoneal injection of CP (13 mg/kg). On the fifth day, serum creatinine and blood urea nitrogen (BUN) levels were significantly increased in CP-intoxicated mice, which was recovered by CA. Renal oxidative stress, evidenced by increased 4-hydroxynonenal (4-HNE) expression, was significantly reduced with CA. Simultaneously, the overexpression of heme oxygenase 1 (HO-1) and cytochrome P450 E1 (CYP2E1) was attenuated. The inhibition of inflammatory response by CA was achieved through the reduction of tumor necrosis factor-α (TNF-α) and cyclooxygenase-2 (COX-2) expression. Additionally, CA significantly suppressed p53, Bax active caspase-3, cyclin D1 and microtubule-associated protein 1 light chain 3 isoform B (LC3B) expression, suggesting the inhibition of both apoptosis and autophagy. The expression of multidrug resistance-associated proteins (Mrp1 and Mrp2) increased and organic cation transporter 2 (Oct2) decreased by CP, protecting the kidneys from nephrotoxicity by reducing the burden of tubular cells. CA dose-dependently restored Mrp1, Mrp2 and Oct2 expression. The recovery

Protein kinase C β inhibits autophagy and sensitizes cervical cancer Hela cells to cisplatin.

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Li, Na; Zhang, Wei

2017-04-28

Recently, autophagy has been indicated to play an essential role in various biological events, such as the response of cervical cancer cells to chemotherapy. However, the exact signalling mechanism that regulates autophagy during chemotherapy remains unclear. In the present study, we investigated the regulation by cisplatin on protein kinase C β (PKC β), on B-cell lymphoma 2 (Bcl-2) and on apoptosis in cervical cancer Hela cells. And then we examined the regulation by cisplatin on autophagy and the role of autophagy on the chemotherapy in Hela cells. In addition, the regulation of the PKC β on the autophagy was also investigated. Our results indicated that cisplatin promoted PKC β in Hela cells. The PKC β inhibitor reduced the cisplatin-induced apoptosis, whereas increased the cisplatin-induced autophagy in Hela cells. On the other side, the PKC β overexpression aggravated the cisplatin-induced apoptosis, whereas down-regulated the cisplatin-induced autophagy. Taken together, our study firstly recognized the involvement of PKC β in the cytotoxicity of cisplatin via inhibiting autophagy in cervical cancer cells. We propose that PKC β would sensitize cervical cancer cells to chemotherapy via reducing the chemotherapy induced autophagy in cancer cells. © 2017 The Author(s).

Lycium barbarum polysaccharide attenuates cisplatin- induced ...

African Journals Online (AJOL)

effects on the life quality of cancer patients. Cisplatin is ... response and hormone balance [12,13]. However not ..... through facilitation of cytochrome C across the mitochondrial ... No conflict of interest associated with this work. Contribution of ...

Concurrent cetuximab, cisplatin, and radiation for squamous cell carcinoma of the head and neck in vitro

International Nuclear Information System (INIS)

Zhang Na; Erjala, Kaisa; Kulmala, Jarmo; Qiu Xueshan; Sundvall, Maria; Elenius, Klaus; Grenman, Reidar

2009-01-01

Background and purpose: For locoregionally advanced HNSCC, chemoradiotherapy with cisplatin or another platinum compound is considered as one of the standard treatment regimes. Cisplatin has improved the loco-regional control, but also increased especially the acute side effects. Cetuximab blocks ligand binding and receptor activation by binding to the extracellular domain of the EGFR. The blockade of EGFR signaling in combination with cytotoxic drugs or with radiotherapy could be a novel effective management with a relatively favourable toxicity for HNSCC. In the present study we have examined in vitro a potentially novel effective management for HNSCC, cetuximab combined with cisplatin and radiotherapy. Materials and methods: Seven head and neck SCC cell lines were studied. Cetuximab concentrations of 0.22-8.20 nM and cisplatin concentrations of 0.038-0.220 μg/ml were used. In order to test the concurrent use of cetuximab, cisplatin and radiation, the cells were treated with the desired drug concentrations immediately after irradiation, plated into 96-well culture plates, and incubated for 4 weeks. The number of positive wells was counted. The PE was calculated and fraction survival data were fitted to the LQ model. AUC value was obtained with numerical integration. The types of interaction were analyzed. Results: Cetuximab and cisplatin constantly induced an additive or supra-additive effect when combined with irradiation in the seven HNSCC cell lines tested. Conclusions: We evaluated concurrent cetuximab, cisplatin, and radiation for HNSCC cell lines. Preliminary efficacy results are encouraging, and further development of this targeted combined modality paradigm is warranted.

Prevention of LPS-Induced Acute Lung Injury in Mice by Progranulin

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Zhongliang Guo

2012-01-01

Full Text Available The acute respiratory distress syndrome (ARDS, a clinical complication of severe acute lung injury (ALI in humans, is a leading cause of morbidity and mortality in critically ill patients. Despite decades of research, few therapeutic strategies for clinical ARDS have emerged. Here we carefully evaluated the effect of progranulin (PGRN in treatment of ARDS using the murine model of lipopolysaccharide (LPS-induced ALI. We reported that administration of PGRN maintained the body weight and survival of ALI mice. We revealed that administration of PGRN significantly reduced LPS-induced pulmonary inflammation, as reflected by reductions in total cell and neutrophil counts, proinflammatory cytokines, as well as chemokines in bronchoalveolar lavage (BAL fluid. Furthermore, administration of PGRN resulted in remarkable reversal of LPS-induced increases in lung permeability as assessed by reductions in total protein, albumin, and IgM in BAL fluid. Consistently, we revealed a significant reduction of histopathology changes of lung in mice received PGRN treatment. Finally, we showed that PGRN/TNFR2 interaction was crucial for the protective effect of PGRN on the LPS-induced ALI. Our findings strongly demonstrated that PGRN could effectively ameliorate the LPS-induced ALI in mice, suggesting a potential application for PGRN-based therapy to treat clinical ARDS.

Orally Administered Enoxaparin Ameliorates Acute Colitis by Reducing Macrophage-Associated Inflammatory Responses.

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Qi Ying Lean

Full Text Available Inflammatory bowel diseases, such as ulcerative colitis, cause significant morbidity and decreased quality of life. The currently available treatments are not effective in all patients, can be expensive and have potential to cause severe side effects. This prompts the need for new treatment modalities. Enoxaparin, a widely used antithrombotic agent, is reported to possess anti-inflammatory properties and therefore we evaluated its therapeutic potential in a mouse model of colitis. Acute colitis was induced in male C57BL/6 mice by administration of dextran sulfate sodium (DSS. Mice were treated once daily with enoxaparin via oral or intraperitoneal administration and monitored for colitis activities. On termination (day 8, colons were collected for macroscopic evaluation and cytokine measurement, and processed for histology and immunohistochemistry. Oral but not intraperitoneal administration of enoxaparin significantly ameliorated DSS-induced colitis. Oral enoxaparin-treated mice retained their body weight and displayed less diarrhea and fecal blood loss compared to the untreated colitis group. Colon weight in enoxaparin-treated mice was significantly lower, indicating reduced inflammation and edema. Histological examination of untreated colitis mice showed a massive loss of crypt architecture and goblet cells, infiltration of immune cells and the presence of edema, while all aspects of this pathology were alleviated by oral enoxaparin. Reduced number of macrophages in the colon of oral enoxaparin-treated mice was accompanied by decreased levels of pro-inflammatory cytokines. Oral enoxaparin significantly reduces the inflammatory pathology associated with DSS-induced colitis in mice and could therefore represent a novel therapeutic option for the management of ulcerative colitis.

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

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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.

Receptor interactive protein kinase 3 promotes Cisplatin-triggered necrosis in apoptosis-resistant esophageal squamous cell carcinoma cells.

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Yang Xu

Full Text Available Cisplatin-based chemotherapy is currently the standard treatment for locally advanced esophageal cancer. Cisplatin has been shown to induce both apoptosis and necrosis in cancer cells, but the mechanism by which programmed necrosis is induced remains unknown. In this study, we provide evidence that cisplatin induces necrotic cell death in apoptosis-resistant esophageal cancer cells. This cell death is dependent on RIPK3 and on necrosome formation via autocrine production of TNFα. More importantly, we demonstrate that RIPK3 is necessary for cisplatin-induced killing of esophageal cancer cells because inhibition of RIPK1 activity by necrostatin or knockdown of RIPK3 significantly attenuates necrosis and leads to cisplatin resistance. Moreover, microarray analysis confirmed an anti-apoptotic molecular expression pattern in esophageal cancer cells in response to cisplatin. Taken together, our data indicate that RIPK3 and autocrine production of TNFα contribute to cisplatin sensitivity by initiating necrosis when the apoptotic pathway is suppressed or absent in esophageal cancer cells. These data provide new insight into the molecular mechanisms underlying cisplatin-induced necrosis and suggest that RIPK3 is a potential marker for predicting cisplatin sensitivity in apoptosis-resistant and advanced esophageal cancer.

Flurbiprofen ameliorates glucose deprivation-induced leptin resistance

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Toru Hosoi

2016-09-01

Full Text Available Leptin resistance is one of the mechanisms involved in the pathophysiology of obesity. The present study showed that glucose deprivation inhibited leptin-induced phosphorylation of signal transducer and activator of transcription 3 (STAT3 and signal transducer and activator of transcription 5 (STAT5 in neuronal cells. Flurbiprofen reversed glucose deprivation-mediated attenuation of STAT3, but not STAT5 activation, in leptin-treated cells. Glucose deprivation increased C/EBP-homologous protein (CHOP and glucose regulated protein 78 (GRP78 induction, indicating the activation of unfolded protein responses (UPR. Flurbiprofen did not affect the glucose deprivation-induced activation of UPR, but did attenuate the glucose deprivation-mediated induction of AMP-activated protein kinase (AMPK phosphorylation. Flurbiprofen may ameliorate glucose deprivation-induced leptin resistance in neuronal cells.

Multiparametric analysis of cisplatin-induced changes in cancer cells using FLIM

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Shirmanova, Marina V.; Sergeeva, Tatiana F.; Gavrina, Alena I.; Dudenkova, Varvara V.; Lukyanov, Konstantin A.; Zagaynova, Elena V.

2018-02-01

Cisplatin is an effective anticancer drug commonly used in the treatment of solid tumors. Although DNA is considered as the primary target, the cisplatin action at the cellular level remains unknown. Advanced fluorescence microscopy techniques allow probing various physiological and physicochemical parameters in living cells and tissues with unsurpassed sensitivity in real time. This study was focused on the investigation of cellular bioenergetics and cytosolic pH in colorectal cancer cells during chemotherapy with cisplatin. Special attention was given to the changes in cisplatininduced apoptosis that was identified using genetically encoded FLIM/FRET sensor of caspase-3 activity. Metabolic measurements using FLIM of the metabolic cofactor NAD(P)H showed decreased contribution from free NAD(P)H (a1, %) in all treated cells with more pronounced alterations in the cells undergoing apoptosis. Analysis of cytosolic pH using genetically encoded fluorescent sensor SypHer1 revealed a rapid increase of the pH value upon cisplatin exposure irrespective of the induction of apoptosis. To the best of our knowledge, a simultaneous assessment of metabolic state, cytosolic pH and caspase-3 activity after treatment with cisplatin was performed for the first time. These findings improve our understanding of the cell response to chemotherapy and mechanisms of cisplatin action.

Reversible p53 inhibition prevents cisplatin ototoxicity without blocking chemotherapeutic efficacy.

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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.

Understanding the Risk Factors and Long-Term Consequences of Cisplatin-Associated Acute Kidney Injury: An Observational Cohort Study.

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Zeenat Yousuf Bhat

Full Text Available Acute kidney injury (AKI is a well-known complication of cisplatin-based chemotherapy; however, its impact on long-term patient survival is unclear. We sought to determine the incidence and risk factors for development of cisplatin-associated AKI and its impact on long-term renal function and patient survival. We identified 233 patients who received 629 cycles of high-dose cisplatin (99±9mg/m2 for treatment of head and neck cancer between 2005 and 2011. These subjects were reviewed for development of AKI. Cisplatin nephrotoxicity (CN was defined as persistent rise in serum creatinine, with a concomitant decline in serum magnesium and potassium, in absence of use of nephrotoxic agents and not reversed with hydration. All patients were hydrated per protocol and none had baseline glomerular filtration rate (GFR via CKD-EPI<60mL/min/1.73m2. The patients were grouped based on development of AKI and were staged for levels of injury, per KDIGO-AKI definition. Renal function was assessed via serum creatinine and estimated glomerular filtration rate (eGFR via CKD-EPI at baseline, 6- and 12-months. Patients with AKI were screened for the absence of nephrotoxic medication use and a temporal decline in serum potassium and magnesium levels. Logistic regression models were constructed to determine risk factors for cisplatin-associated AKI. Twelve-month renal function was compared among groups using ANOVA. Kaplan-Maier curves and Cox proportional hazard models were constructed to study its impact on patient survival. Of 233 patients, 158(68% developed AKI; 77 (49% developed stage I, 55 (35% developed stage II, and 26 (16% developed stage III AKI. Their serum potassium and magnesium levels correlated negatively with level of injury (p<0.05. African American race was a significant risk factor for cisplatin-associated AKI, OR 2.8 (95% CI 1.3 to 6.3 and 2.8 (95% CI 1.2 to 6.7 patients with stage III AKI had the lowest eGFR value at 12 months (p = 0.05 and long

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

Nephroprotective Effect of Bauhinia tomentosa Linn against Cisplatin-Induced Renal Damage.

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Kannan, Narayanan; Sakthivel, Kunnathur Murugesan; Guruvayoorappan, Chandrasekaran

2016-01-01

Cisplatin (CP) is an important chemotherapeutic drug used for the treatment of a wide variety of solid tumors. However, clinical use of CP has been limited due to its adverse effect of nephrotoxicity. In the present study, we evaluate the nephroprotective effect of Bauhinia tomentosa against CP-induced renal damage in rats. Administration of methonolic extract of B. tomentosa (250 mg/kg b.w.) results in a significant increase in antioxidant enzymes including superoxide dismutase (SOD), glutathione (GSH), and catalase (CAT). Furthermore, treatment with B. tomentosa increased body weight and relative organ weight when compared with that of the CP-induced control group. Moreover, treatment with B. tomentosa extract significantly decreased lipid peroxidation(LPO), serum urea, and creatinine when compared with the CP-induced control group. Thus, the present study highlights the potential role of B. tomentosa and its use as a new protective strategy against CP-induced nephrotoxicity.

Usefulness of antiemetic therapy with aprepitant, palonosetron, and dexamethasone for lung cancer patients on cisplatin-based or carboplatin-based chemotherapy.

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Kitazaki, Takeshi; Fukuda, Yuichi; Fukahori, Susumu; Oyanagi, Kazuhiko; Soda, Hiroshi; Nakamura, Yoichi; Kohno, Shigeru

2015-01-01

The purpose of the study is to investigate the usefulness of the triplet regimen comprising aprepitant, palonosetron, and dexamethasone in patients treated with highly emetogenic chemotherapy (HEC) and moderately emetogenic chemotherapy (MEC). Patients with lung cancer (aged 65.8 ± 8.4 years) who received carboplatin-based MEC and those treated with cisplatin-based HEC were enrolled. The antiemetic regimen for both types of chemotherapy consisted of aprepitant, palonosetron, and dexamethasone based on the May 2010 guidelines prepared by the Japan Society of Clinical Oncology. The incidence of chemotherapy-induced nausea and vomiting (CINV) and the use of salvage treatment were assessed. The primary endpoints were the percentage of patients with a complete response (CR: no nausea and no salvage treatment) during the entire study period (5 days) after chemotherapy, during the acute phase (day 1), and during the delayed phase (days 2-5). CR rates for the entire period were 86 and 71% in patients receiving carboplatin-based and cisplatin-based chemotherapy, respectively. CR rates were respectively 98 and 100% in the acute phase versus 87 and 71% in the delayed phase. Most of the patients could ingest food throughout the entire period after chemotherapy. Assessment of various risk factors for acute and delayed CINV (gender, age, prior vomiting due to antineoplastic therapy, prior experience of motion sickness, and history of drinking) revealed no significant influence of these factors on the CR rate for the entire period in patients receiving either carboplatin-based or cisplatin-based chemotherapy. The present triple therapy can be recommended for supporting both carboplatin-based and cisplatin-based chemotherapy regimens.

Nuclear thioredoxin-1 is required to suppress cisplatin-mediated apoptosis of MCF-7 cells

International Nuclear Information System (INIS)

Chen, Xiao-Ping; Liu, Shou; Tang, Wen-Xin; Chen, Zheng-Wang

2007-01-01

Different cell line with increased thioredoxin-1 (Trx-1) showed a decreased or increased sensitivity to cell killing by cisplatin. Recently, several studies found that the subcellular localization of Trx-1 is closely associated with its functions. In this study, we explored the association of the nuclear Trx-1 with the cisplatin-mediated apoptosis of breast cancer cells MCF-7. Firstly, we found that higher total Trx-1 accompanied by no change of nuclear Trx-1 can not influence apoptosis induced by cisplatin in MCF-7 cells transferred with Trx-1 cDNA. Secondly, higher nuclear Trx-1 accompanied by no change of total Trx-1 can protect cells from apoptosis induced by cisplatin. Thirdly, high nuclear Trx-1 involves in the cisplatin-resistance in cisplatin-resistive cells. Meanwhile, we found that the mRNA level of p53 is closely correlated with the level of nuclear Trx-1. In summary, we concluded that the nuclear Trx-1 is required to resist apoptosis of MCF-7 cells induced by cisplatin, probably through up-regulating the anti-apoptotic gene, p53

Cisplatin Targeting of Bacterial Ribosomal RNA Hairpins

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Gayani N. P. Dedduwa-Mudalige

2015-09-01

Full Text Available Cisplatin is a clinically important chemotherapeutic agent known to target purine bases in nucleic acids. In addition to major deoxyribonucleic acid (DNA intrastrand cross-links, cisplatin also forms stable adducts with many types of ribonucleic acid (RNA including siRNA, spliceosomal RNAs, tRNA, and rRNA. All of these RNAs play vital roles in the cell, such as catalysis of protein synthesis by rRNA, and therefore serve as potential drug targets. This work focused on platination of two highly conserved RNA hairpins from E. coli ribosomes, namely pseudouridine-modified helix 69 from 23S rRNA and the 790 loop of helix 24 from 16S rRNA. RNase T1 probing, MALDI mass spectrometry, and dimethyl sulfate mapping revealed platination at GpG sites. Chemical probing results also showed platination-induced RNA structural changes. These findings reveal solvent and structural accessibility of sites within bacterial RNA secondary structures that are functionally significant and therefore viable targets for cisplatin as well as other classes of small molecules. Identifying target preferences at the nucleotide level, as well as determining cisplatin-induced RNA conformational changes, is important for the design of more potent drug molecules. Furthermore, the knowledge gained through studies of RNA-targeting by cisplatin is applicable to a broad range of organisms from bacteria to human.

A Phase II study of palonosetron, aprepitant, dexamethasone and olanzapine for the prevention of cisplatin-based chemotherapy-induced nausea and vomiting in patients with thoracic malignancy.

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Nakashima, Kazuhisa; Murakami, Haruyasu; Yokoyama, Kouichi; Omori, Shota; Wakuda, Kazushige; Ono, Akira; Kenmotsu, Hirotsugu; Naito, Tateaki; Nishiyama, Fumie; Kikugawa, Mami; Kaneko, Masayo; Iwamoto, Yumiko; Koizumi, Satomi; Mori, Keita; Isobe, Takeshi; Takahashi, Toshiaki

2017-09-01

The three-drug combination of a 5-hydroxytryptamine type 3 receptor antagonist, a neurokinin 1 receptor antagonist and dexamethasone is recommended for patients receiving highly emetogenic chemotherapy. However, standard antiemetic therapy is not completely effective in all patients. We conducted an open-label, single-center, single-arm Phase II study to evaluate the efficacy of olanzapine in combination with standard antiemetic therapy in preventing chemotherapy-induced nausea and vomiting in patients with thoracic malignancy receiving their first cycle of cisplatin-based chemotherapy. Patients received 5 mg oral olanzapine on Days 1-5 in combination with standard antiemetic therapy. The primary endpoint was complete response (no vomiting and no use of rescue therapy) during the overall Phase (0-120 h post-chemotherapy). Twenty-three men and seven women were enrolled between May and October 2015. The median age was 64 years (range: 36-75 years). The most common chemotherapy regimen was 75 mg/m2 cisplatin and 500 mg/m2 pemetrexed, which was administered to 14 patients. Complete response rates in acute (0-24 h post-chemotherapy), delayed (24-120 h post-chemotherapy) and overall phases were 100%, 83% and 83% (90% confidence interval: 70-92%; 95% confidence interval: 66-93%), respectively. There were no Grade 3 or Grade 4 adverse events. Although four patients (13%) experienced Grade 1 somnolence, no patients discontinued olanzapine. The addition of 5 mg oral olanzapine to standard antiemetic therapy demonstrates promising efficacy in preventing cisplatin-based chemotherapy-induced nausea and vomiting and an acceptable safety profile in patients with thoracic malignancy. © The Author 2017. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Monitoring cisplatin-induced ototoxicity.

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Ana SÁNCHEZ-MARTÍNEZ

2018-03-01

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.

A Mechanism for the Temporal Potentiation of Genipin to the Cytotoxicity of Cisplatin in Colon Cancer Cells.

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Wang, Ruihua; MoYung, K C; Zhao, Y J; Poon, Karen

2016-01-01

To investigate the potentiation effect of Genipin to Cisplatin induced cell senescence in HCT-116 colon cancer cells in vitro. Cell viability was estimated by Propidium iodide and Hoechst 3342, reactive oxygen species (ROS) with DHE, mitochondrial membrane potential (MMP) with JC-1 MMP assay Kit and electron current production with microbial fuel cells (MFC). Genipin inhibited the UCP2 mediated anti-oxidative proton leak significantly promoted the Cisplatin induced ROS and subsequent cell death, which was similar to that of UCP2-siRNA. Cells treated with Cisplatin alone or combined with Genipin, ROS negatively, while MMP positively correlated with cell viability. Cisplatin induced ROS was significantly decreased by detouring electrons to MFC, or increased by Genipin combined treatment. Compensatory effects of UCP2 up-regulation with time against Genipin treatment were suggested. Shorter the Genipin treatment before Cisplatin better promoted the Cisplatin induced ROS and subsequent cell death. The interaction of leaked electron with Cisplatin was important during ROS generation. Inhibition of UCP2-mediated proton leak with Genipin potentiated the cytotoxicity of Cisplatin. Owing to the compensatory effects against Genipin, shorter Genipin treatment before Cisplatin was recommended in order to achieve better potentiation effect.

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 ...

Zinc Ameliorate Oxidative Stress and Hormonal Disturbance Induced by Methomyl, Abamectin, and Their Mixture in Male Rats

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Sameeh A. Mansour

2017-12-01

Full Text Available Exposure to mixtures of toxicants (e.g., pesticides is common in real life and a subject of current concern. The present investigation was undertaken to assess some toxicological effects in male rats following exposure to methomyl (MET, abamectin (ABM, and their combination (MET+ABM, and to evaluate the ameliorative effect of zinc co-administration. Three groups of rats were designated for MET, ABM, and the mixture treatments. Three other groups were designated for zinc in conjunction with the pesticides. Additionally, one group received water only (control, and the other represented a positive zinc treatment. The obtained results revealed that MET was acutely more toxic than ABM. The tested pesticides induced significant elevation in lipid peroxidation and catalase levels, while declined the levels of the other tested parameters e.g., Superoxide dismutase (SOD, Glutathione-S-transferase (GST, Glutathione peroxidase (GPx, Glutathione reductase (GR, Cytochrome P450 (CYP450, testosterone, and thyroxine. Biochemical alterations induced by the mixture were greater than those recorded for each of the individual insecticides. The joint action analysis, based on the obtained biochemical data, revealed the dominance of antagonistic action among MET and ABM. Zinc supplementation achieved noticeable ameliorative effects. It was concluded that zinc may act as a powerful antioxidant, especially in individuals who are occupationally exposed daily to low doses of such pesticides.

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.

Effects of cisplatin on potassium currents in CT26 cells

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Naveen Sharma

2016-01-01

Conclusion: Potassium currents were detected in CT26 cells and the currents were reduced by the application of tetraethylammonium (TEA chloride, iberiotoxin, a big conductance calcium-activated potassium channel blocker and barium. The potassium currents were enhanced to 192< by the application of cisplatin (0.5 mM. Moreover, the increase of potassium currents by cisplatin was further inhibited by the application of TEA confirming the action of cisplatin on potassium channels. In addition, relative current induced by cisplatin in CT26 cells was bit larger than in normal IEC-6 cells.

Maslinic acid ameliorates NMDA receptor blockade-induced schizophrenia-like behaviors in mice.

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Jeon, Se Jin; Kim, Eunji; Lee, Jin Su; Oh, Hee Kyong; Zhang, Jiabao; Kwon, Yubeen; Jang, Dae Sik; Ryu, Jong Hoon

2017-11-01

Schizophrenia is a chronic psychotic disorder characterized by positive, negative, and cognitive symptoms. Primary treatments for schizophrenia relieve the positive symptoms but are less effective against the negative and cognitive symptoms. In the present study, we investigated whether maslinic acid, isolated from Syzygium aromaticum (clove), can ameliorate schizophrenia-like behaviors in mice induced by MK-801, an N-methyl-d-aspartate (NMDA) receptor antagonist. After maslinic acid treatment in the MK-801 model, we examined the behavioral alteration and signaling pathways in the prefrontal cortex. Mice were treated with maslinic acid (30 mg/kg), and their behaviors were evaluated through an array of behavioral tests. The effects of maslinic acid were also examined in the signaling pathways in the prefrontal cortex. A single administration of maslinic acid blocked the MK-801-induced hyperlocomotion and reversed the MK-801-induced sensorimotor gating deficit in the acoustic startle response test. In the social novelty preference test, maslinic acid ameliorated the social behavior deficits induced by MK-801. The MK-801-induced attention and recognition memory impairments were also alleviated by a single administration of maslinic acid. Furthermore, maslinic acid normalized the phosphorylation levels of Akt-GSK-3β and ERK-CREB in the prefrontal cortex. Overall, maslinic acid ameliorated the schizophrenia-like symptoms induced by MK-801, and these effects may be partly mediated through Akt-GSK-3β and ERK-CREB activation. These findings suggest that maslinic acid could be a candidate for the treatment of several symptoms of schizophrenia, including positive symptoms, sensorimotor gating disruption, social interaction deficits, and cognitive impairments. Copyright © 2017 Elsevier Ltd. All rights reserved.

Herbal medicines for the treatment of cancer chemotherapy-induced side effects.

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Ohnishi, Shunsuke; Takeda, Hiroshi

2015-01-01

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 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.

Case report of cold-weather-induced radiation recall dermatitis after chemoradiotherapy with cisplatin

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Kindts, Isabelle; Stellamans, Karin; Planckaert, Nikie; Goethals, Laurence [AZ Groeninge Hospital, Department of Radiation Oncology, Kortrijk (Belgium); Bonny, Michiel [AZ Groeninge Hospital, Department of Dermatology, Kortrijk (Belgium)

2014-08-15

The radiation recall reaction (RRR) is an inflammatory reaction that occurs in previously irradiated areas. The phenomenon is probably due to an idiosyncratic hypersensitivity reaction, in which a second agent can recall the inflammatory reaction. This case report documents a cold-weather-induced radiation recall dermatitis (RRD). We observed a severe RRD in a patient after chemoradiotherapy treatment with cisplatin for a nasopharyngeal carcinoma, precipitated by cold temperatures, which developed 9 days after completion of therapy. In the medical literature, RRD following extreme cold temperatures seems to be a peculiar event. Until further information on the interaction is available, future studies on combined chemotherapy with cisplatin should be carefully monitored and any side effects clearly documented. This case suggests that environmental conditions may play a contributing role in the development of RRD. This case also implies that neither fraction size nor total radiation dose is a determining factor in the development of the dermatologic reaction. (orig.) [German] Die ''Radiation-Recall-Reaktion'' (RRR) ist eine Entzuendungsreaktion, die in zuvor bestrahlten Bereichen auftritt. Das Phaenomen wird wahrscheinlich durch eine spezifische Ueberempfindlichkeitsreaktion verursacht, bei der ein zweites Agens die Entzuendungsreaktion hervorruft. Dieser Fallbericht beschreibt eine kaltwetterinduzierte RR-Hautentzuendung. Wir beobachteten bei dem Patienten nach einer Radiochemotherapie mit Cisplatin aufgrund eines Nasopharynxkarzinoms eine heftige RR-Dermatitis (RRD) aufgrund kalter Temperaturen, die sich 9 Tage nach Therapiebeendigung entwickelte. In der medizinischen Literatur scheint eine RRD infolge extrem kalter Temperaturen ein besonderes Ereignis. Bis weitere Informationen zu der Interaktion verfuegbar sind, sollten zukuenftige Studien zur Kombinationstherapie mit Cisplatin sorgfaeltig ueberwacht und Nebenwirkungen eindeutig dokumentiert

Case report of cold-weather-induced radiation recall dermatitis after chemoradiotherapy with cisplatin

International Nuclear Information System (INIS)

Kindts, Isabelle; Stellamans, Karin; Planckaert, Nikie; Goethals, Laurence; Bonny, Michiel

2014-01-01

The radiation recall reaction (RRR) is an inflammatory reaction that occurs in previously irradiated areas. The phenomenon is probably due to an idiosyncratic hypersensitivity reaction, in which a second agent can recall the inflammatory reaction. This case report documents a cold-weather-induced radiation recall dermatitis (RRD). We observed a severe RRD in a patient after chemoradiotherapy treatment with cisplatin for a nasopharyngeal carcinoma, precipitated by cold temperatures, which developed 9 days after completion of therapy. In the medical literature, RRD following extreme cold temperatures seems to be a peculiar event. Until further information on the interaction is available, future studies on combined chemotherapy with cisplatin should be carefully monitored and any side effects clearly documented. This case suggests that environmental conditions may play a contributing role in the development of RRD. This case also implies that neither fraction size nor total radiation dose is a determining factor in the development of the dermatologic reaction. (orig.) [de

Fluoxetine treatment ameliorates depression induced by perinatal arsenic exposure via a neurogenic mechanism

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Tyler, Christina R.; Solomon, Benjamin R.; Ulibarri, Adam L.; Allan, Andrea M.

2014-01-01

Several epidemiological studies have reported an association between arsenic exposure and increased rates of psychiatric disorders, including depression, in exposed populations. We have previously demonstrated that developmental exposure to low amounts of arsenic induces depression in adulthood along with several morphological and molecular aberrations, particularly associated with the hippocampus and the hypothalamic–pituitary–adrenal (HPA) axis. The extent and potential reversibility of this toxin-induced damage has not been characterized to date. In this study, we assessed the effects of fluoxetine, a selective serotonin reuptake inhibitor antidepressant, on adult animals exposed to arsenic during development. Perinatal arsenic exposure (PAE) induced depressive-like symptoms in a mild learned helplessness task and in the forced swim task after acute exposure to a predator odor (2,4,5-trimethylthiazoline, TMT). Chronic fluoxetine treatment prevented these behaviors in both tasks in arsenic-exposed animals and ameliorated arsenic-induced blunted stress responses, as measured by corticosterone (CORT) levels before and after TMT exposure. Morphologically, chronic fluoxetine treatment reversed deficits in adult hippocampal neurogenesis (AHN) after PAE, specifically differentiation and survival of neural progenitor cells. Protein expression of BDNF, CREB, the glucocorticoid receptor (GR), and HDAC2 was significantly increased in the dentate gyrus of arsenic animals after fluoxetine treatment. This study demonstrates that damage induced by perinatal arsenic exposure is reversible with chronic fluoxetine treatment resulting in restored resiliency to depression via a neurogenic mechanism. PMID:24952232

Possible Protective Effect of Sertraline against Cisplatin-Induced Ototoxicity: An Experimental Study

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Murat Ozturk

2013-01-01

Full Text Available Background/Objective. Cisplatin is a widely used chemotherapeutic agent, but its ototoxicity side effect can occur in the majority of patients. Lots of agents were tried to prevent this, but there is not a routine treatment modality yet. The aim of this study was to evaluate the otoprotective effect of sertraline, which is an antidepressant with neuroprotective effects, against cisplatin, in rats. Design. Experimental animal study. Material and Methods. Forty-eight rats were randomly separated in two groups as groups I and II. Group I was identified as the control group and only a single dose of intraperitoneal cisplatin was administered. In group II, in addition to cisplatin, sertraline was administered to the rats through an oral cannula for ten-day period. Distortion product otoacoustic emission measurements were performed at the first day and the 10th day. Results. When the ototoxicity rates after cisplatin in group I and group II in distortion product otoacoustic emission measurements were compared, it was statistically significantly lower in group II in frequencies of 5652, 6165, 6726, 7336, and 7996 Hz (. Conclusion. Sertraline seems to have a protective effect on cisplatin ototoxicity and could be used to prevent the ototoxicity and also to treat the depression that occurred in cancer patients together.

Nuclear proteome analysis of cisplatin-treated HeLa cells

International Nuclear Information System (INIS)

Wu Wei; Yan Chunlan; Gan Tieer; Chen Zhanghui; Lu Xianghong; Duerksen-Hughes, Penelope J.; Zhu Xinqiang; Yang Jun

2010-01-01

Cisplatin has been widely accepted as one of the most efficient anticancer drugs for decades. However, the mechanisms for the cytotoxic effects of cisplatin are still not fully understood. Cisplatin primarily targets DNA, resulting in the formation of DNA double strand breaks and eventually causing cell death. In this study, we applied two-dimensional electrophoresis coupled with LC-MS/MS to analyze the nuclear proteome of HeLa cells treated with cisplatin, in an effort to uncover new mechanistic clues regarding the cellular response to cisplatin. A total of 19 proteins were successfully identified, and these proteins are involved in a variety of basal metabolic and biological processes in cells, including biosynthesis, cell cycle, glycolysis and apoptosis. Six were related to the regulation of mRNA splicing, and we therefore asked whether the Fas gene might undergo alternative splicing following cisplatin treatment. This proved to be the case, as the splicing forms of Fas were modified in cisplatin-treated HeLa cells. This work provides novel information, from the perspective of the nuclear response, for understanding the cytotoxicity caused by cisplatin-induced DNA damage.

Flos Puerariae Extract Ameliorates Cognitive Impairment in Streptozotocin-Induced Diabetic Mice

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Zhong-he Liu

2015-01-01

Full Text Available Objective. The effects of Flos Puerariae extract (FPE on cognitive impairment associated with diabetes were assessed in C57BL/6J mice. Methods. Experimental diabetic mice model was induced by one injection of 50 mg/kg streptozotocin (STZ for 5 days consecutively. FPE was orally administrated at the dosages of 50, 100, or 200 mg/kg/day, respectively. The learning and memory ability was assessed by Morris water maze test. Body weight, blood glucose, free fatty acid (FFA and total cholesterol (TCH in serum, malondialdehyde (MDA, superoxide dismutase (SOD, catalase (CAT, glutathione peroxidase (GSH-Px, and acetylcholinesterase (AChE activities in cerebral cortex and hippocampus were also measured. Results. Oral administration of FPE significantly improved cognitive deficits in STZ-induced diabetic mice. FPE treatment also maintained body weight and ameliorated hyperglycemia and dyslipidemia in diabetic mice. Additionally, decreased MDA level, enhanced CAT, and GSH-Px activities in cerebral cortex or hippocampus, as well as alleviated AChE activity in cerebral cortex, were found in diabetic mice supplemented with FPE. Conclusion. This study suggests that FPE ameliorates memory deficits in experimental diabetic mice, at least partly through the normalization of metabolic abnormalities, ameliorated oxidative stress, and AChE activity in brain.

Calotropin from Asclepias curasavica induces cell cycle arrest and apoptosis in cisplatin-resistant lung cancer cells.

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Mo, En-Pan; Zhang, Rong-Rong; Xu, Jun; Zhang, Huan; Wang, Xiao-Xiong; Tan, Qiu-Tong; Liu, Fang-Lan; Jiang, Ren-Wang; Cai, Shao-Hui

2016-09-16

Calotropin (M11), an active compound isolated from Asclepias curasavica L., was found to exert strong inhibitory and pro-apoptotic activity specifically against cisplatin-induced resistant non-small cell lung cancer (NSCLC) cells (A549/CDDP). Molecular mechanism study revealed that M11 induced cell cycle arrest at the G2/M phase through down-regulating cyclins, CDK1, CDK2 and up-regulating p53 and p21. Furthermore, M11 accelerated apoptosis through the mitochondrial apoptotic pathway which was accompanied by increase Bax/Bcl-2 ratio, decrease in mitochondrial membrane potential, increase in reactive oxygen species production, activations of caspases 3 and 9 as well as cleavage of poly ADP-ribose polymerase (PARP). The activation and phosphorylation of JNK was also found to be involved in M11-induced apoptosis, and SP610025 (specific JNK inhibitor) partially prevented apoptosis induced by M11. In contrast, all of the effects that M11 induce cell cycle arrest and apoptosis in A549/CDDP cells were not significant in A549 cells. Drugs with higher sensitivity against resistant tumor cells than the parent cells are rather rare. Results of this study supported the potential application of M11 on the non-small lung cancer (NSCLC) with cisplatin resistance. Copyright © 2016 Elsevier Inc. All rights reserved.

Oral intake of hydrogen-rich water ameliorated chlorpyrifos-induced neurotoxicity in rats

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Wang, Tingting; Zhao, Ling; Liu, Mengyu; Xie, Fei; Ma, Xuemei, E-mail: xmma@bjut.edu.cn; Zhao, Pengxiang; Liu, Yunqi; Li, Jiala; Wang, Minglian; Yang, Zhaona; Zhang, Yutong

2014-10-01

Chronic exposure to low-levels of organophosphate (OP) compounds, such as chlorpyrifos (CPF), induces oxidative stress and could be related to neurological disorders. Hydrogen has been identified as a novel antioxidant which could selectively scavenge hydroxyl radicals. We explore whether intake of hydrogen-rich water (HRW) can protect Wistar rats from CPF-induced neurotoxicity. Rats were gavaged daily with 6.75 mg/kg body weight (1/20 LD{sub 50}) of CPF and given HRW by oral intake. Nissl staining and electron microscopy results indicated that HRW intake had protective effects on the CPF-induced damage of hippocampal neurons and neuronal mitochondria. Immunostaining results showed that the increased glial fibrillary acidic protein (GFAP) expression in astrocytes induced by CPF exposure can be ameliorated by HRW intake. Moreover, HRW intake also attenuated CPF-induced oxidative stress as evidenced by enhanced level of MDA, accompanied by an increase in GSH level and SOD and CAT activity. Acetylcholinesterase (AChE) activity tests showed significant decrease in brain AChE activity after CPF exposure, and this effect can be ameliorated by HRW intake. An in vitro study demonstrated that AChE activity was more intense in HRW than in normal water with or without chlorpyrifos-oxon (CPO), the metabolically-activated form of CPF. These observations suggest that HRW intake can protect rats from CPF-induced neurotoxicity, and the protective effects of hydrogen may be mediated by regulating the oxidant and antioxidant status of rats. Furthermore, this work defines a novel mechanism of biological activity of hydrogen by directly increasing the AChE activity. - Highlights: • Hydrogen molecules protect rats from CPF-induced damage of hippocampal neurons. • The increased GFAP expression induced by CPF can also be ameliorated by hydrogen. • Hydrogen molecules attenuated the increase in CPF-induced oxidative stress. • Hydrogen molecules attenuated AChE inhibition in vivo

Oral intake of hydrogen-rich water ameliorated chlorpyrifos-induced neurotoxicity in rats

International Nuclear Information System (INIS)

Wang, Tingting; Zhao, Ling; Liu, Mengyu; Xie, Fei; Ma, Xuemei; Zhao, Pengxiang; Liu, Yunqi; Li, Jiala; Wang, Minglian; Yang, Zhaona; Zhang, Yutong

2014-01-01

Chronic exposure to low-levels of organophosphate (OP) compounds, such as chlorpyrifos (CPF), induces oxidative stress and could be related to neurological disorders. Hydrogen has been identified as a novel antioxidant which could selectively scavenge hydroxyl radicals. We explore whether intake of hydrogen-rich water (HRW) can protect Wistar rats from CPF-induced neurotoxicity. Rats were gavaged daily with 6.75 mg/kg body weight (1/20 LD 50 ) of CPF and given HRW by oral intake. Nissl staining and electron microscopy results indicated that HRW intake had protective effects on the CPF-induced damage of hippocampal neurons and neuronal mitochondria. Immunostaining results showed that the increased glial fibrillary acidic protein (GFAP) expression in astrocytes induced by CPF exposure can be ameliorated by HRW intake. Moreover, HRW intake also attenuated CPF-induced oxidative stress as evidenced by enhanced level of MDA, accompanied by an increase in GSH level and SOD and CAT activity. Acetylcholinesterase (AChE) activity tests showed significant decrease in brain AChE activity after CPF exposure, and this effect can be ameliorated by HRW intake. An in vitro study demonstrated that AChE activity was more intense in HRW than in normal water with or without chlorpyrifos-oxon (CPO), the metabolically-activated form of CPF. These observations suggest that HRW intake can protect rats from CPF-induced neurotoxicity, and the protective effects of hydrogen may be mediated by regulating the oxidant and antioxidant status of rats. Furthermore, this work defines a novel mechanism of biological activity of hydrogen by directly increasing the AChE activity. - Highlights: • Hydrogen molecules protect rats from CPF-induced damage of hippocampal neurons. • The increased GFAP expression induced by CPF can also be ameliorated by hydrogen. • Hydrogen molecules attenuated the increase in CPF-induced oxidative stress. • Hydrogen molecules attenuated AChE inhibition in vivo and in

Synergistic effect of melatonin and ghrelin in preventing cisplatin-induced ovarian damage via regulation of FOXO3a phosphorylation and binding to the p27Kip1 promoter in primordial follicles.

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Jang, Hoon; Na, Younghwa; Hong, Kwonho; Lee, Sangho; Moon, Sohyeon; Cho, Minha; Park, Miseon; Lee, Ok-Hee; Chang, Eun Mi; Lee, Dong Ryul; Ko, Jung Jae; Lee, Woo Sik; Choi, Youngsok

2017-10-01

Premature ovarian failure during chemotherapy is a serious problem for young women with cancer. To preserve the fertility of these patients, approaches to prevent chemotherapy-induced ovarian failure are needed. In a previous study, we reported that melatonin treatment prevents the depletion of the dormant follicle pool via repression of the simultaneous activation of dormant primordial follicles by cisplatin. However, melatonin's protective effect was only partial and thus insufficient. In this study, we found that the hormone ghrelin enhances the protective effect of melatonin against cisplatin-induced ovarian failure in mouse model. Co-administration of melatonin and ghrelin more effectively prevented cisplatin-induced follicle disruption. Simultaneous treatment with melatonin and ghrelin almost restored the number of primordial follicles and the corpus luteum in cisplatin-treated ovaries, compared with single administration. We found melatonin and ghrelin receptors on the cell membrane of premature oocytes of primordial follicles. In addition, melatonin and ghrelin co-administration inhibited the cisplatin-induced phosphorylation of PTEN and FOXO3a that induces cytoplasmic translocation of FOXO3a. Inhibition of FOXO3a phosphorylation by melatonin and ghrelin increased the binding affinity of FOXO3a for the p27 Kip1 promoter in primordial follicles. Co-administration of melatonin and ghrelin in cisplatin-treated ovaries restored the expression of p27 Kip1 , which is critical for retention of the dormant status of primordial follicles. In conclusion, these findings suggest that melatonin and ghrelin co-administration is suitable for use as a fertoprotective adjuvant therapy during cisplatin chemotherapy in young female cancer patients. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

EGCG Enhances Cisplatin Sensitivity by Regulating Expression of the Copper and Cisplatin Influx Transporter CTR1 in Ovary Cancer.

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Xuemin Wang

Full Text Available Cisplatin is one of the first-line platinum-based chemotherapeutic agents for treatment of many types of cancer, including ovary cancer. CTR1 (copper transporter 1, a transmembrane solute carrier transporter, has previously been shown to increase the cellular uptake and sensitivity of cisplatin. It is hypothesized that increased CTR1 expression would enhance the sensitivity of cancer cells to cisplatin (cDDP. The present study demonstrates for the first time that (--epigallocatechin-3-gallate (EGCG, a major polyphenol from green tea, can enhance CTR1 mRNA and protein expression in ovarian cancer cells and xenograft mice. EGCG inhibits the rapid degradation of CTR1 induced by cDDP. The combination of EGCG and cDDP increases the accumulation of cDDP and DNA-Pt adducts, and subsequently enhances the sensitivity of ovarian cancer SKOV3 and OVCAR3 cells to the chemotherapeutic agent. In the OVCAR3 ovarian cancer xenograft nude mice model, the combination of the lower concentration of cDDP and EGCG strongly repressed the tumor growth and exhibited protective effect on the nephrotoxicity induced by cisplatin. Overall, these findings uncover a novel chemotherapy mechanism of EGCG as an adjuvant for the treatment of ovarian cancer.

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

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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

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

TET1 promotes cisplatin-resistance via demethylating the vimentin promoter in ovarian cancer.

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Han, Xi; Zhou, Yuanyuan; You, Yuanyi; Lu, Jiaojiao; Wang, Lijie; Hou, Huilian; Li, Jing; Chen, Wei; Zhao, Le; Li, Xu

2017-04-01

The development of chemo-resistance impairs the outcome of the first line platinum-based chemotherapies for ovarian cancer. Deregulation of DNA methylation/demethylation provides a critical mechanism for the occurrence of chemo-resistance. The ten-eleven translocation (TET) family of dioxygenases including TET1/2/3 plays an important part in DNA demethylation, but their roles in cisplatin resistance have not been elucidated. Using cisplatin-sensitive and cisplatin-resistant ovarian cancer cell models, we found that TET1 was significantly upregulated in cisplatin-resistant CP70 cells compared with that in cisplatin-sensitive A2780 cells. Ectopic expression of TET1 in A2780 cells promoted cisplatin resistance and decreased cytotoxicity induced by cisplatin, while inhibition of TET1 by siRNA transfection in CP70 cells attenuated cisplatin resistance and enhanced cytotoxicity of cisplatin. Increased TET1 induced re-expression of vimentin through active DNA demethylation, and cause partial epithelial-to-mesenchymal (EMT) in A2780 cells. Contrarily, knocking down of TET1 in CP70 cells reduced vimentin expression and reversed EMT process. Immunohistochemical analysis of TET1 in human ovarian cancer tissues revealed that TET1 existed in nucleus and cytoplasm in ovarian cancer tissues. And the expression of nuclear TET1 was positively correlated with residual tumor and chemotherapeutic response. Thus, TET1 expression causes resistance to cisplatin and one of the targets of TET1 action is vimentin in ovarian cancer. © 2017 International Federation for Cell Biology.

Structural damage of chicken red blood cells exposed to platinum nanoparticles and cisplatin

DEFF Research Database (Denmark)

Kutwin, Marta; Sawosz, Ewa; Jaworski, Sławomir

2014-01-01

of platinum nanoparticles (NP-Pt) and cisplatin with blood compartments are important for future applications. This study investigated structural damage, cell membrane deformation and haemolysis of chicken embryo red blood cells (RBC) after treatment with cisplatin and NP-Pt. Cisplatin (4 μg/ml) and NP-Pt (2......,6 μg/ml), when incubated with chicken embryo RBC, were detrimental to cell structure and induced haemolysis. The level of haemolytic injury was increased after cisplatin and NP-Pt treatments compared to the control group. Treatment with cisplatin caused structural damage to cell membranes...

Vorinostat enhances the cisplatin-mediated anticancer effects in small cell lung cancer cells.

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Pan, Chun-Hao; Chang, Ying-Fang; Lee, Ming-Shuo; Wen, B-Chen; Ko, Jen-Chung; Liang, Sheng-Kai; Liang, Mei-Chih

2016-11-07

Vorinostat, a histone deacetylase (HDAC) inhibitor, is a promising agent for cancer therapy. Combining vorinostat with cisplatin may relax the chromatin structure and facilitate the accessibility of cisplatin, thus enhancing its cytotoxicity. Studies have not yet investigated the effects of the combination of vorinostat and cisplatin on small cell lung cancer (SCLC). We first assessed the efficacy of vorinostat with etoposide/cisplatin (EP; triple combination) and then investigated the effects of cotreatment with vorinostat and cisplatin on H209 and H146 SCLC cell lines. The anticancer effects of various combinations were determined in terms of cell viability, apoptosis, cell cycle distribution, and vorinostat-regulated proteins. We also evaluated the efficacy of vorinostat/cisplatin combination in H209 xenograft nude mice. Our data revealed that the triple combination engendered a significant reduction of cell viability and high apoptotic cell death. In addition, vorinostat combined with cisplatin enhanced cell growth inhibition, induced apoptosis, and promoted cell cycle arrest. We observed that the acetylation levels of histone H3 and α-tubulin were higher in combination treatments than in vorinostat treatment alone. Moreover, vorinostat reduced the expression of thymidylate synthase (TS), and TS remained inhibited after cotreament with cisplatin. Furthermore, an in vivo study revealed that the combination of vorinostat and cisplatin significantly inhibited tumor growth in xenograft nude mice (tumor growth inhibition T/C% = 20.5 %). Combined treatments with vorinostat promote the cytotoxicity of cisplatin and induce the expression of vorinostat-regulated acetyl proteins, eventually enhancing antitumor effects in SCLC cell lines. Triple combinations with a low dosage of cisplatin demonstrate similar therapeutic effects. Such triple combinations, if applied clinically, may reduce the undesired adverse effects of cisplatin. The effects of the combination of

Nitric oxide synthase inhibition ameliorates nicotine-induced sperm function decline in male rats

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Ibukun P. Oyeyipo

2015-09-01

Conclusion: Taken together, the present data indicate the abilities of l-NAME to ameliorate nicotine-induced spermatotoxic effects in male rats via a mechanism dependent on the circulating testosterone level.

Pharmacological investigations of Punica granatum in glycerol-induced acute renal failure in rats.

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Singh, Amrit Pal; Singh, Amteshwar Jaggi; Singh, Nirmal

2011-09-01

The present study was designed to investigate the ameliorative potential and possible mechanism of hydroalcoholic extract of flowers of P. granatum in glycerol-induced acute renal failure (ARF) in rats. The rats were subjected to rhabdomyolytic ARF by single intramuscular injection of hypertonic glycerol (50% v/v; 8 ml/kg) and the animals were sacrificed after 24 hours of glycerol injection. The plasma creatinine, blood urea nitrogen, creatinine clearance, and histopathological studies were performed to assess the degree of renal injury. Pretreatment with hydroalcoholic extract of flowers of P. granatum (125 and 250 mg/kg p.o. twice daily for 3 days) significantly attenuated hypertonic glycerol-induced renal dysfunction in a dose-dependent manner. BADGE (Bisphenol-A-diglycidyl ether) (30 mg/kg), a peroxisome proliferator-activated receptor (PPAR)-γ antagonist, and N(omega)-nitro-l-arginine-methyl ester (L-NAME) (10, 20, and 40 mg/kg), nitric oxide synthase inhibitor, were employed to explore the mechanism of renoprotective effects of Punica granatum. Administration of BADGE (30 mg/kg) and L-NAME (40 mg/kg) abolished the beneficial effects of P. granatum in glycerol-induced renal dysfunction. Hydroalcoholic extract of flowers of P. granatum has ameliorative potential in attenuating myoglobinuric renal failure and its renoprotective effects involve activation of PPAR-γ and nitric oxide-dependent signaling pathway.

[3-bromopyruvate enhances cisplatin sensitivity of hepatocellular carcinoma cells in vitro].

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Zhao, Surong; Zhang, Yuanyuan; Wu, Chengzhu; Li, Hongmei; Jiang, Chenchen; Jiang, Zhiwen; Liu, Hao

2014-01-01

To investigate the effect of 3-bromopyruvate (3-BP) in sensitizing hepatocellular carcinoma cells to cisplatin-induced apoptosis and its possible mechanism. The growth inhibition of HepG2 and SMMC7721 cells following exposures to different concentrations of 3-BP and cisplatin was measured by MTT assay. The apoptosis of cells treated with 100 µmol/L 3-BP with or without 8 µmol/L cisplatin was assessed using flow cytometry with PI staining, and the activity of caspase-3 and intracellular ATP level were detected using commercial detection kits; the expression of XIAP and PARP was analyzed using Western blotting. 3-BP produced obvious inhibitory effects on HepG2 and SMMC7721 cells at the concentrations of 50-400 µmol/L with IC50 values of 238.9∓13.9 µmol/L and 278.7∓11.7 µmol/L for a 48-h treatment, respectively. Cisplatin also inhibited the growth of HepG2 and SMMC7721 cells at the concentrations of 2-32 µmol/L, with IC50 values of 16.4∓0.9 µmol/L and 20.9∓1.8 µmol/L after a 48-h treatment, respectively. Treatment with 100 µmol/L 3-BP combined with 8 µmol/L cisplatin for 48 h resulted in a growth inhibition rate of (60.6∓2.2)% in HepG2 cells and (56.8∓2.3)% in SMMC7721 cells, which were significantly higher than those in cells treated with 3-BP or cisplatin alone. The combined treatment for 48 h induced an apoptotic rate of (51.1∓4.3)% in HepG2 cells and (46.5∓3.9)% in SMMC7721 cells, which were also markedly higher than those in cells with 3-BP or cisplatin treatment alone. 3-BP can sensitize HepG2 and SMMC7721 cells to cisplatin-induced apoptosis possibly by causing intracellular ATP deficiency, down-regulating XIAP, and increasing caspase-3 activity.

Curcumin ameliorates cardiac dysfunction induced by mechanical trauma.

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Li, Xintao; Cao, Tingting; Ma, Shuo; Jing, Zehao; Bi, Yue; Zhou, Jicheng; Chen, Chong; Yu, Deqin; Zhu, Liang; Li, Shuzhuang

2017-11-05

Curcumin, a phytochemical component derived from turmeric (Carcuma longa), has been extensively investigated because of its anti-inflammatory and anti-oxidative properties. Inflammation and oxidative stress play critical roles in posttraumatic cardiomyocyte apoptosis, which contributes to secondary cardiac dysfunction. This research was designed to identify the protective effect of curcumin on posttraumatic cardiac dysfunction and investigate its underlying mechanism. Noble-Collip drum was used to prepare a mechanical trauma (MT) model of rats, and the hemodynamic responses of traumatized rats were observed by ventricular intubation 12h after trauma. Myocardial apoptosis was determined through terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining and caspase-3 activity assay. Tumor necrosis factor-α (TNF-α) and reactive oxygen species (ROS) generated by monocytes and myocardial cells were identified through enzyme-linked immunosorbent assay (ELISA), and the intracellular alteration of Ca 2+ in cardiomyocytes was examined through confocal microscopy. In vivo, curcumin effectively ameliorated MT-induced secondary cardiac dysfunction and significantly decreased the apoptotic indices of the traumatized myocardial cells. In vitro, curcumin inhibited TNF-α production by monocytes and reduced the circulating TNF-α levels. With curcumin pretreatment, ROS production and Ca 2+ overload in H9c2 cells were attenuated when these cells were incubated with traumatic plasma. Therefore, curcumin can effectively ameliorate MT-induced cardiac dysfunction mainly by inhibiting systemic inflammatory responses and by weakening oxidative stress reaction and Ca 2+ overload in cardiomyocytes. Copyright © 2017 Elsevier B.V. All rights reserved.

Low-doses of cisplatin injure hippocampal synapses: a mechanism for 'chemo' brain?

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Andres, Adrienne L; Gong, Xing; Di, Kaijun; Bota, Daniela A

2014-05-01

Chemotherapy-related cognitive deficits are a major neurological problem, but the underlying mechanisms are unclear. The death of neural stem/precursor cell (NSC) by cisplatin has been reported as a potential cause, but this requires high doses of chemotherapeutic agents. Cisplatin is frequently used in modern oncology, and it achieves high concentrations in the patient's brain. Here we report that exposure to low concentrations of cisplatin (0.1μM) causes the loss of dendritic spines and synapses within 30min. Longer exposures injured dendritic branches and reduced dendritic complexity. At this low concentration, cisplatin did not affect NSC viability nor provoke apoptosis. However, higher cisplatin levels (1μM) led to the rapid loss of synapses and dendritic disintegration, and neuronal-but not NSC-apoptosis. In-vivo treatment with cisplatin at clinically relevant doses also caused a reduction of dendritic branches and decreased spine density in CA1 and CA3 hippocampal neurons. An acute increase in cell death was measured in the CA1 and CA3 neurons, as well as in the NSC population located in the subgranular zone of the dentate gyrus in the cisplatin treated animals. The density of dendritic spines is related to the degree of neuronal connectivity and function, and pathological changes in spine number or structure have significant consequences for brain function. Therefore, this synapse and dendritic damage might contribute to the cognitive impairment observed after cisplatin treatment. Copyright © 2014 Elsevier Inc. All rights reserved.

Synergism between dipyridamole and cisplatin in human breast cancer cells in vitro

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Janice R. Perussi

2003-05-01

Full Text Available Cisplatin is very effective in the treatment of metastatic breast cancer. However, the development of cellular resistance is a serious problem in cisplatin chemotherapy. In the present work, the effects of dipyridamole (DPM on the cellular accumulation and cytotoxicity of cisplatin was studied in cisplatinsensitive (MDA/S and cisplatinresistant (MDA/R human breast cancer cells. In the presence of 30 µM DPM, the IC50 of cisplatin was reduced by 39% for both cell lines. Combination index analysis revealed that cisplatin and dipyridamole interact synergistically in MDA/R cells. In the MDA/S cells, the cellular accumulation of cisplatin increased by 57 ± 8% in the presence of 30 µM DPM. In the MDA/R cells, the cellular accumulation of cisplatin remained the same with or without 30 µM DPM. The results suggest that the enhancement of cisplatin cytotoxicity by DPM in MDA/S cells may be related to a DPM-induced increase in cisplatin accumulation, but the enhanced cytotoxicity in MDA/R cells employs a mechanism that does not involve an increase in the cellular accumulation of cisplatin.

Induction of Heat Shock Protein 70 Ameliorates Ultraviolet-Induced Photokeratitis in Mice

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Yukihiro Horie

2013-01-01

Full Text Available Acute ultraviolet (UV B exposure causes photokeratitis and induces apoptosis in corneal cells. Geranylgeranylacetone (GGA is an acyclic polyisoprenoid that induces expression of heat shock protein (HSP70, a soluble intracellular chaperone protein expressed in various tissues, protecting cells against stress conditions. We examined whether induction of HSP70 has therapeutic effects on UV-photokeratitis in mice. C57 BL/6 mice were divided into four groups, GGA-treated (500 mg/kg/mouse and UVB-exposed (400 mJ/cm2, GGA-untreated UVB-exposed (400 mJ/cm2, GGA-treated (500 mg/kg/mouse but not exposed and naive controls. Eyeballs were collected 24 h after irradiation, and corneas were stained with hematoxylin and eosin (H&E and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL. HSP70, reactive oxygen species (ROS production, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB and protein kinase B (Akt expression were also evaluated. Irradiated corneal epithelium was significantly thicker in the eyes of mice treated with GGA compared with those given the vehicle alone (p < 0.01. Significantly fewer TUNEL-positive cells were observed in the eyes of GGA-treated mice than controls after irradiation (p < 0.01. Corneal HSP70 levels were significantly elevated in corneas of mice treated with GGA (p < 0.05. ROS signal was not affected by GGA. NF-κB activation was reduced but phospho-(Ser/Ther Akt substrate expression was increased in corneas after irradiation when treated with GGA. GGA-treatment induced HSP70 expression and ameliorated UV-induced corneal damage through the reduced NF-κB activation and possibly increased Akt phosphorilation.

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

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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

Pharmacogenomic Variants May Influence the Urinary Excretion of Novel Kidney Injury Biomarkers in Patients Receiving Cisplatin

Science.gov (United States)

Chang, Cara; Hu, Yichun; Hogan, Susan L.; Mercke, Nickie; Gomez, Madeleine; O’Bryant, Cindy; Bowles, Daniel W.; George, Blessy; Wen, Xia; Aleksunes, Lauren M.; Joy, Melanie S.

2017-01-01

Nephrotoxicity is a dose limiting side effect associated with the use of cisplatin in the treatment of solid tumors. The degree of nephrotoxicity is dictated by the selective accumulation of cisplatin in renal tubule cells due to: (1) uptake by organic cation transporter 2 (OCT2) and copper transporter 1 (CTR1); (2) metabolism by glutathione S-transferases (GSTs) and γ-glutamyltransferase 1 (GGT1); and (3) efflux by multidrug resistance-associated protein 2 (MRP2) and multidrug and toxin extrusion protein 1 (MATE1). The purpose of this study was to determine the significance of single nucleotide polymorphisms that regulate the expression and function of transporters and metabolism genes implicated in development of acute kidney injury (AKI) in cisplatin treated patients. Changes in the kidney function were assessed using novel urinary protein biomarkers and traditional markers. Genotyping was conducted by the QuantStudio 12K Flex Real-Time PCR System using a custom open array chip with metabolism, transport, and transcription factor polymorphisms of interest to cisplatin disposition and toxicity. Traditional and novel biomarker assays for kidney toxicity were assessed for differences according to genotype by ANOVA. Allele and genotype frequencies were determined based on Caucasian population frequencies. The polymorphisms rs596881 (SLC22A2/OCT2), and rs12686377 and rs7851395 (SLC31A1/CTR1) were associated with renoprotection and maintenance of estimated glomerular filtration rate (eGFR). Polymorphisms in SLC22A2/OCT2, SLC31A1/CTRI, SLC47A1/MATE1, ABCC2/MRP2, and GSTP1 were significantly associated with increases in the urinary excretion of novel AKI biomarkers: KIM-1, TFF3, MCP1, NGAL, clusterin, cystatin C, and calbindin. Knowledge concerning which genotypes in drug transporters are associated with cisplatin-induced nephrotoxicity may help to identify at-risk patients and initiate strategies, such as using lower or fractionated cisplatin doses or avoiding

Integrin Activation Contributes to Lower Cisplatin Sensitivity in MV3 Melanoma Cells by Inducing the Wnt Signalling Pathway

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Maria B. R. Piva

2017-09-01

Full Text Available Background: integrins have been associated with the development of chemotherapy resistant tumour cells, mostly those of hematopoietic origin, by mediating the binding to the extracellular matrix. The relevance for solid tumour cells and the underlying mechanisms remain elusive. Methods: using MTT assays, we detected the loss in cisplatin sensitivity of human MV3 melanoma cells upon integrin activation. Underlying cellular pathways were evaluated by flow cytometry. A crosstalk between integrin activation and the canonical wnt signalling pathway was tested by measuring β-catenin activity. Results: MV3 cells display a higher resistance against cisplatin cytotoxicity when cellular integrins were activated by manganese or collagen. Proteome profiler array showed a deregulation of the integrin expression pattern by cisplatin. Integrin activation by manganese induces the phosphorylation of PI3K/AKT. The inhibition of PI3K using BEZ235 strongly increases cell sensitivity to cisplatin, blocking manganese and collagen effects. PI3K/AKT activates wnt signalling by blocking Gsk3-β, which was confirmed by β-catenin up-regulation and nuclear localization. Integrins did not affect E-cadherin expression levels, thus endothelial to mesenchymal transition (EMT can be excluded. Conclusion: This is the first report on an integrin/wnt signalling activation axis addressing the consequences for chemotherapy sensitiveness of melanoma cells, which thus offers novel therapeutic targets for approaches to interfere with chemoresistance.

Nonacetaminophen Drug-Induced Acute Liver Failure.

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Thomas, Arul M; Lewis, James H

2018-05-01

Acute liver failure of all causes is diagnosed in between 2000 and 2500 patients annually in the United States. Drug-induced acute liver failure is the leading cause of acute liver failure, accounting for more than 50% of cases. Nonacetaminophen drug injury represents 11% of all cases in the latest registry from the US Acute Liver Failure Study Group. Although rare, acute liver failure is clinically dramatic when it occurs, and requires a multidisciplinary approach to management. In contrast with acetaminophen-induced acute liver failure, non-acetaminophen-induced acute liver failure has a more ominous prognosis with a lower liver transplant-free survival. Copyright © 2018 Elsevier Inc. All rights reserved.

Cytoplasmic p21 is a potential predictor for cisplatin sensitivity in ovarian cancer

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Xia, Xi; Weng, Yanjie; Liao, Shujie; Han, Zhiqiang; Liu, Ronghua; Zhu, Tao; Wang, Shixuan; Xu, Gang; Meng, Li; Zhou, Jianfeng; Ma, Ding; Ma, Quanfu; Li, Xiao; Ji, Teng; Chen, Pingbo; Xu, Hongbin; Li, Kezhen; Fang, Yong; Weng, Danhui

2011-01-01

P21 (WAF1/Cip1) binds to cyclin-dependent kinase complexes and inhibits their activities. It was originally described as an inhibitor of cancer cell proliferation. However, many recent studies have shown that p21 promotes tumor progression when accumulated in the cell cytoplasm. So far, little is known about the correlation between cytoplasmic p21 and drug resistance. This study was aimed to investigate the role of p21 in the cisplatin resistance of ovarian cancer. RT-PCR, western blot and immunofluorescence were used to detect p21 expression and location in cisplatin-resistant ovarian cancer cell line C13* and its parental line OV2008. Regulation of cytoplasmic p21 was performed through transfection of p21 siRNA, Akt2 shRNA and Akt2 constitutively active vector in the two cell lines; their effects on cisplatin-induced apoptosis were evaluated by flow cytometry. Tumor tissue sections of clinical samples were analyzed by immunohistochemistry. p21 predominantly localizes to the cytoplasm in C13* compared to OV2008. Persistent exposure to low dose cisplatin in OV2008 leads to p21 translocation from nuclear to cytoplasm, while it had not impact on p21 localization in C13*. Knockdown of cytoplasmic p21 by p21 siRNA transfection in C13* notably increased cisplatin-induced apoptosis through activation of caspase 3. Inhibition of p21 translocation into the cytoplasm by transfection of Akt2 shRNA into C13* cells significantly increased cisplatin-induced apoptosis, while induction of p21 translocation into the cytoplasm by transfection of constitutively active Akt2 in OV2008 enhanced the resistance to cisplatin. Immunohistochemical analysis of clinical ovarian tumor tissues demonstrated that cytoplasmic p21 was negatively correlated with the response to cisplatin based treatment. Cytoplasmic p21 is a novel biomarker of cisplatin resistance and it may represent a potential therapeutic target for ovarian tumors that are refractory to conventional treatment

Uric acid ameliorates indomethacin-induced enteropathy in mice through its antioxidant activity.

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Yasutake, Yuichi; Tomita, Kengo; Higashiyama, Masaaki; Furuhashi, Hirotaka; Shirakabe, Kazuhiko; Takajo, Takeshi; Maruta, Koji; Sato, Hirokazu; Narimatsu, Kazuyuki; Yoshikawa, Kenichi; Okada, Yoshikiyo; Kurihara, Chie; Watanabe, Chikako; Komoto, Shunsuke; Nagao, Shigeaki; Matsuo, Hirotaka; Miura, Soichiro; Hokari, Ryota

2017-11-01

Uric acid is excreted from blood into the intestinal lumen, yet the roles of uric acid in intestinal diseases remain to be elucidated. The study aimed to determine whether uric acid could reduce end points associated with nonsteroidal anti-inflammatory drug (NSAID)-induced enteropathy. A mouse model of NSAID-induced enteropathy was generated by administering indomethacin intraperitoneally to 8-week-old male C57BL/6 mice, and then vehicle or uric acid was administered orally. A group of mice treated with indomethacin was also concurrently administered inosinic acid, a uric acid precursor, and potassium oxonate, an inhibitor of uric acid metabolism, intraperitoneally. For in vitro analysis, Caco-2 cells treated with indomethacin were incubated in the presence or absence of uric acid. Oral administration of uric acid ameliorated NSAID-induced enteropathy in mice even though serum uric acid levels did not increase. Intraperitoneal administration of inosinic acid and potassium oxonate significantly elevated serum uric acid levels and ameliorated NSAID-induced enteropathy in mice. Both oral uric acid treatment and intraperitoneal treatment with inosinic acid and potassium oxonate significantly decreased lipid peroxidation in the ileum of mice with NSAID-induced enteropathy. Treatment with uric acid protected Caco-2 cells from indomethacin-induced oxidative stress, lipid peroxidation, and cytotoxicity. Uric acid within the intestinal lumen and in serum had a protective effect against NSAID-induced enteropathy in mice, through its antioxidant activity. Uric acid could be a promising therapeutic target for NSAID-induced enteropathy. © 2017 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.

Comparison of weekly administration of cisplatin versus three courses of cisplatin 100 mg/m2 for definitive radiochemotherapy of locally advanced head-and-neck cancers

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Rades, Dirk; Seidl, Daniel; Janssen, Stefan; Bajrovic, Amira; Karner, Katarina; Strojan, Primoz; Schild, Steven E

2016-01-01

To compare definitive radiochemotherapy with weekly administration of 30–40 mg/m 2 of cisplatin to 100 mg/m 2 of cisplatin on days 1, 22 and 43 for outcomes and toxicity in patients with squamous cell carcinoma of the head-and-neck. Seventy-five patients receiving radiochemotherapy with weekly cisplatin (30–40 mg/m 2 ) were compared to 58 patients receiving radiochemotherapy with 100 mg/m 2 cisplatin on days 1, 22 and 43. Radiochemotherapy regimen plus seven characteristics (age, gender, performance score, tumor site, T-/N-category, histologic grading) were evaluated for locoregional control (LRC), metastases-free survival (MFS) and overall survival (OS). Radiochemotherapy groups were compared for toxicity. On multivariate analysis, improved LRC was associated with cisplatin 100 mg/m 2 (hazard ratio [HR] 1.57; p = 0.008) and female gender (HR 4.37; p = 0.003). Radiochemotherapy regimen was not significantly associated with MFS on univariate analysis (p = 0.66). On multivariate analysis, better MFS was associated with ECOG performance score 0–1 (HR 5.63; p < 0.001) and histological grade 1–2 (HR 1.81; p = 0.002). On multivariate analysis, improved OS was associated with cisplatin 100 mg/m 2 (HR 1.33; p = 0.023), ECOG performance score 0–1 (HR 2.15; p = 0.029) and female gender (HR 1.98; p = 0.026). Cisplatin 100 mg/m 2 was associated with higher rates of grade ≥3 hematotoxicity (p = 0.004), grade ≥2 renal failure (p = 0.004) and pneumonia/sepsis (p = 0.033). Radiochemotherapy with 100 mg/m 2 of cisplatin every 3 weeks resulted in better LRC and OS than weekly doses of 30–40 mg/m 2 . Given the limitations of a retrospective study, 100 mg/m 2 of cisplatin appears preferable. Since this regimen was associated with considerable acute toxicity, patients require close monitoring

Role of TRPV1 channels in ischemia/reperfusion-induced acute kidney injury.

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Lan Chen

Full Text Available OBJECTIVES: Transient receptor potential vanilloid 1 (TRPV1 -positive sensory nerves are widely distributed in the kidney, suggesting that TRPV1-mediated action may participate in the regulation of renal function under pathophysiological conditions. Stimulation of TRPV1 channels protects against ischemia/reperfusion (I/R-induced acute kidney injury (AKI. However, it is unknown whether inhibition of these channels is detrimental in AKI or not. We tested the role of TRPV1 channels in I/R-induced AKI by modulating these channels with capsaicin (TRPV1 agonist, capsazepine (TRPV1 antagonist and using Trpv1-/- mice. METHODS AND RESULTS: Anesthetized C57BL/6 mice were subjected to 25 min of renal ischemia and 24 hrs of reperfusion. Mice were pretreated with capsaicin (0.3 mg/kg body weight or capsazepine (50 mg/kg body weight. Capsaicin ameliorated the outcome of AKI, as measured by serum creatinine levels, tubular damage,neutrophil gelatinase-associated lipocalin (NGAL abundance and Ly-6B.2 positive polymorphonuclear inflammatory cells in injured kidneys. Neither capsazepine nor deficiency of TRPV1 did deteriorate renal function or histology after AKI. Measurements of endovanilloids in kidney tissue indicate that 20-hydroxyeicosatetraeonic acid (20-HETE or epoxyeicosatrienoic acids (EETs are unlikely involved in the beneficial effects of capsaicin on I/R-induced AKI. CONCLUSIONS: Activation of TRPV1 channels ameliorates I/R-induced AKI, but inhibition of these channels does not affect the outcome of AKI. Our results may have clinical implications for long-term safety of renal denervation to treat resistant hypertension in man, with respect to the function of primary sensory nerves in the response of the kidney to ischemic stimuli.

The Ameliorative Effects of L-2-Oxothiazolidine-4-Carboxylate on Acetaminophen-Induced Hepatotoxicity in Mice

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Jun Ho Shin

2013-03-01

Full Text Available The aim of the study was to investigate the ameliorative effects and the mechanism of action of L-2-oxothiazolidine-4-carboxylate (OTC on acetaminophen (APAP-induced hepatotoxicity in mice. Mice were randomly divided into six groups: normal control group, APAP only treated group, APAP + 25 mg/kg OTC, APAP + 50 mg/kg OTC, APAP + 100 mg/kg OTC, and APAP + 100 mg/kg N-acetylcysteine (NAC as a reference control group. OTC treatment significantly reduced serum alanine aminotransferase and aspartate aminotransferase levels in a dose dependent manner. OTC treatment was markedly increased glutathione (GSH production and glutathione peroxidase (GSH-px activity in a dose dependent manner. The contents of malondialdehyde and 4-hydroxynonenal in liver tissues were significantly decreased by administration of OTC and the inhibitory effect of OTC was similar to that of NAC. Moreover, OTC treatment on APAP-induced hepatotoxicity significantly reduced the formation of nitrotyrosin and terminal deoxynucleotidyl transferase dUTP nick end labeling positive areas of liver tissues in a dose dependent manner. Furthermore, the activity of caspase-3 in liver tissues was reduced by administration of OTC in a dose dependent manner. The ameliorative effects of OTC on APAP-induced liver damage in mice was similar to that of NAC. These results suggest that OTC has ameliorative effects on APAP-induced hepatotoxicity in mice through anti-oxidative stress and anti-apoptotic processes.

Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma.

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Alfonso Baldi

Full Text Available BACKGROUND: Malignant mesothelioma (MM is a rare, highly aggressive tumor, associated to asbestos exposure. To date no chemotherapy regimen for MM has proven to be definitively curative, and new therapies for MM treatment need to be developed. We have previously shown in vivo that piroxicam/cisplatin combined treatment in MM, specifically acts on cell cycle regulation triggering apoptosis, with survival increase. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed, at molecular level, the apoptotic increase caused by piroxicam/cisplatin treatment in MM cell lines. By means of genome wide analyses, we analyzed transcriptional gene deregulation both after the single piroxicam or cisplatin and the combined treatment. Here we show that apoptotic increase following combined treatment is mediated by p21, since apoptotic increase in piroxicam/cisplatin combined treatment is abolished upon p21 silencing. CONCLUSIONS/SIGNIFICANCE: Piroxicam/cisplatin combined treatment determines an apoptosis increase in MM cells, which is dependent on the p21 expression. The results provided suggest that piroxicam/cisplatin combination might be tested in clinical settings in tumor specimens that express p21.

Apoptosis Induced by Piroxicam plus Cisplatin Combined Treatment Is Triggered by p21 in Mesothelioma

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Baldi, Alfonso; Piccolo, Maria Teresa; Boccellino, Maria Rosaria; Donizetti, Aldo; Cardillo, Irene; La Porta, Raffaele; Quagliuolo, Lucio; Spugnini, Enrico P.; Cordero, Francesca; Citro, Gennaro; Menegozzo, Massimo; Calogero, Raffaele A.; Crispi, Stefania

2011-01-01

Background Malignant mesothelioma (MM) is a rare, highly aggressive tumor, associated to asbestos exposure. To date no chemotherapy regimen for MM has proven to be definitively curative, and new therapies for MM treatment need to be developed. We have previously shown in vivo that piroxicam/cisplatin combined treatment in MM, specifically acts on cell cycle regulation triggering apoptosis, with survival increase. Methodology/Principal Findings We analyzed, at molecular level, the apoptotic increase caused by piroxicam/cisplatin treatment in MM cell lines. By means of genome wide analyses, we analyzed transcriptional gene deregulation both after the single piroxicam or cisplatin and the combined treatment. Here we show that apoptotic increase following combined treatment is mediated by p21, since apoptotic increase in piroxicam/cisplatin combined treatment is abolished upon p21 silencing. Conclusions/Significance Piroxicam/cisplatin combined treatment determines an apoptosis increase in MM cells, which is dependent on the p21 expression. The results provided suggest that piroxicam/cisplatin combination might be tested in clinical settings in tumor specimens that express p21. PMID:21858171

Exercise Ameliorates High Fat Diet Induced Cardiac Dysfunction by Increasing Interleukin 10

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Varun eKesherwani

2015-04-01

Full Text Available Increasing evidence suggests that a sedentary lifestyle and a high fat diet (HFD leads to cardiomyopathy. Moderate exercise ameliorates cardiac dysfunction, however underlying molecular mechanisms are poorly understood. Increased inflammation due to induction of pro-inflammatory cytokine such as tumor necrosis factor-alpha (TNF-α and attenuation of anti-inflammatory cytokine such as interleukin10 (IL-10 contributes to cardiac dysfunction in obese and diabetics. We hypothesized that exercise training ameliorates HFD- induced cardiac dysfunction by mitigating obesity and inflammation through upregulation of IL-10 and downregulation of TNF-α. To test this hypothesis, eight week old, female C57BL/6J mice were fed with HFD and exercised (swimming 1hr/day for 5 days/week for eight weeks. The four treatment groups: normal diet (ND, HFD, HFD + exercise (HFD + Ex and ND + Ex were analyzed for mean body weight, blood glucose level, TNF-α, IL-10, cardiac fibrosis by Masson Trichrome, and cardiac dysfunction by echocardiography. Mean body weights were increased in HFD but comparatively less in HFD + Ex. The level of TNF-α was elevated and IL-10 was downregulated in HFD but ameliorated in HFD + Ex. Cardiac fibrosis increased in HFD and was attenuated by exercise in the HFD + Ex group. The percentage ejection fraction and fractional shortening were decreased in HFD but comparatively increased in HFD + Ex. There was no difference between ND and ND + Ex for the above parameters except an increase in IL-10 level following exercise. Based on these results, we conclude that exercise mitigates HFD- induced cardiomyopathy by decreasing obesity, inducing IL-10, and reducing TNF-α in mice.

Amelioration of liver injury by continuously targeted intervention against TNFRp55 in rats with acute-on-chronic liver failure.

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Yumin Xu

Full Text Available Acute-on-chronic liver failure (ACLF is an acute deterioration of established liver disease. Blocking the TNF (tumor necrosis factor/TNFR (tumor necrosis factor receptor 1 pathway may reduce hepatocyte apoptosis/necrosis, and subsequently decrease mortality during development of ACLF. We demonstrated that a long-acting TNF antagonist (soluble TNF receptor: IgG Fc [sTNFR:IgG-Fc] prevented/reduced development of acute liver failure by blocking the TNF/TNFR1 (TNFRp55 pathway. However, it is still unclear if sTNFR:IgG-Fc can inhibit hepatocyte damage during development of ACLF.Chronic liver disease (liver fibrosis/cirrhosis was induced in Wistar rats by repeatedly challenging with human serum albumin (HSA, and confirmed by histopathology. ACLF was induced with D-galactosamine (D-GalN/lipopolysaccharide (LPS i.p. in the rats with chronic liver disease. Serum and liver were collected for biochemical, pathological and molecular biological examinations.Reduced mortality was observed in sTNFR:IgG-Fc treated ACLF rats, consistent with reduced interleukin (IL-6 levels in serum and liver, as well as reduced hepatic caspase-3 activity, compared to that of mock treated group. Reduced hepatic damage was confirmed with histopathology in the sTNFR:IgG-Fc treated group, which is consistent with reduced Bcl-2 and Bax, at mRNA and protein levels, but increased hepatocyte proliferation (PCNA. This is also supported by the findings that caspase-3 production was up-regulated significantly in ACLF group compared to the mock treated group. Moreover, up-regulated caspase-3 was inhibited following sTNFR:IgG-Fc treatment. Finally, there was up-regulation of hepatic IL-22R in sTNFR:IgG-Fc treated ACLF rats.sTNFR:IgG-Fc improved survival rate during development of ACLF via ameliorating liver injury with a potential therapeutic value.

Addition of 3-day aprepitant to ondansetron and dexamethasone for prophylaxis of chemotherapy-induced nausea and vomiting among patients with diffuse large B cell lymphoma receiving 5-day cisplatin-based chemotherapy

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Raafat Abdel-Malek

2017-09-01

Conclusion: This triple anti-emetic regimen showed efficacy in controlling the multi-day cisplatin-induced nausea and vomiting. Further randomized controlled trials are needed to compare between 3-day and 7-day aprepitant for multi-day cisplatin regimens.

Cannabis-induced Moto-Cognitive Dysfunction in Wistar Rats: Ameliorative Efficacy of Nigella Sativa.

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Imam, Aminu; Ajao, Moyosore Saliu; Amin, Abdulbasit; Abdulmajeed, Wahab Imam; Ibrahim, Abdulmumin; Olajide, Olayemi Joseph; Ajibola, Musa Iyiola; Alli-Oluwafuyi, Abdulmusawir; Balogun, Wasiu Gbolahan

2016-09-01

Cannabis is a widely used illicit drug with various threats of personality syndrome, and Nigella sativa has been widely implicated as having therapeutic efficacy in many neurological diseases. The present study investigates the ameliorative efficacy of Nigella sativa oil (NSO) on cannabis-induced moto-cognitive defects. Scopolamine (1 mg/kg i.p.) was given to induce dementia as a standard base line for cannabis (20 mg/kg)-induced cognitive impairment, followed by an oral administration of NSO (1 ml/kg) for 14 consecutive days. The Morris water maze (MWM) paradigm was used to assess the memory index, the elevated plus maze was used for anxiety-like behaviour, and the open field test was used for locomotor activities; thereafter, the rats were sacrificed and their brains were removed for histopathologic studies. Cannabis-like Scopolamine caused memory impairment, delayed latency in the MWM, and anxiety-like behaviour, coupled with alterations in the cerebello-hippocampal neurons. The post-treatment of rats with NSO mitigated cannabis-induced cognitive dysfunction as with scopolamine and impaired anxiety-like behaviour by increasing open arm entry, line crossing, and histological changes. The observed ameliorative effects of NSO make it a promising agent against moto-cognitive dysfunction and cerebelo-hippocampal alterations induced by cannabis.

Heme Attenuation Ameliorates Irritant Gas Inhalation-Induced Acute Lung Injury.

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Aggarwal, Saurabh; Lam, Adam; Bolisetty, Subhashini; Carlisle, Matthew A; Traylor, Amie; Agarwal, Anupam; Matalon, Sadis

2016-01-10

Exposure to irritant gases, such as bromine (Br2), poses an environmental and occupational hazard that results in severe lung and systemic injury. However, the mechanism(s) of Br2 toxicity and the therapeutic responses required to mitigate lung damage are not known. Previously, it was demonstrated that Br2 upregulates the heme degrading enzyme, heme oxygenase-1 (HO-1). Since heme is a major inducer of HO-1, we determined whether an increase in heme and heme-dependent oxidative injury underlies the pathogenesis of Br2 toxicity. C57BL/6 mice were exposed to Br2 gas (600 ppm, 30 min) and returned to room air. Thirty minutes postexposure, mice were injected intraperitoneally with a single dose of the heme scavenging protein, hemopexin (Hx) (3 μg/gm body weight), or saline. Twenty-four hours postexposure, saline-treated mice had elevated total heme in bronchoalveolar lavage fluid (BALF) and plasma and acute lung injury (ALI) culminating in 80% mortality after 10 days. Hx treatment significantly lowered heme, decreased evidence of ALI (lower protein and inflammatory cells in BALF, lower lung wet-to-dry weight ratios, and decreased airway hyperreactivity to methacholine), and reduced mortality. In addition, Br2 caused more severe ALI and mortality in mice with HO-1 gene deletion (HO-1-/-) compared to wild-type controls, while transgenic mice overexpressing the human HO-1 gene (hHO-1) showed significant protection. This is the first study delineating the role of heme in ALI caused by Br2. The data suggest that attenuating heme may prove to be a useful adjuvant therapy to treat patients with ALI.

Hypoxia-Induced Cisplatin Resistance in Non-Small Cell Lung Cancer Cells Is Mediated by HIF-1α and Mutant p53 and Can Be Overcome by Induction of Oxidative Stress.

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Deben, Christophe; Deschoolmeester, Vanessa; De Waele, Jorrit; Jacobs, Julie; Van den Bossche, Jolien; Wouters, An; Peeters, Marc; Rolfo, Christian; Smits, Evelien; Lardon, Filip; Pauwels, Patrick

2018-04-21

The compound APR-246 (PRIMA-1 MET ) is a known reactivator of (mutant) p53 and inducer of oxidative stress which can sensitize cancer cells to platinum-based chemotherapeutics. However, the effect of a hypoxic tumor environment has been largely overlooked in this interaction. This study focusses on the role of hypoxia-inducible factor-1α (HIF-1α) and the p53 tumor suppressor protein in hypoxia-induced cisplatin resistance in non-small cell lung cancer (NSCLC) cells and the potential of APR-246 to overcome this resistance. We observed that hypoxia-induced cisplatin resistance only occurred in the p53 mutant NCI-H2228 Q331 * cell line, and not in the wild type A549 and mutant NCI-H1975 R273H cell lines. Cisplatin reduced HIF-1α protein levels in NCI-H2228 Q331 * cells, leading to a shift in expression from HIF-1α-dependent to p53-dependent transcription targets under hypoxia. APR-246 was able to overcome hypoxia-induced cisplatin resistance in NCI-H2228 Q331 * cells in a synergistic manner without affecting mutant p53 Q331 * transcriptional activity, but significantly depleting total glutathione levels more efficiently under hypoxic conditions. Synergism was dependent on the presence of mutant p53 Q331 * and the induction of reactive oxygen species, with depletion of one or the other leading to loss of synergism. Our data further support the rationale of combining APR-246 with cisplatin in NSCLC, since their synergistic interaction is retained or enforced under hypoxic conditions in the presence of mutant p53.

Hypoxia-Induced Cisplatin Resistance in Non-Small Cell Lung Cancer Cells Is Mediated by HIF-1α and Mutant p53 and Can Be Overcome by Induction of Oxidative Stress

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Christophe Deben

2018-04-01

Full Text Available The compound APR-246 (PRIMA-1MET is a known reactivator of (mutant p53 and inducer of oxidative stress which can sensitize cancer cells to platinum-based chemotherapeutics. However, the effect of a hypoxic tumor environment has been largely overlooked in this interaction. This study focusses on the role of hypoxia-inducible factor-1α (HIF-1α and the p53 tumor suppressor protein in hypoxia-induced cisplatin resistance in non-small cell lung cancer (NSCLC cells and the potential of APR-246 to overcome this resistance. We observed that hypoxia-induced cisplatin resistance only occurred in the p53 mutant NCI-H2228Q331* cell line, and not in the wild type A549 and mutant NCI-H1975R273H cell lines. Cisplatin reduced HIF-1α protein levels in NCI-H2228Q331* cells, leading to a shift in expression from HIF-1α-dependent to p53-dependent transcription targets under hypoxia. APR-246 was able to overcome hypoxia-induced cisplatin resistance in NCI-H2228Q331* cells in a synergistic manner without affecting mutant p53Q331* transcriptional activity, but significantly depleting total glutathione levels more efficiently under hypoxic conditions. Synergism was dependent on the presence of mutant p53Q331* and the induction of reactive oxygen species, with depletion of one or the other leading to loss of synergism. Our data further support the rationale of combining APR-246 with cisplatin in NSCLC, since their synergistic interaction is retained or enforced under hypoxic conditions in the presence of mutant p53.

The maintenance of cisplatin- and paclitaxel-induced mechanical and cold allodynia is suppressed by cannabinoid CB2 receptor activation and independent of CXCR4 signaling in models of chemotherapy-induced peripheral neuropathy

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Deng Liting

2012-09-01

Full Text Available Abstract Background Chemotherapeutic agents produce dose-limiting peripheral neuropathy through mechanisms that remain poorly understood. We previously showed that AM1710, a cannabilactone CB2 agonist, produces antinociception without producing central nervous system (CNS-associated side effects. The present study was conducted to examine the antinociceptive effect of AM1710 in rodent models of neuropathic pain evoked by diverse chemotherapeutic agents (cisplatin and paclitaxel. A secondary objective was to investigate the potential contribution of alpha-chemokine receptor (CXCR4 signaling to both chemotherapy-induced neuropathy and CB2 agonist efficacy. Results AM1710 (0.1, 1 or 5 mg/kg i.p. suppressed the maintenance of mechanical and cold allodynia in the cisplatin and paclitaxel models. Anti-allodynic effects of AM1710 were blocked by the CB2 antagonist AM630 (3 mg/kg i.p., but not the CB1 antagonist AM251 (3 mg/kg i.p., consistent with a CB2-mediated effect. By contrast, blockade of CXCR4 signaling with its receptor antagonist AMD3100 (10 mg/kg i.p. failed to attenuate mechanical or cold hypersensitivity induced by either cisplatin or paclitaxel. Moreover, blockade of CXCR4 signaling failed to alter the anti-allodynic effects of AM1710 in the paclitaxel model, further suggesting distinct mechanisms of action. Conclusions Our results indicate that activation of cannabinoid CB2 receptors by AM1710 suppresses both mechanical and cold allodynia in two distinct models of chemotherapy-induced neuropathic pain. By contrast, CXCR4 signaling does not contribute to the maintenance of chemotherapy-induced established neuropathy or efficacy of AM1710. Our studies suggest that CB2 receptors represent a promising therapeutic target for the treatment of toxic neuropathies produced by cisplatin and paclitaxel chemotherapeutic agents.

C-Jun N-terminal kinase signalling pathway in response to cisplatin.

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Yan, Dong; An, GuangYu; Kuo, Macus Tien

2016-11-01

Cisplatin (cis diamminedichloroplatinum II, cDDP) is one of the most effective cancer chemotherapeutic agents and is used in the treatment of many types of human malignancies. However, inherent tumour resistance is a major barrier to effective cisplatin therapy. So far, the mechanism of cDDP resistance has not been well defined. In general, cisplatin is considered to be a cytotoxic drug, for damaging DNA and inhibiting DNA synthesis, resulting in apoptosis via the mitochondrial death pathway or plasma membrane disruption. cDDP-induced DNA damage triggers signalling pathways that will eventually decide between cell life and death. As a member of the mitogen-activated protein kinases family, c-Jun N-terminal kinase (JNK) is a signalling pathway in response to extracellular stimuli, especially drug treatment, to modify the activity of numerous proteins locating in the mitochondria or the nucleus. Recent studies suggest that JNK signalling pathway plays a major role in deciding the fate of the cell and inducing resistance to cDDP-induced apoptosis in human tumours. c-Jun N-terminal kinase regulates several important cellular functions including cell proliferation, differentiation, survival and apoptosis while activating and inhibiting substrates for phosphorylation transcription factors (c-Jun, ATF2: Activating transcription factor 2, p53 and so on), which subsequently induce pro-apoptosis and pro-survival factors expression. Therefore, it is suggested that JNK signal pathway is a double-edged sword in cDDP treatment, simultaneously being a significant pro-apoptosis factor but also being associated with increased resistance to cisplatin-based chemotherapy. This review focuses on current knowledge concerning the role of JNK in cell response to cDDP, as well as their role in cisplatin resistance. © 2016 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

BH3-mimetics- and cisplatin-induced cell death proceeds through different pathways depending on the availability of death-related cellular components.

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Vicente Andreu-Fernández

Full Text Available BACKGROUND: Owing to their important function in regulating cell death, pharmacological inhibition of Bcl-2 proteins by dubbed BH3-mimetics is a promising strategy for apoptosis induction or sensitization to chemotherapy. However, the role of Apaf-1, the main protein constituent of the apoptosome, in the process has yet not been analyzed. Furthermore as new chemotherapeutics develop, the possible chemotherapy-induced toxicity to rapidly dividing normal cells, especially sensitive differentiated cells, has to be considered. Such undesirable effects would probably be ameliorated by selectively and locally inhibiting apoptosis in defined sensitive cells. METHODOLOGY AND PRINCIPAL FINDINGS: Mouse embryonic fibroblasts (MEFS from Apaf-1 knock out mouse (MEFS KO Apaf-1 and Bax/Bak double KO (MEFS KO Bax/Bak, MEFS from wild-type mouse (MEFS wt and human cervix adenocarcinoma (HeLa cells were used to comparatively investigate the signaling cell death-induced pathways of BH3-mimetics, like ABT737 and GX15-070, with DNA damage-inducing agent cisplatin (cis-diammineplatinum(II dichloride, CDDP. The study was performed in the absence or presence of apoptosis inhibitors namely, caspase inhibitors or apoptosome inhibitors. BH3-mimetic ABT737 required of Apaf-1 to exert its apoptosis-inducing effect. In contrast, BH3-mimetic GX15-070 and DNA damage-inducing CDDP induced cell death in the absence of both Bax/Bak and Apaf-1. GX15-070 induced autophagy-based cell death in all the cell lines analyzed. MEFS wt cells were protected from the cytotoxic effects of ABT737 and CDDP by chemical inhibition of the apoptosome through QM31, but not by using general caspase inhibitors. CONCLUSIONS: BH3-mimetic ABT737 not only requires Bax/Bak to exert its apoptosis-inducing effect, but also Apaf-1, while GX15-070 and CDDP induce different modalities of cell death in the absence of Bax/Bak or Apaf-1. Inclusion of specific Apaf-1 inhibitors in topical and well

PTEN overexpression improves cisplatin-resistance of human ovarian cancer cells through upregulating KRT10 expression

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Wu, Huijuan; Wang, Ke; Liu, Wenxin; Hao, Quan

2014-01-01

Highlights: • Overexpression of PTEN enhanced the sensitivity of C13K cells to cisplatin. • KRT10 is a downstream molecule of PTEN involved in the resistance-reversing effect. • Overexpression of KRT10 enhanced the chemosensitivity of C13K cells to cisplatin. - Abstract: Multi-drug resistance (MDR) is a common cause of the failure of chemotherapy in ovarian cancer. PTEN, a tumor suppressor gene, has been demonstrated to be able to reverse cisplatin-resistance in ovarian cancer cell line C13K. However, the downstream molecules of PTEN involved in the resistance-reversing effect have not been completely clarified. Therefore, we screened the downstream molecules of PTEN and studied their interactions in C13K ovarian cancer cells using a 3D culture model. Firstly, we constructed an ovarian cancer cell line stably expressing PTEN, C13K/PTEN. MTT assay showed that overexpression of PTEN enhanced the sensitivity of C13K cells to cisplatin, but not to paclitaxel. Then we examined the differently expressed proteins that interacted with PTEN in C13K/PTEN cells with or without cisplatin treatment by co-immunoprecipitation. KRT10 was identified as a differently expressed protein in cisplatin-treated C13K/PTEN cells. Further study confirmed that cisplatin could induce upregulation of KRT10 mRNA and protein in C13K/PTEN cells and there was a directly interaction between KRT10 and PTEN. Forced expression of KRT10 in C13K cells also enhanced cisplatin-induced proliferation inhibition and apoptosis of C13K cells. In addition, KRT10 siRNA blocked cisplatin-induced proliferation inhibition of C13K/PTEN cells. In conclusion, our data demonstrate that KRT10 is a downstream molecule of PTEN which improves cisplatin-resistance of ovarian cancer and forced KRT10 overexpression may also act as a therapeutic method for overcoming MDR in ovarian cancer

GTSE1 expression represses apoptotic signaling and confers cisplatin resistance in gastric cancer cells

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Subhash, Vinod Vijay; Tan, Shi Hui; Tan, Woei Loon; Yeo, Mei Shi; Xie, Chen; Wong, Foong Ying; Kiat, Zee Ying; Lim, Robert; Yong, Wei Peng

2015-01-01

Platinum based therapy is commonly used in the treatment of advanced gastric cancer. However, resistance to chemotherapy is a major challenge that causes marked variation in individual response rate and survival rate. In this study, we aimed to identify the expression of GTSE1 and its correlation with cisplatin resistance in gastric cancer cells. Methylation profiling was carried out in tissue samples from gastric cancer patients before undergoing neoadjuvent therapy using docetaxel, cisplatin and 5FU (DCX) and in gastric cancer cell lines. The correlation between GTSE1 expression and methylation in gastric cancer cells was determined by RT-PCR and MSP respectively. GTSE1 expression was knocked-down using shRNA’s and its effects on cisplatin cytotoxicity and cell survival were detected by MTS, proliferation and clonogenic survival assays. Additionally, the effect of GTSE1 knock down in drug induced apoptosis was determined by western blotting and apoptosis assays. GTSE1 exhibited a differential methylation index in gastric cancer patients and in cell lines that correlated with DCX treatment response and cisplatin sensitivity, respectively. In-vitro, GTSE1 expression showed a direct correlation with hypomethylation. Interestingly, Cisplatin treatment induced a dose dependent up regulation as well as nuclear translocation of GTSE1 expression in gastric cancer cells. Knock down of GTSE1 enhanced cisplatin cytotoxity and led to a significant reduction in cell proliferation and clonogenic survival. Also, loss of GTSE1 expression caused a significant increase in P53 mediated apoptosis in cisplatin treated cells. Our study identifies GTSE1 as a biomarker for cisplatin resistance in gastric cancer cells. This study also suggests the repressive role of GTSE1 in cisplatin induced apoptosis and signifies its potential utility as a therapeutic target for better clinical management of gastric cancer patients. The online version of this article (doi:10.1186/s12885

Silencing of BAG3 promotes the sensitivity of ovarian cancer cells to cisplatin via inhibition of autophagy.

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Qiu, Shuang; Sun, Liang; Jin, Ye; An, Qi; Weng, Changjiang; Zheng, Jianhua

2017-07-01

Ovarian cancer is the most lethal disease among all gynecological malignancies. Interval cytoreductive surgery and cisplatin‑based chemotherapy are the recommended therapeutic strategies. However, acquired resistance to cisplatin remains a big challenge for the overall survival and prognosis in ovarian cancer. Complicated molecular mechanisms are involved in the process. At present, increasing evidence indicates that autophagy plays an important role in the prosurvival and resistance against chemotherapy. In the present study, as a novel autophagy regulator, BCL2‑associated athanogene 3 (BAG3) was investigated to study its role in cisplatin sensitivity in epithelial ovarian cancer. However, whether BAG3 participates in cisplatin sensitivity by inducing autophagy and the underlying mechanism in ovarian cancer cells remain to be clarified. Through the use of quantitative real-time PCR, western blot analysis, CCK-8 and immunofluorescence assays our data revealed that cisplatin-induced autophagy protected ovarian cancer cells from the toxicity of the drug and that this process was regulated by BAG3. Silencing of BAG3 increased cisplatin-induced apoptosis. The results also revealed BAG3 as a potential therapeutic target which enhanced the efficacy of cisplatin in ovarian cancer.

Possible (enzymatic) routes and biological sites for metabolic reduction of BNP7787, a new protector against cisplatin-induced side-effects.

NARCIS (Netherlands)

Verschraagen, M.; Boven, E.; Torun, E; Hausheer, FH; Vijgh, van der WJ

2004-01-01

Disodium 2,2'-dithio-bis-ethane sulfonate (BNP7787) is under investigation as a potential new chemoprotector against cisplatin-induced nephrotoxicity. The selective protection of BNP7787 appears to arise from the preferential uptake of the drug in the kidneys, where BNP7787 would undergo

The genome-wide expression profile of Curcuma longa-treated cisplatin-stimulated HEK293 cells

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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

Corticosteroid treatment ameliorates acute lung injury induced by 2009 swine origin influenza A (H1N1 virus in mice.

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Chenggang Li

Full Text Available BACKGROUND: The 2009 influenza pandemic affected people in almost all countries in the world, especially in younger age groups. During this time, the debate over whether to use corticosteroid treatment in severe influenza H1N1 infections patients resurfaced and was disputed by clinicians. There is an urgent need for a susceptible animal model of 2009 H1N1 infection that can be used to evaluate the pathogenesis and the therapeutic effect of corticosteroid treatment during infection. METHODOLOGY/PRINCIPAL FINDINGS: We intranasally inoculated two groups of C57BL/6 and BALB/c mice (using 4- or 6-to 8-week-old mice to compare the pathogenesis of several different H1N1 strains in mice of different ages. Based on the results, a very susceptible 4-week-old C57BL/6 mouse model of Beijing 501 strain of 2009 H1N1 virus infection was established, showing significantly elevated lung edema and cytokine levels compared to controls. Using our established animal model, the cytokine production profile and lung histology were assessed at different times post-infection, revealing increased lung lesions in a time-dependent manner. In additional,the mice were also treated with dexamethasone, which significantly improved survival rate and lung lesions in infected mice compared to those in control mice. Our data showed that corticosteroid treatment ameliorated acute lung injury induced by the 2009 A/H1N1 virus in mice and suggested that corticosteroids are valid drugs for treating 2009 A/H1N1 infection. CONCLUSIONS/SIGNIFICANCE: Using the established, very susceptible 2009 Pandemic Influenza A (H1N1 mouse model, our studies indicate that corticosteroids are a potential therapeutic remedy that may address the increasing concerns over future 2009 A/H1N1 pandemics.

Phytochemical screening, and assessment of ameliorating effect of aqueous and ethanolic extracts of Gmelina arborea on drug induced hepatic and renal insufficiency in rats.

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Anthony, Ogbonnaya Enyinnaya; Mbuh, Awah Francis; Emmanuel, Mounmbegna Philippe

2012-04-01

Phytochemical screening of stem bark and leaves of Gmelina arborea; and effect of aqueous and ethanolic extracts of Gmelina arborea stembark on hepatic and renal insufficiency in rats was assessed in this study. Phytochemical screening was carried out on the air-dried leaf, oven-dried leaf, air-dried stembark and oven-dried stembark samples. Sixty five (65) wister albino rats, (50.7-117.5 g) were divided into thirteen groups of five animals each. Three groups serve as Controls and were administered Cisplatin (5mg/kg b.w; i.p), Paracetamol (200mg/kg b.w; i.p) and Normal saline (0.002 ml/kg b.w; oral). Other groups were administered, either, cisplatin and extracts (1g/kg b.w; oral); Paracetamol and extracts (1g/kg b.w; oral); extracts alone; or drugs and combination of extracts. Animals were starved, 24 hours prior to sacrifice and sacrificed on the 9th day after commencement of treatment. Phytochemical screening results show the presence of alkaloid, flavonoid, tannin, saponin, cyanogenic glycoside, phytate, and carbohydrate. Saponin and carbohydrate were shown to be much higher in concentration than other phytochemicals. The percentage composition of cyanogenic glycoside and phytate were highest in air-dried stembark and oven-dried leaf samples, respectively. All the Gmelina arborea extracts and extract mixture administered to both paracetamol and cisplatin treated animals, significantly, lowers both the activities of the SGOT and SGPT, and the levels of serum creatinine and urea. When administered alone, the aqueous and ethanolic extracts show little or no sign of toxicity. Thus Gmelina arborea extracts may have ameliorating effect on hepatic and renal insufficiency caused by paracetamol and cisplatin respectively, and any inherent toxicity may be reduced or eliminated through adequate heat treatment.

Post-infectious acute glomerulonephritis with podocytopathy induced by parvovirus B19 infection.

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Hara, Satoshi; Hirata, Masayoshi; Ito, Kiyoaki; Mizushima, Ichiro; Fujii, Hiroshi; Yamada, Kazunori; Nagata, Michio; Kawano, Mitsuhiro

2018-03-01

Human parvovirus B19 infection causes a variety of glomerular diseases such as post-infectious acute glomerulonephritis and collapsing glomerulopathy. Although each of these appears independently, it has not been fully determined why parvovirus B19 provokes such a variety of different glomerular phenotypes. Here, we report a 68-year-old Japanese man who showed endocapillary proliferative glomerulonephritis admixed with podocytopathy in association with parvovirus B19 infection. The patient showed acute onset of heavy proteinuria, microscopic hematuria and kidney dysfunction with arthralgia and oliguria after close contact with a person suffering from erythema infectiosum. In the kidney biopsy specimen, glomeruli revealed diffuse and global endocapillary infiltration of inflammatory cells, with some also showing tuft collapse with aberrant vacuolation, swelling, and hyperplasia of glomerular epithelial cells. Immunofluorescence revealed dense granular C3 deposition that resembled the "starry sky pattern". Intravenous glucocorticoid pulse therapy followed by oral prednisolone and cyclosporine combination therapy resulted in considerable amelioration of the kidney dysfunction and urinary abnormalities. The present case reveals that parvovirus B19 infection can induce different glomerular phenotypes even in the same kidney structure. This finding may provide hints useful for the further elucidation of the pathogenesis of parvovirus B19-induced glomerular lesions. © 2018 Japanese Society of Pathology and John Wiley & Sons Australia, Ltd.

Peroxisome proliferator-activated receptor alpha acts as a mediator of endoplasmic reticulum stress-induced hepatocyte apoptosis in acute liver failure

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Li Zhang

2016-07-01

Full Text Available Peroxisome proliferator-activated receptor α (PPARα is a key regulator to ameliorate liver injury in cases of acute liver failure (ALF. However, its regulatory mechanisms remain largely undetermined. Endoplasmic reticulum stress (ER stress plays an important role in a number of liver diseases. This study aimed to investigate whether PPARα activation inhibits ER stress-induced hepatocyte apoptosis, thereby protecting against ALF. In a murine model of D-galactosamine (D-GalN- and lipopolysaccharide (LPS-induced ALF, Wy-14643 was administered to activate PPARα, and 4-phenylbutyric acid (4-PBA was administered to attenuate ER stress. PPARα activation ameliorated liver injury, because pre-administration of its specific inducer, Wy-14643, reduced the serum aminotransferase levels and preserved liver architecture compared with that of controls. The protective effect of PPARα activation resulted from the suppression of ER stress-induced hepatocyte apoptosis. Indeed, (1 PPARα activation decreased the expression of glucose-regulated protein 78 (Grp78, Grp94 and C/EBP-homologous protein (CHOP in vivo; (2 the liver protection by 4-PBA resulted from the induction of PPARα expression, as 4-PBA pre-treatment promoted upregulation of PPARα, and inhibition of PPARα by small interfering RNA (siRNA treatment reversed liver protection and increased hepatocyte apoptosis; (3 in vitro PPARα activation by Wy-14643 decreased hepatocyte apoptosis induced by severe ER stress, and PPARα inhibition by siRNA treatment decreased the hepatocyte survival induced by mild ER stress. Here, we demonstrate that PPARα activation contributes to liver protection and decreases hepatocyte apoptosis in ALF, particularly through regulating ER stress. Therefore, targeting PPARα could be a potential therapeutic strategy to ameliorate ALF.

Ameliorative effect of Asparagus racemosus root extract against pentylenetetrazol-induced kindling and associated depression and memory deficit.

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Pahwa, Priyanka; Goel, Rajesh Kumar

2016-04-01

Asparagus racemosus (A. racemosus) roots are extensively used in traditional medicine for the management of epilepsy. The aim of the present study was to investigate the ameliorative effect of A. racemosus root extract (ARE) against pentylenetetrazol-induced kindling and associated depression and memory deficit. Kindling was successfully induced by repeated administration of a subconvulsant dose of PTZ (35 mg/kg; i.p.) at an interval of 48 ± 2 h in 43 days (21 injections). Pretreatment with valproate (300 mg/kg; i.p.), a major antiepileptic drug as well as ARE significantly suppressed the progression of kindling. Moreover, ARE also ameliorated the kindling-associated depression and memory deficit as indicated by decreased immobility time and increased step-down latency, respectively, as compared to vehicle control animals. Further, these behavioral observations were complemented with analogous neurochemical changes. In conclusion, the results of the present study showed that ARE treatment has an ameliorative effect against PTZ-induced kindling and associated behavioral comorbidities. Copyright © 2016 Elsevier Inc. All rights reserved.

Downregulation of SWI/SNF chromatin remodeling factor subunits modulates cisplatin cytotoxicity

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Kothandapani, Anbarasi; Gopalakrishnan, Kathirvel; Kahali, Bhaskar; Reisman, David; Patrick, Steve M.

2012-01-01

Chromatin remodeling complex SWI/SNF plays important roles in many cellular processes including transcription, proliferation, differentiation and DNA repair. In this report, we investigated the role of SWI/SNF catalytic subunits Brg1 and Brm in the cellular response to cisplatin in lung cancer and head/neck cancer cells. Stable knockdown of Brg1 and Brm enhanced cellular sensitivity to cisplatin. Repair kinetics of cisplatin DNA adducts revealed that downregulation of Brg1 and Brm impeded the repair of both intrastrand adducts and interstrand crosslinks (ICLs). Cisplatin ICL-induced DNA double strand break repair was also decreased in Brg1 and Brm depleted cells. Altered checkpoint activation with enhanced apoptosis as well as impaired chromatin relaxation was observed in Brg1 and Brm deficient cells. Downregulation of Brg1 and Brm did not affect the recruitment of DNA damage recognition factor XPC to cisplatin DNA lesions, but affected ERCC1 recruitment, which is involved in the later stages of DNA repair. Based on these results, we propose that SWI/SNF chromatin remodeling complex modulates cisplatin cytotoxicity by facilitating efficient repair of the cisplatin DNA lesions. -- Highlights: ► Stable knockdown of Brg1 and Brm enhances cellular sensitivity to cisplatin. ► Downregulation of Brg1 and Brm impedes the repair of cisplatin intrastrand adducts and interstrand crosslinks. ► Brg1 and Brm deficiency results in impaired chromatin relaxation, altered checkpoint activation as well as enhanced apoptosis. ► Downregulation of Brg1 and Brm affects recruitment of ERCC1, but not XPC to cisplatin DNA lesions.

Improved Hepatoprotective Effect of Liposome-Encapsulated Astaxanthin in Lipopolysaccharide-Induced Acute Hepatotoxicity

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Chun-Hung Chiu

2016-07-01

Full Text Available Lipopolysaccharide (LPS-induced acute hepatotoxicity is significantly associated with oxidative stress. Astaxanthin (AST, a xanthophyll carotenoid, is well known for its potent antioxidant capacity. However, its drawbacks of poor aqueous solubility and low bioavailability have limited its utility. Liposome encapsulation is considered as an effective alternative use for the improvement of bioavailability of the hydrophobic compound. We hypothesized that AST encapsulated within liposomes (LA apparently shows improved stability and transportability compared to that of free AST. To investigate whether LA administration can efficiently prevent the LPS-induced acute hepatotoxicity, male Sprague-Dawley rats (n = six per group were orally administered liposome-encapsulated AST at 2, 5 or 10 mg/kg-day (LA-2, LA-5, and LA-10 for seven days and then were LPS-challenged (i.p., 5 mg/kg. The LA-10 administered group, but not the other groups, exhibited a significant amelioration of serum glutamic pyruvic transaminase (GPT, glutamic oxaloacetic transaminase (GOT, blood urea nitrogen (BUN, creatinine (CRE, hepatic malondialdehyde (MDA and glutathione peroxidase (GSH-Px, IL-6, and hepatic nuclear NF-κB and inducible nitric oxide synthase (iNOS, suggesting that LA at a 10 mg/kg-day dosage renders hepatoprotective effects. Moreover, the protective effects were even superior to that of positive control N-acetylcysteine (NAC, 200 mg/kg-day. Histopathologically, NAC, free AST, LA-2 and LA-5 partially, but LA-10 completely, alleviated the acute inflammatory status. These results indicate that hydrophobic AST after being properly encapsulated by liposomes improves bioavailability and can also function as potential drug delivery system in treating hepatotoxicity.

Non-cytotoxic Concentration of Cisplatin Decreases Neuroplasticity-Related Proteins and Neurite Outgrowth Without Affecting the Expression of NGF in PC12 Cells.

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Ferreira, Rafaela Scalco; Dos Santos, Neife Aparecida Guinaim; Martins, Nádia Maria; Fernandes, Laís Silva; Dos Santos, Antonio Cardozo

2016-11-01

Cisplatin is the most effective and neurotoxic platinum chemotherapeutic agent. It induces a peripheral neuropathy characterized by distal axonal degeneration that might progress to degeneration of cell bodies and apoptosis. Most symptoms occur nearby distal axonal branches and axonal degeneration might induce peripheral neuropathy regardless neuronal apoptosis. The toxic mechanism of cisplatin has been mainly associated with DNA damage, but cisplatin might also affect neurite outgrowth. Nevertheless, the neurotoxic mechanism of cisplatin remains unclear. We investigated the early effects of cisplatin on axonal plasticity by using non-cytotoxic concentrations of cisplatin and PC12 cells as a model of neurite outgrowth and differentiation. PC12 cells express NGF-receptors (trkA) and respond to NGF by forming neurites, branches and synaptic vesicles. For comparison, we used a neuronal model (SH-SY5Y cells) that does not express trkA nor responds to NGF. Cisplatin did not change NGF expression in PC12 cells and decreased neurite outgrowth in both models, suggesting a NGF/trkA independent mechanism. It also reduced axonal growth (GAP-43) and synaptic (synapsin I and synaptophysin) proteins in PC12 cells, without inducing mitochondrial damage or apoptosis. Therefore, cisplatin might affect axonal plasticity before DNA damage, NGF/trkA down-regulation, mitochondrial damage or neuronal apoptosis. This is the first study to show that neuroplasticity-related proteins might be early targets of the neurotoxic action of cisplatin and their role on cisplatin-induced peripheral neuropathy should be investigated in vivo.

Synergistic interaction between cisplatin and gemcitabine in neuroblastoma cell lines and multicellular tumor spheroids

NARCIS (Netherlands)

Besançon, Odette G.; Tytgat, Godelieve A. M.; Meinsma, Rutger; Leen, René; Hoebink, Jerry; Kalayda, Ganna V.; Jaehde, Ulrich; Caron, Huib N.; van Kuilenburg, André B. P.

2012-01-01

The efficacy and mechanism of action of cisplatin and gemcitabine were investigated in a panel of neuroblastoma cell lines and multicellular tumor spheroids. In neuroblastoma spheroids, the combination of cisplatin and gemcitabine induced a complete cytostasis at clinical relevant concentrations. A

Heme Attenuation Ameliorates Irritant Gas Inhalation-Induced Acute Lung Injury

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Aggarwal, Saurabh; Lam, Adam; Bolisetty, Subhashini; Carlisle, Matthew A.; Traylor, Amie; Agarwal, Anupam

2016-01-01

Abstract Aims: Exposure to irritant gases, such as bromine (Br2), poses an environmental and occupational hazard that results in severe lung and systemic injury. However, the mechanism(s) of Br2 toxicity and the therapeutic responses required to mitigate lung damage are not known. Previously, it was demonstrated that Br2 upregulates the heme degrading enzyme, heme oxygenase-1 (HO-1). Since heme is a major inducer of HO-1, we determined whether an increase in heme and heme-dependent oxidative injury underlies the pathogenesis of Br2 toxicity. Results: C57BL/6 mice were exposed to Br2 gas (600 ppm, 30 min) and returned to room air. Thirty minutes postexposure, mice were injected intraperitoneally with a single dose of the heme scavenging protein, hemopexin (Hx) (3 μg/gm body weight), or saline. Twenty-four hours postexposure, saline-treated mice had elevated total heme in bronchoalveolar lavage fluid (BALF) and plasma and acute lung injury (ALI) culminating in 80% mortality after 10 days. Hx treatment significantly lowered heme, decreased evidence of ALI (lower protein and inflammatory cells in BALF, lower lung wet-to-dry weight ratios, and decreased airway hyperreactivity to methacholine), and reduced mortality. In addition, Br2 caused more severe ALI and mortality in mice with HO-1 gene deletion (HO-1−/−) compared to wild-type controls, while transgenic mice overexpressing the human HO-1 gene (hHO-1) showed significant protection. Innovation: This is the first study delineating the role of heme in ALI caused by Br2. Conclusion: The data suggest that attenuating heme may prove to be a useful adjuvant therapy to treat patients with ALI. Antioxid. Redox Signal. 24, 99–112. PMID:26376667

Stevia Prevents Acute and Chronic Liver Injury Induced by Carbon Tetrachloride by Blocking Oxidative Stress through Nrf2 Upregulation

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Ramos-Tovar, Erika; Hernández-Aquino, Erika; Casas-Grajales, Sael; Buendia-Montaño, Laura D.; Tsutsumi, Víctor

2018-01-01

The effect of stevia on liver cirrhosis has not been previously investigated. In the present study, the antioxidant and anti-inflammatory properties of stevia leaves were studied in male Wistar rats with carbon tetrachloride- (CCl4-) induced acute and chronic liver damage. Acute and chronic liver damage induced oxidative stress, necrosis, and cholestasis, which were significantly ameliorated by stevia. Chronic CCl4 treatment resulted in liver cirrhosis, as evidenced by nodules of hepatocytes surrounded by thick bands of collagen and distortion of the hepatic architecture, and stevia significantly prevented these alterations. Subsequently, the underlying mechanism of action of the plant was analyzed. Our study for the first time shows that stevia upregulated Nrf2, thereby counteracting oxidative stress, and prevented necrosis and cholestasis through modulation of the main proinflammatory cytokines via NF-κB inhibition. These multitarget mechanisms led to the prevention of experimental cirrhosis. Given the reasonable safety profile of stevia, our results indicated that it may be useful for the clinical treatment of acute and chronic liver diseases. PMID:29849889

Plecanatide and dolcanatide, novel guanylate cyclase-C agonists, ameliorate gastrointestinal inflammation in experimental models of murine colitis.

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Shailubhai, Kunwar; Palejwala, Vaseem; Arjunan, Krishna Priya; Saykhedkar, Sayali; Nefsky, Bradley; Foss, John A; Comiskey, Stephen; Jacob, Gary S; Plevy, Scott E

2015-11-06

To evaluate the effect of orally administered plecanatide or dolcanatide, analogs of uroguanylin, on amelioration of colitis in murine models. The cyclic guanosine monophosphate (cGMP) stimulatory potency of plecanatide and dolcanatide was measured using a human colon carcinoma T84 cell-based assay. For animal studies all test agents were formulated in phosphate buffered saline. Sulfasalazine or 5-amino salicylic acid (5-ASA) served as positive controls. Effect of oral treatment with test agents on amelioration of acute colitis induced either by dextran sulfate sodium (DSS) in drinking water or by rectal instillation of trinitrobenzene sulfonic (TNBS) acid, was examined in BALB/c and/or BDF1 mice. Additionally, the effect of orally administered plecanatide on the spontaneous colitis in T-cell receptor alpha knockout (TCRα(-/-)) mice was also examined. Amelioration of colitis was assessed by monitoring severity of colitis, disease activity index and by histopathology. Frozen colon tissues were used to measure myeloperoxidase activity. Plecanatide and dolcanatide are structurally related analogs of uroguanylin, which is an endogenous ligand of guanylate cyclase-C (GC-C). As expected from the agonists of GC-C, both plecanatide and dolcanatide exhibited potent cGMP-stimulatory activity in T84 cells. Once-daily treatment by oral gavage with either of these analogs (0.05-0.5 mg/kg) ameliorated colitis in both DSS and TNBS-induced models of acute colitis, as assessed by body weight, reduction in colitis severity (P < 0.05) and disease activity index (P < 0.05). Amelioration of colitis by either of the drug candidates was comparable to that achieved by orally administered sulfasalazine or 5-ASA. Plecanatide also effectively ameliorated colitis in TCRα(-/-) mice, a model of spontaneous colitis. As dolcanatide exhibited higher resistance to proteolysis in simulated gastric and intestinal juices, it was selected for further studies. This is the first-ever study reporting

Probiotics and Probiotic Metabolic Product Improved Intestinal Function and Ameliorated LPS-Induced Injury in Rats.

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Deng, Bo; Wu, Jie; Li, Xiaohui; Men, Xiaoming; Xu, Ziwei

2017-11-01

In the present study, we sought to determine the effects of Bacillus subtilis (BAS) and Bacillus licheniformis (BAL) in rats after lipopolysaccharide (LPS)-induced acute intestinal inflammation. We also determined whether the B. subtilis metabolic product (BASM) is as effective as the live-cell probiotic. 60 male SD rats were randomly assigned to five groups and administered a diet containing 0.05% B. licheniformis (BAL group), 0.05% B. subtilis (BAS group), 0.5% B. subtilis metabolic product (BASM group), or a basic diet (PC group and NC group) for 40 days. On day 40, BAL, BAS, BASM, and NC groups were injected with 4 mg/kg body weight LPS. 4 h later, all rats were anesthetized and sacrificed. The results showed that the administration of B. licheniformis and B. subtilis improved intestinal function as evidenced by histology, increased enzyme activity, and mucosal thickness. They also increased the number of intraepithelial lymphocytes and decreased mucosal myeloperoxidase activity and plasma TNF-α. In addition, the cecal content of B. subtilis-treated rats had significantly increased microbial diversity, decreased numbers of Firmicutes, and increased numbers of Bacteroidetes as compared to rats fed basic diets. Similar to BAS group, the cecal content of B. licheniformis-treated rats decreased the number of Firmicutes. Administration of B. subtilis metabolic product had similar effects on intestinal function, inflammation response, and microbial diversity as B. subtilis but these effects were attenuated. In conclusion, administration of probiotic strains B. licheniformis or B. subtilis improved intestinal function, ameliorated the inflammation response, and modulated microflora after LPS-induced acute inflammation in rats. Non-living cells also exerted probiotic properties but live cells tended to function better.

Membrane Transporters as Mediators of Cisplatin Effects and Side Effects

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Giuliano Ciarimboli

2012-01-01

Full Text Available Transporters are important mediators of specific cellular uptake and thus, not only for effects, but also for side effects, metabolism, and excretion of many drugs such as cisplatin. Cisplatin is a potent cytostatic drug, whose use is limited by its severe acute and chronic nephro-, oto-, and peripheral neurotoxicity. For this reason, other platinum derivatives, such as carboplatin and oxaliplatin, with less toxicity but still with antitumoral action have been developed. Several transporters, which are expressed on the cell membranes, have been associated with cisplatin transport across the plasma membrane and across the cell: the copper transporter 1 (Ctr1, the copper transporter 2 (Ctr2, the P-type copper-transporting ATPases ATP7A and ATP7B, the organic cation transporter 2 (OCT2, and the multidrug extrusion transporter 1 (MATE1. Some of these transporters are also able to accept other platinum derivatives as substrate. Since membrane transporters display a specific tissue distribution, they can be important molecules that mediate the entry of platinum derivatives in target and also nontarget cells possibly mediating specific effects and side effects of the chemotherapeutic drug. This paper summarizes the literature on toxicities of cisplatin compared to that of carboplatin and oxaliplatin and the interaction of these platinum derivatives with membrane transporters.

Synergistic anticancer effects of cisplatin and histone deacetylase inhibitors (SAHA and TSA) on cholangiocarcinoma cell lines.

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Asgar, Md Ali; Senawong, Gulsiri; Sripa, Banchob; Senawong, Thanaset

2016-01-01

Clinical application of cisplatin against cholangiocarcinoma is often associated with resistance and toxicity posing urgent demand for combination therapy. In this study, we evaluated the combined anticancer effect of cisplatin and histone deacetylase inhibitors (HDACIs), suberoylanilide hydroxamic acid (SAHA) and trichostatin A (TSA), on the cholangiocarcinoma KKU-100 and KKU-M214 cell lines. Antiproliferative activity was evaluated using MTT assay. Apoptosis induction and cell cycle arrest were analyzed by flow cytometry. Cell cycle and apoptosis regulating proteins were evaluated by western blot analysis. MTT assay showed that cisplatin, SAHA and TSA dose-dependently reduced the viability of KKU-100 and KKU-M214 cells. The combination of cisplatin and HDACIs exerted significantly more cytotoxicity than the single drugs. Combination indices below 1.0 reflect synergism between cisplatin and HDACIs, leading to positive dose reductions of cisplatin and HDACIs. Cisplatin and HDACIs alone induced G0/G1 phase arrest in KKU-100 cells, but the drug combinations increased sub-G1 percent more than either drug. However, cisplatin and HDACIs alone or in combination increased only the sub-G1 percent in KKU-M214 cells. Annexin V-FITC staining revealed that cisplatin and HDACIs combinations induced more apoptotic cell death of both KKU-100 and KKU-M214 cells than the single drug. In KKU-100 cells, growth inhibition was accompanied by upregulation of p53 and p21 and downregulation of CDK4 and Bcl-2 due to exposure to cisplatin, SAHA and TSA alone or in combination. Moreover, combination of agents exerted higher impacts on protein expression. Single agents or combination did not affect p53 expression, however, combination of cisplatin and HDACIs increased the expression of p21 in KKU-M214 cells. Taken together, cisplatin and HDACIs combination may improve the therapeutic outcome in cholangiocarcinoma patients.

In vitro effects of cisplatin-functionalized silica nanoparticles on chondrocytes

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Bhowmick, Tridib Kumar; Yoon, Diana [University of Maryland, Department of Chemical and Biomolecular Engineering (United States); Patel, Minal; Fisher, John [University of Maryland, Fischell Department of Bioengineering (United States); Ehrman, Sheryl, E-mail: sehrman@umd.ed [University of Maryland, Department of Chemical and Biomolecular Engineering (United States)

2010-10-15

In this study, we evaluated the combined effect of a known toxic molecule, cisplatin, in combination with relatively nontoxic nanoparticles, amorphous fumed silica, on chondrocyte cells. Cisplatin was attached to silica nanoparticles using aminopropyltriethoxy silane as a linker molecule, and characterized in terms of size, shape, specific surface area, as well as the dissolution of cisplatin from the silica surface. The primary particle diameter of the as-received silica nanoparticles ranged from 7.1 to 61 nm, estimated from measurements of specific surface area, and the primary particles were aggregated. The effects of cisplatin-functionalized silica particles with different specific surface areas (41, 85, 202, 237, and 297 m{sup 2}/g) were compared in vitro on chondrocytes, the parenchymal cell of hyaline cartilage. The results show that adverse effects on cell function, as evidenced by reduced metabolic activity measured by the MTT assay and increased membrane permeability observed using the Live/Dead stain, can be correlated with specific surface area of the silica. Cisplatin-functionalized silica nanoparticles with the highest specific surface area incited the greatest response, which was almost equivalent to that induced by free cisplatin. This result suggests the importance of particle specific surface area in interactions between cells and surface-functionalized nanomaterials.

In vitro effects of cisplatin-functionalized silica nanoparticles on chondrocytes

Science.gov (United States)

Bhowmick, Tridib Kumar; Yoon, Diana; Patel, Minal; Fisher, John; Ehrman, Sheryl

2010-10-01

In this study, we evaluated the combined effect of a known toxic molecule, cisplatin, in combination with relatively nontoxic nanoparticles, amorphous fumed silica, on chondrocyte cells. Cisplatin was attached to silica nanoparticles using aminopropyltriethoxy silane as a linker molecule, and characterized in terms of size, shape, specific surface area, as well as the dissolution of cisplatin from the silica surface. The primary particle diameter of the as-received silica nanoparticles ranged from 7.1 to 61 nm, estimated from measurements of specific surface area, and the primary particles were aggregated. The effects of cisplatin-functionalized silica particles with different specific surface areas (41, 85, 202, 237, and 297 m2/g) were compared in vitro on chondrocytes, the parenchymal cell of hyaline cartilage. The results show that adverse effects on cell function, as evidenced by reduced metabolic activity measured by the MTT assay and increased membrane permeability observed using the Live/Dead stain, can be correlated with specific surface area of the silica. Cisplatin-functionalized silica nanoparticles with the highest specific surface area incited the greatest response, which was almost equivalent to that induced by free cisplatin. This result suggests the importance of particle specific surface area in interactions between cells and surface-functionalized nanomaterials.

Quantitative strategies to determine cisplatin adducts with DNA nucleotides in drosofila larvae and tumoral cell cultures

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Garcia Sar, D.; Montes-Bayon, M.; Hann, S.; Koellensperger, G.; Blanco-Gonzalez, E.; Sanz-Medel, A.

2009-01-01

Full text: The antitumoral effect of cisplatin [cis-diamminodichloroplatinum(II)] in mammals is related to its binding to DNA components. A novel sensitive and selective method is proposed to quantify cisplatin-DNA adducts induced in vivo in somatic cells of Drosophila melanogaster at biologically relevant concentrations. The method uses HPLC-ICPMS in combination with species-specific isotope dilution analysis (cisplatin enriched in 194 Pt). For the first time, a cisplatin-DNA adduct is quantified by this approach. The obtained results show the great potential of this system to advance our molecular understanding of the biological effects of cisplatin. (author)

Induction of Activating Transcription Factor 3 Is Associated with Cisplatin Responsiveness in Non–Small Cell Lung Carcinoma Cells

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Jair Bar

2016-09-01

Full Text Available Non–small cell lung carcinoma (NSCLC is the most common cause of cancer deaths, with platin-based combination chemotherapy the most efficacious therapies. Gains in overall survival are modest, highlighting the need for novel therapeutic approaches including the development of next-generation platin combination regimens. The goal of this study was to identify novel regulators of platin-induced cytotoxicity as potential therapeutic targets to further enhance platin cytotoxicity. Employing RNA-seq transcriptome analysis comparing two parental NSCLC cell lines Calu6 and H23 to their cisplatin-resistant sublines, Calu6cisR1 and H23cisR1, activating transcription factor 3 (ATF3 was robustly induced in cisplatin-treated parental sensitive cell lines but not their resistant sublines, and in three of six tumors evaluated, but not in their corresponding normal adjacent lung tissue (0/6. Cisplatin-induced JNK activation was a key regulator of this ATF3 induction. Interestingly, in both resistant sublines, this JNK induction was abrogated, and the expression of an activated JNK construct in these cells enhanced both cisplatin-induced cytotoxicity and ATF3 induction. An FDA-approved drug compound screen was employed to identify enhancers of cisplatin cytotoxicity that were dependent on ATF3 gene expression. Vorinostat, a histone deacetylase inhibitor, was identified in this screen and demonstrated synergistic cytotoxicity with cisplatin in both the parental Calu6 and H23 cell lines and importantly in their resistant sublines as well that was dependent on ATF3 expression. Thus, we have identified ATF3 as an important regulator of cisplatin cytotoxicity and that ATF3 inducers in combination with platins are a potential novel therapeutic approach for NSCLC.

Amelioration of carbon tetrachloride-induced hepatic injury by emulsified Antrodia extract

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Wei-Chih Chang

2018-03-01

Full Text Available Objective(s: Antrodia cinnamomea (AC is found with anti-inflammatory and immunomodulatory biological activities. In this study, we investigated the anti-hepatitis effect of the emulsified AC extract from RO water or supercritical fluid CO2 with ethanol co-solvent extract methods of AC preparations. Materials and Methods: Five groups of eight to ten weeks male rats with a count of ten for each group were studied to evaluate the protection of two kinds of AC extract from hepatic injury. Acute liver injury of rats was induced by injecting 40% carbon tetrachloride (CCl4 1 mg/kg intraperitoneally. Positive and negative control groups rats were perfused with CCl4 or isotonic saline, respectively. Experimental groups received oral administration once/day of AC preparations before CCl4 treatment: water AC extract (WAE group, or emulsified AC extract from supercritical fluid extraction (EAE group for 5 days, and sacrificed on the 6th day and the blood and liver samples were collected under chloral hydrate anesthesia. The anti-inflammatory, antioxidant markers, and relevant signaling pathways were measured (AST, ALT, ROS, IL-1, IL-6, NO, and COX-2, MAPKs, and caspase-3. Results: EAE at 50 mg/kg significantly decreased the serum AST, ALT, IL-1, IL-6, NO, and ROS levels. Both extracts reduced the activation of p-ERK in the liver samples, but EAE inhibited COX-2 and caspase-3 protein expression better than WAE. The EAE ameliorated CCl4-induced hepatic injury significantly; as compared with WAE and the positive control. Conclusion: The hepatoprotection of EAE could be attributed to the antioxidant and anti-inflammatory effects of Antrodia.

Role of Insulin-Like Growth Factor-1 Signaling Pathway in Cisplatin-Resistant Lung Cancer Cells

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Sun Yunguang; Zheng Siyuan; Torossian, Artour; Speirs, Christina K.; Schleicher, Stephen; Giacalone, Nicholas J.; Carbone, David P.; Zhao Zhongming; Lu Bo

2012-01-01

Purpose: The development of drug-resistant phenotypes has been a major obstacle to cisplatin use in non–small-cell lung cancer. We aimed to identify some of the molecular mechanisms that underlie cisplatin resistance using microarray expression analysis. Methods and Materials: H460 cells were treated with cisplatin. The differences between cisplatin-resistant lung cancer cells and parental H460 cells were studied using Western blot, MTS, and clonogenic assays, in vivo tumor implantation, and microarray analysis. The cisplatin-R cells were treated with human recombinant insulin-like growth factor (IGF) binding protein-3 and siRNA targeting IGF-1 receptor. Results: Cisplatin-R cells illustrated greater expression of the markers CD133 and aldehyde dehydrogenase, more rapid in vivo tumor growth, more resistance to cisplatin- and etoposide-induced apoptosis, and greater survival after treatment with cisplatin or radiation than the parental H460 cells. Also, cisplatin-R demonstrated decreased expression of insulin-like growth factor binding protein-3 and increased activation of IGF-1 receptor signaling compared with parental H460 cells in the presence of IGF-1. Human recombinant IGF binding protein-3 reversed cisplatin resistance in cisplatin-R cells and targeting of IGF-1 receptor using siRNA resulted in sensitization of cisplatin-R-cells to cisplatin and radiation. Conclusions: The IGF-1 signaling pathway contributes to cisplatin-R to cisplatin and radiation. Thus, this pathway represents a potential target for improved lung cancer response to treatment.

Role of Insulin-Like Growth Factor-1 Signaling Pathway in Cisplatin-Resistant Lung Cancer Cells

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Sun Yunguang [Department of Radiation Oncology, Vanderbilt University Medical Center, Nashville, TN (United States); Zheng Siyuan [Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN (United States); Torossian, Artour; Speirs, Christina K.; Schleicher, Stephen; Giacalone, Nicholas J. [Department of Radiation Oncology, Vanderbilt University Medical Center, Nashville, TN (United States); Carbone, David P. [Department of Hematology and Oncology, Vanderbilt University Medical Center, Nashville, TN (United States); Zhao Zhongming, E-mail: zhongming.zhao@vanderbilt.edu [Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN (United States); Lu Bo, E-mail: bo.lu@vanderbilt.edu [Department of Radiation Oncology, Vanderbilt University Medical Center, Nashville, TN (United States)

2012-03-01

Purpose: The development of drug-resistant phenotypes has been a major obstacle to cisplatin use in non-small-cell lung cancer. We aimed to identify some of the molecular mechanisms that underlie cisplatin resistance using microarray expression analysis. Methods and Materials: H460 cells were treated with cisplatin. The differences between cisplatin-resistant lung cancer cells and parental H460 cells were studied using Western blot, MTS, and clonogenic assays, in vivo tumor implantation, and microarray analysis. The cisplatin-R cells were treated with human recombinant insulin-like growth factor (IGF) binding protein-3 and siRNA targeting IGF-1 receptor. Results: Cisplatin-R cells illustrated greater expression of the markers CD133 and aldehyde dehydrogenase, more rapid in vivo tumor growth, more resistance to cisplatin- and etoposide-induced apoptosis, and greater survival after treatment with cisplatin or radiation than the parental H460 cells. Also, cisplatin-R demonstrated decreased expression of insulin-like growth factor binding protein-3 and increased activation of IGF-1 receptor signaling compared with parental H460 cells in the presence of IGF-1. Human recombinant IGF binding protein-3 reversed cisplatin resistance in cisplatin-R cells and targeting of IGF-1 receptor using siRNA resulted in sensitization of cisplatin-R-cells to cisplatin and radiation. Conclusions: The IGF-1 signaling pathway contributes to cisplatin-R to cisplatin and radiation. Thus, this pathway represents a potential target for improved lung cancer response to treatment.

Poly(amido)amine (PAMAM) dendrimer-cisplatin complexes for chemotherapy of cisplatin-resistant ovarian cancer cells

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Yellepeddi, Venkata Kashyap; Vangara, Kiran Kumar; Palakurthi, Srinath

2013-09-01

Dendrimer-cisplatin complexes were prepared using PAMAM dendrimers with terminal -NH2 and -COOH groups as well as biotin-conjugated dendrimers. Preformulation parameters of dendrimer-cisplatin complexes were studied using differential scanning calorimetry (DSC) and inductively coupled plasma-mass spectrometry (ICP-MS). Cytotoxicity and mechanism of cytotoxicity of dendrimer-cisplatin complexes was investigated in OVCAR-3, SKOV, A2780 and cisplatin-resistant CP70 human ovarian cancer cell lines. The loading of cisplatin in dendrimers was 11 % (w/w). PAMAM G4 dendrimers with amine surface groups (biotinylated and native) have shown 2.5- to 3.0-fold reduction in IC50 values in ovarian cancer cells when compared with carboxylate surface dendrimers ( p cisplatin complexes resulted in a 7.0-fold increase ( p cisplatin chemotherapy of ovarian cancer.

Obestatin Accelerates the Recovery in the Course of Ischemia/Reperfusion-Induced Acute Pancreatitis in Rats.

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Jakub Bukowczan

Full Text Available Several previous studies have shown that obestatin exhibits protective and regenerative effects in some organs including the stomach, kidney, and the brain. In the pancreas, pretreatment with obestatin inhibits the development of cerulein-induced acute pancreatitis, and promotes survival of pancreatic beta cells and human islets. However, no studies investigated the effect of obestatin administration following the onset of experimental acute pancreatitis.The aim of this study was to evaluate the impact of obestatin therapy in the course of ischemia/reperfusion-induced pancreatitis. Moreover, we tested the influence of ischemia/reperfusion-induced acute pancreatitis and administration of obestatin on daily food intake and pancreatic exocrine secretion.Acute pancreatitis was induced by pancreatic ischemia followed by reperfusion of the pancreas. Obestatin (8 nmol/kg/dose was administered intraperitoneally twice a day, starting 24 hours after the beginning of reperfusion. The effect of obestatin in the course of necrotizing pancreatitis was assessed between 2 and 14 days, and included histological, functional, and biochemical analyses. Secretory studies were performed on the third day after sham-operation or induction of acute pancreatitis in conscious rats equipped with chronic pancreatic fistula.Treatment with obestatin ameliorated morphological signs of pancreatic damage including edema, vacuolization of acinar cells, hemorrhages, acinar necrosis, and leukocyte infiltration of the gland, and led to earlier pancreatic regeneration. Structural changes were accompanied by biochemical and functional improvements manifested by accelerated normalization of interleukin-1β level and activity of myeloperoxidase and lipase, attenuation of the decrease in pancreatic DNA synthesis, and by an improvement of pancreatic blood flow. Induction of acute pancreatitis by pancreatic ischemia followed by reperfusion significantly decreased daily food intake and

Starvation-induced activation of ATM/Chk2/p53 signaling sensitizes cancer cells to cisplatin

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Shi Yandong

2012-12-01

Full Text Available Abstract Background Optimizing the safety and efficacy of standard chemotherapeutic agents such as cisplatin (CDDP is of clinical relevance. Serum starvation in vitro and short-term food starvation in vivo both stress cells by the sudden depletion of paracrine growth stimulation. Methods The effects of serum starvation on CDDP toxicity were investigated in normal and cancer cells by assessing proliferation, cell cycle distribution and activation of DNA-damage response and of AMPK, and were compared to effects observed in cells grown in serum-containing medium. The effects of short-term food starvation on CDDP chemotherapy were assessed in xenografts-bearing mice and were compared to effects on tumor growth and/or regression determined in mice with no diet alteration. Results We observed that serum starvation in vitro sensitizes cancer cells to CDDP while protecting normal cells. In detail, in normal cells, serum starvation resulted in a complete arrest of cellular proliferation, i.e. depletion of BrdU-incorporation during S-phase and accumulation of the cells in the G0/G1-phase of the cell cycle. Further analysis revealed that proliferation arrest in normal cells is due to p53/p21 activation, which is AMPK-dependent and ATM-independent. In cancer cells, serum starvation also decreased the fraction of S-phase cells but to a minor extent. In contrast to normal cells, serum starvation-induced p53 activation in cancer cells is both AMPK- and ATM-dependent. Combination of CDDP with serum starvation in vitro increased the activation of ATM/Chk2/p53 signaling pathway compared to either treatment alone resulting in an enhanced sensitization of cancer cells to CDDP. Finally, short-term food starvation dramatically increased the sensitivity of human tumor xenografts to cisplatin as indicated not only by a significant growth delay, but also by the induction of complete remission in 60% of the animals bearing mesothelioma xenografts, and in 40% of the

Normal Tissue Complication Probability Analysis of Acute Gastrointestinal Toxicity in Cervical Cancer Patients Undergoing Intensity Modulated Radiation Therapy and Concurrent Cisplatin

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Simpson, Daniel R.; Song, William Y.; Moiseenko, Vitali; Rose, Brent S.; Yashar, Catheryn M.; Mundt, Arno J.; Mell, Loren K.

2012-01-01

Purpose: To test the hypothesis that increased bowel radiation dose is associated with acute gastrointestinal (GI) toxicity in cervical cancer patients undergoing concurrent chemotherapy and intensity-modulated radiation therapy (IMRT), using a previously derived normal tissue complication probability (NTCP) model. Methods: Fifty patients with Stage I–III cervical cancer undergoing IMRT and concurrent weekly cisplatin were analyzed. Acute GI toxicity was graded using the Radiation Therapy Oncology Group scale, excluding upper GI events. A logistic model was used to test correlations between acute GI toxicity and bowel dosimetric parameters. The primary objective was to test the association between Grade ≥2 GI toxicity and the volume of bowel receiving ≥45 Gy (V 45 ) using the logistic model. Results: Twenty-three patients (46%) had Grade ≥2 GI toxicity. The mean (SD) V 45 was 143 mL (99). The mean V 45 values for patients with and without Grade ≥2 GI toxicity were 176 vs. 115 mL, respectively. Twenty patients (40%) had V 45 >150 mL. The proportion of patients with Grade ≥2 GI toxicity with and without V 45 >150 mL was 65% vs. 33% (p = 0.03). Logistic model parameter estimates V50 and γ were 161 mL (95% confidence interval [CI] 60–399) and 0.31 (95% CI 0.04–0.63), respectively. On multivariable logistic regression, increased V 45 was associated with an increased odds of Grade ≥2 GI toxicity (odds ratio 2.19 per 100 mL, 95% CI 1.04–4.63, p = 0.04). Conclusions: Our results support the hypothesis that increasing bowel V 45 is correlated with increased GI toxicity in cervical cancer patients undergoing IMRT and concurrent cisplatin. Reducing bowel V 45 could reduce the risk of Grade ≥2 GI toxicity by approximately 50% per 100 mL of bowel spared.

Upregulation of AMWAP: a novel mechanism for HDAC inhibitors to protect against cisplatin nephrotoxicity.

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Tang, Jinhua; Zhuang, Shougang

2016-02-01

Histone deacetylases have been reported to protect against renal tubular damage in several animal models of acute renal injury, including cisplatin nephrotoxicity. However, the mechanism involved is not well defined. In this study, Ranganathan et al. identify activated microglia/macrophage WAP domain protein as the novel mediator of histone deacetylase inhibitor-mediated renal protection in a murine model of cisplatin nephrotoxicity. Activated microglia/macrophage WAP-mediated renal protection is associated with suppression of inflammation and renal epithelial cell apoptosis. Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

The relationship of thioredoxin-1 and cisplatin resistance: its impact on ROS and oxidative metabolism in lung cancer cells.

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Wangpaichitr, Medhi; Sullivan, Elizabeth J; Theodoropoulos, George; Wu, Chunjing; You, Min; Feun, Lynn G; Lampidis, Theodore J; Kuo, Macus T; Savaraj, Niramol

2012-03-01

Elimination of cisplatin-resistant lung cancer cells remains a major obstacle. We have shown that cisplatin-resistant tumors have higher reactive oxygen species (ROS) levels and can be exploited for targeted therapy. Here, we show that increased secretion of the antioxidant thioredoxin-1 (TRX1) resulted in lowered intracellular TRX1 and contributed to higher ROS in cisplatin-resistant tumors in vivo and in vitro. By reconstituting TRX1 protein in cisplatin-resistant cells, we increased sensitivity to cisplatin but decreased sensitivity to elesclomol (ROS inducer). Conversely, decreased TRX1 protein in parental cells reduced the sensitivity to cisplatin but increased sensitivity to elesclomol. Cisplatin-resistant cells had increased endogenous oxygen consumption and mitochondrial activity but decreased lactic acid production. They also exhibited higher levels of argininosuccinate synthetase (ASS) and fumarase mRNA, which contributed to oxidative metabolism (OXMET) when compared with parental cells. Restoring intracellular TRX1 protein in cisplatin-resistant cells resulted in lowering ASS and fumarase mRNAs, which in turn sensitized them to arginine deprivation. Interestingly, cisplatin-resistant cells also had significantly higher basal levels of acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS). Overexpressing TRX1 lowered ACC and FAS proteins expressions in cisplatin-resistant cells. Chemical inhibition and short interfering RNA of ACC resulted in significant cell death in cisplatin-resistant compared with parental cells. Conversely, TRX1 overexpressed cisplatin-resistant cells resisted 5-(tetradecyloxy)-2-furoic acid (TOFA)-induced death. Collectively, lowering TRX1 expression through increased secretion leads cisplatin-resistant cells to higher ROS production and increased dependency on OXMET. These changes raise an intriguing therapeutic potential for future therapy in cisplatin-resistant lung cancer.

[Effect and mechanism of endoplasmic reticulum stress on cisplatin resistance in ovarian carcinoma].

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Tian, Jing; Hu, Xiaoming; Qu, Quanxin

2014-05-01

The study intended to investigate the effect and mechanism of endoplasmic reticulum stress on cisplatin resistance in ovarian carcinoma. RT-PCR and Western blot were used to test the expression of mTOR and Beclin1 mRNA and protein in ovarian cancer SKOV3 cells after saquinavir induction. MTT assay was used to analyze the influence of saquinavir on cisplatin sensitivity in SKOV3 cells. The IC50 of SKOV3 cells was (5.490 ± 1.148) µg/ml. After induced by Saquinavair 10 µmol/L and 20 µmol/L, the IC50 of SKOV3 cells was increased to (11.199 ± 0.984) µg/ml and (14.906 ± 2.015) µg/ml, respectively. It suggested that the sensitivity of ovarian cancer cells to cisplatin was decreased significantly (P = 0.001). The expression of mTOR and Beclin1 mRNA and protein was significantly different among the five groups: the (Saquinavair+DDP) group of, Saquinavair group, LY294002 group, DDP group and control group (P cisplatin sensitivity in the SKOV3 cells after Saquinavir induced ER stress (P cisplatin in SKOV3 cells. The mechanism of the decrease of sensitivity to cisplatin in SKOV3 cells may be that ERS regulates cell autophagy through the mTOR and Beclin1 pathways. ERS of tumor cells and autophagy may become a new target to improve the therapeutic effect of chemotherapy and to reverse the drug resistance in tumor treatment.

Management of cisplatin toxicity and chromosomal aberration by vitamin E in male rats

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Ali, S.E.; Mohamed, N.E.; Salama, M.A.

2007-01-01

Cisplatin is one of the most active antineoplastic drugs showing a broad therapeutic activity spectrum against different types of human neoplasms. To elvaute the subacute toxicity of the drug and to test the probable preventive effect of vitamin E in rats, forty-eight male albino rats were used in this study. Animals were classified into four groups, control, vitamin E, cisplatin and vitamin E with cisplatin. Vitamin E was administered orally at a dose of 2 mg/rat for two weeks prior to cisplatin intraperitoneal injection (5 mg/kg as a single dose) and then administration of vitamin E which was continued for two another weeks (end of experiment). The changes in body weight, counts of RBC and WBC, lipid peroxide, Na + , K + , chromosomal aberration and aldosterone hormone were recorded. Cisplatin administration caused 57.4% and 60% mortality at 3 and 5 weeks intervals. Regular intake of vitamin E induced significant role against the physiological disorders and chromosomal alterations occurred after cisplatin drug administration. The present study is directed to demonstrate the toxic effect of cisplatin on mortality, body weight, blood cells, aldosterone hormone, lipid peroxidation, Na + , K + , urea, creatinia as well as on chromosomal pattern and the efficacy of vitamin E in modulating cisplatin toxicity

Inhibition of autophagy by andrographolide resensitizes cisplatin-resistant non-small cell lung carcinoma cells via activation of the Akt/mTOR pathway

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Mi, Shanwei; Xiang, Gang; Yuwen, Daolu; Gao, Jian; Guo, Wenjie; Wu, Xuefeng; Wu, Xudong; Sun, Yang; Su, Yongqian; Shen, Yan; Xu, Qiang

2016-01-01

Resistance to cisplatin is a major obstacle for the success of non-small cell lung cancer therapy. The mechanisms underlying cisplatin resistance are not fully understood. In this study, we found that the increase of basal auotophagy accompanied the development of cisplatin resistance. Meanwhile the blockade of the Akt/mTOR pathway occurred in the process. Inhibition of this pathway was induced by cisplatin treatment in the resistant non-small cell lung carcinoma cells. Andrographolide, a natural diterpenoid, promoted the activation of the Akt/mTOR signaling by downregulating PTEN and suppressed autophagy, which subsequently resensitized the resistant cells to cisplatin-mediated apoptosis. Cisplatin treatment in combination with andrographolide significantly prevented the growth of the resistant cells in vivo. These results highlight the involvement of autophagy in cisplatin-resistance development and suggest that inhibition of autophagy via tuning the Akt/mTOR signaling could be a promising strategy in the therapy for cisplatin-resistant non-small cell lung cancer. - Highlights: • The increase of basal auotophagy accompanied the development of cisplatin resistance in NSCLC cells. • Cisplatin induced the blockade of the Akt/mTOR pathway. • Andrographolide promoted the activation of the Akt/mTOR signaling. • Andrographolide downregulated PTEN expression. • Cisplatin treatment in combination with andrographolide resensitized the resistant cells to cisplatin.

Inhibition of autophagy by andrographolide resensitizes cisplatin-resistant non-small cell lung carcinoma cells via activation of the Akt/mTOR pathway

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Mi, Shanwei; Xiang, Gang [State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093 (China); Yuwen, Daolu [Department of Clinical Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029 (China); Gao, Jian; Guo, Wenjie; Wu, Xuefeng; Wu, Xudong; Sun, Yang [State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093 (China); Su, Yongqian [Department of Clinical Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029 (China); Shen, Yan, E-mail: shenyan@nju.edu.cn [State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093 (China); Xu, Qiang, E-mail: molpharm@163.com [State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093 (China)

2016-11-01

Resistance to cisplatin is a major obstacle for the success of non-small cell lung cancer therapy. The mechanisms underlying cisplatin resistance are not fully understood. In this study, we found that the increase of basal auotophagy accompanied the development of cisplatin resistance. Meanwhile the blockade of the Akt/mTOR pathway occurred in the process. Inhibition of this pathway was induced by cisplatin treatment in the resistant non-small cell lung carcinoma cells. Andrographolide, a natural diterpenoid, promoted the activation of the Akt/mTOR signaling by downregulating PTEN and suppressed autophagy, which subsequently resensitized the resistant cells to cisplatin-mediated apoptosis. Cisplatin treatment in combination with andrographolide significantly prevented the growth of the resistant cells in vivo. These results highlight the involvement of autophagy in cisplatin-resistance development and suggest that inhibition of autophagy via tuning the Akt/mTOR signaling could be a promising strategy in the therapy for cisplatin-resistant non-small cell lung cancer. - Highlights: • The increase of basal auotophagy accompanied the development of cisplatin resistance in NSCLC cells. • Cisplatin induced the blockade of the Akt/mTOR pathway. • Andrographolide promoted the activation of the Akt/mTOR signaling. • Andrographolide downregulated PTEN expression. • Cisplatin treatment in combination with andrographolide resensitized the resistant cells to cisplatin.

Non-specific chemical inhibition of the Fanconi anemia pathway sensitizes cancer cells to cisplatin

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Jacquemont Céline

2012-04-01

Full Text Available Abstract Background Platinum compounds such as cisplatin and carboplatin are DNA crosslinking agents widely used for cancer chemotherapy. However, the effectiveness of platinum compounds is often tempered by the acquisition of cellular drug resistance. Until now, no pharmacological approach has successfully overcome cisplatin resistance in cancer treatment. Since the Fanconi anemia (FA pathway is a DNA damage response pathway required for cellular resistance to DNA interstrand crosslinking agents, identification of small molecules that inhibit the FA pathway may reveal classes of chemicals that sensitize cancer cells to cisplatin. Results Through a cell-based screening assay of over 16,000 chemicals, we identified 26 small molecules that inhibit ionizing radiation and cisplatin-induced FANCD2 foci formation, a marker of FA pathway activity, in multiple human cell lines. Most of these small molecules also compromised ionizing radiation-induced RAD51 foci formation and homologous recombination repair, indicating that they are not selective toward the regulation of FANCD2. These compounds include known inhibitors of the proteasome, cathepsin B, lysosome, CHK1, HSP90, CDK and PKC, and several uncharacterized chemicals including a novel proteasome inhibitor (Chembridge compound 5929407. Isobologram analyses demonstrated that half of the identified molecules sensitized ovarian cancer cells to cisplatin. Among them, 9 demonstrated increased efficiency toward FA pathway-proficient, cisplatin-resistant ovarian cancer cells. Six small molecules, including bortezomib (proteasome inhibitor, CA-074-Me (cathepsin B inhibitor and 17-AAG (HSP90 inhibitor, synergized with cisplatin specifically in FA-proficient ovarian cancer cells (2008 + FANCF, but not in FA-deficient isogenic cells (2008. In addition, geldanamycin (HSP90 inhibitor and two CHK1 inhibitors (UCN-01 and SB218078 exhibited a significantly stronger synergism with cisplatin in FA

Mifepristone sensitizing cisplatin for cervical adenocarcinoma HeLa cell sensitivity to chemotherapy and its mechanism.

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Li, Caihong; Ye, Hong

2013-01-01

The study was designed to investigate proliferation inhibition for cervical adenocarcinoma HeLa cell treated with cisplatin combined with mifepristone and access its possible mechanism. HeLa cell was processed by different concentrations of mifepristone, cisplatin, and their combination respectively. Cell's proliferation inhibition rate and induction apoptosis ability were detected by MTT assay, FCM; the expression of P53, survivin and HPV E6 protein were measured by Western Blot. The results showed that cisplatin inhibits proliferation of HeLa cells in different concentrations (p 0.05). Mifepristone at low concentrations (cisplatin can significantly enhance the inhibitory effect of cisplatin on HeLa cell line. Flow cytometry showed that mifepristone at low concentrations (cisplatin can induce apparent apoptosis of HeLa cell line in concentration dependent manner. Western blotting demonstrated that the expression of P53 protein increased and the expression of HPV E6 survivin protein decreased in HeLa cells treated with MIF at low concentrations (cisplatin. Mifepristone at low concentrations (cisplatin to HeLa cells. The strengthening effect of growth inhibition and chemosensitivity to cisplatin of mifepristone are associated with down-regulating HPV E6 survivin protein and upregulating p53 protein.

Cisplatin-induced injury of the renal distal convoluted tubule is associated with hypomagnesaemia in mice

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Angelen, A.A. van; Glaudemans, B.; Kemp, A. van der; Hoenderop, J.G.J.; Bindels, R.J.M.

2013-01-01

Background Cisplatin is an effective anti-neoplastic drug, but its clinical use is limited due to dose-dependent nephrotoxicity. The majority of cisplatin-treated patients develop hypomagnesaemia, often associated with a reduced glomerular filtration rate (GFR), polyuria and other electrolyte

c-FLIP and the NOXA/Mcl-1 axis participate in the synergistic effect of pemetrexed plus cisplatin in human choroidal melanoma cells.

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Zhao, Xiaofei; Kong, Feng; Wang, Lei; Zhang, Han

2017-01-01

Choroidal melanoma is the most common primary malignant intraocular tumor, and very few effective therapies are available to treat it. Our study aimed to understand whether pemetrexed plus cisplatin exerts a beneficial synergistic effect in human choroidal melanoma cells and to delineate the underlying molecular mechanism. To accomplish these aims, we treated choroidal melanoma cells with pemetrexed and cisplatin and assessed cell survival with SRB and MTT assays. Proteins were detected using western blotting analysis. NOXA and CHOP were knocked down with siRNA. We found that pemetrexed or cisplatin alone inhibited survival and induced apoptosis in human choroidal melanoma cells. Furthermore, the expression levels of c-FLIP, an anti-apoptotic protein in the extrinsic apoptosis pathway, and Mcl-1, an anti-apoptotic protein in the intrinsic apoptosis pathway, were decreased by pemetrexed or cisplatin respectively, while the expression of a pro-apoptotic protein in the intrinsic apoptosis pathway, NOXA, was up-regulated. Moreover, pemetrexed or cisplatin alone increased the protein expression of the endoplasmic reticulum stress markers IRE1α, Bip and CHOP. Silencing CHOP expression reduced NOXA expression. These findings suggest that the pemetrexed or cisplatin induced intrinsic apoptosis via activation of the ER stress response. Importantly, combining the two compounds more strongly induced apoptosis. Following the cotreatment, CHOP and NOXA expression increased, while c-FLIP and Mcl-1 expression decreased, and these effects were more pronounced than when using either compound alone. This result suggests that pemetrexed and cisplatin synergistically activate ER stress response-induced apoptosis in choroidal melanoma cells. To summarize, the c-FLIP and NOXA/Mcl-1 axis participated in the synergistic effect of pemetrexed plus cisplatin in human choroidal melanoma cells. Intrinsic apoptosis was induced via activation of the ER stress response. Our study provides

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

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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.

The Rhizome Mixture of Anemarrhena asphodeloides and Coptidis chinensis Ameliorates Acute and Chronic Colitis in Mice by Inhibiting the Binding of Lipopolysaccharide to TLR4 and IRAK1 Phosphorylation

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Jin-Ju Jeong

2014-01-01

Full Text Available In the previous study, the mixture of the rhizome of Anemarrhena asphodeloides (AA, family Liliaceae and the rhizome of Coptidis chinensis (CC, family Ranunculaceae (AC-mix improved TNBS- or oxazolone-induced colitis in mice. Therefore, to investigate its anticolitic mechanism, we measured its effect in acute and chronic DSS-induced colitic mice and investigated its anti-inflammatory mechanism in peritoneal macrophages. AC-mix potently suppressed DSS-induced body weight loss, colon shortening, myeloperoxidase activity, and TNF-α, IL-1β, and IL-6 expressions in acute or chronic DSS-stimulated colitic mice. Among AC-mix ingredients, AA, CC, and their main constituents mangiferin and berberine potently inhibited the expression of proinflammatory cytokines TNF-α and IL-1β, as well as the activation of NF-κB in LPS-stimulated peritoneal macrophages. AA and mangiferin potently inhibited IRAK phosphorylation, but CC and berberine potently inhibited the binding of LPS to TLR4 on macrophages, as well as the phosphorylation of IRAK1. AC-mix potently inhibited IRAK phosphorylation and LPS binding to TLR4 on macrophages. Based on these findings, AC-mix may ameliorate colitis by the synergistic inhibition of IRAK phosphorylation and LPS binding to TLR4 on macrophages.

Xeroderma Pigmentosum Group A Promotes Autophagy to Facilitate Cisplatin Resistance in Melanoma Cells through the Activation of PARP1.

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Ge, Rui; Liu, Lin; Dai, Wei; Zhang, Weigang; Yang, Yuqi; Wang, Huina; Shi, Qiong; Guo, Sen; Yi, Xiuli; Wang, Gang; Gao, Tianwen; Luan, Qi; Li, Chunying

2016-06-01

Xeroderma pigmentosum group A (XPA), a key protein in the nucleotide excision repair pathway, has been shown to promote the resistance of tumor cells to chemotherapeutic drugs by facilitating the DNA repair process. However, the role of XPA in the resistance of melanoma to platinum-based drugs like cisplatin is largely unknown. In this study, we initially found that XPA was expressed at higher levels in cisplatin-resistant melanoma cells than in cisplatin-sensitive ones. Furthermore, the knockdown of XPA not only increased cellular apoptosis but also inhibited cisplatin-induced autophagy, which rendered the melanoma cells more sensitive to cisplatin. Moreover, we discovered that the increased XPA in resistant melanoma cells promoted poly(adenosine diphosphate-ribose) polymerase 1 (PARP1) activation and that the inhibition of PARP1 could attenuate the cisplatin-induced autophagy. Finally, we proved that the inhibition of PARP1 and the autophagy process made resistant melanoma cells more susceptible to cisplatin treatment. Our study shows that XPA can promote cell-protective autophagy in a DNA repair-independent manner by enhancing the activation of PARP1 in melanoma cells resistant to cisplatin and that the XPA-PARP1-mediated autophagy process can be targeted to overcome cisplatin resistance in melanoma chemotherapy. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Radio-chemo-therapy with 5FU and cisplatin for bladder cancer after TUR-bladder

International Nuclear Information System (INIS)

Schuchardt, U.; Birkenhake, S.; Leykam, S.; Martus, P.; Sauer, R.

1996-01-01

Purpose/Objective: To determine toxicity and efficacy of radio-chemo-therapy (RCT) with 5FU and cisplatin in patients with bladder cancer. Endpoints are initial response, cystectomy-rates and overall-survival. Materials and Methods: From 11/93 to 1/95 13 patients suffering from bladder cancer were first treated with TUR-bladder (TURB). Patient characteristics were as follows: Within 6 weeks after operation the pelvis was irradiated with 54.0 Gy (median) in conventional fractionation (10 MV photons 4-field-box). The bladder was boosted up to 59.4 Gy (median) in isocentric rotation technique. 7 patients were treated with 45 Gy paraaortal. During the first and 5th treatment week chemotherapy (CT) was simultaneously given: 800 mg/m 2* d CISPLATIN as bolus-infusion 30 min prior to RT. 2 months later a further TURB was performed for restaging. Cystectomy was recommended, if invasive cancer was found at this time. Acute hematological and gastrointestinal toxicity was recorded according to the WHO-criteria. Results: At least 81% (e.g. 75% of 2nd course) of CT was applied in 10/13 patients. Median doses were 3500 mg/m 2 5FU and 200 mg/m 2 CISPLATIN. Acute toxicity to bladder and bowel reached grade 2 WHO only. Hematotoxicity (median values) and results ar shown in the following table. Conclusion: Concomitant RCT with 5FU and CISPLATIN seems to be a promising modality for organ-preserving therapy of bladder cancer. Preliminary results show sufficient effect and acceptable toxicity. Since patient number is still low, further investigation is recommended

Molecular mechanism behind the synergistic activity of diphenylmethyl selenocyanate and Cisplatin against murine tumor model.

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Chakraborty, Pramita; Roy, Somnath Singha; Bhattacharya, Sudin

2015-01-01

Various preclinical, clinical and epidemiological studies have already well established the cancer chemopreventive and chemoprotective potential of selenium compounds. In addition to its protective efficacy, recent studies have also proved the abilities of selenium compounds to induce cell death specifically in malignant cells. Therefore, our intention is to improve the therapeutic efficacy of an alkylating agent, cisplatin, by the adjuvant use of an organoselenium compound, diphenylmethyl selenocyanate (DMSE). It was observed that combined treatment decreased the tumor burden significantly through reactive oxygen species generation and modulation of antioxidant and detoxifying enzyme system in tumor cells. These activities ultimately led to significant DNA damage and apoptosis in tumor cells. Study of the molecular pathway disclosed that the adjuvant treatment caused induction of p53, Bax and suppressed Bcl-2 followed by the activation of caspase cascade. Furthermore, a concomitant decrease in cisplatin-induced nephrotoxicity and hematopoietic toxicity by DMSE might also have enhanced the efficacy of cisplatin and provided survival advantage to the host. Results suggested that the combination treatment with DMSE and cisplatin may offer potential therapeutic benefit, and utilization of cisplatin in cancer chemotherapy exempt of its limitations.

Amelioration of ongoing experimental autoimmune encephalomyelitis with fluoxetine.

Science.gov (United States)

Bhat, Roopa; Mahapatra, Sidharth; Axtell, Robert C; Steinman, Lawrence

2017-12-15

In patients with multiple sclerosis, the selective serotonin reuptake inhibitor, fluoxetine, resulted in less acute disease activity. We tested the immune modulating effects of fluoxetine in a mouse model of multiple sclerosis, i.e. experimental autoimmune encephalomyelitis (EAE). We show that fluoxetine delayed the onset of disease and reduced clinical paralysis in mice with established disease. Fluoxetine had abrogating effects on proliferation of immune cells and inflammatory cytokine production by both antigen-presenting cells and T cells. Specifically, in CD 4 T cells, fluoxetine increased Fas-induced apoptosis. We conclude that fluoxetine possesses immune-modulating effects resulting in the amelioration of symptoms in EAE. Copyright © 2017 Elsevier B.V. All rights reserved.

High prevalence of cisplatin-induced ototoxicity in Cape Town ...

African Journals Online (AJOL)

Background. Cisplatin is administered as the first-line treatment of soft-tissue cancers. It has a reported cure rate of up to 85%, but is associated with a high incidence of ototoxicity, characterised by irreversible bilateral hearing loss and affecting 23 - 50% of adults who receive the drug. Objectives. To determine the incidence ...

Identification of genes associated with cisplatin resistance in human oral squamous cell carcinoma cell line

International Nuclear Information System (INIS)

Zhang, Ping; Zhang, Zhiyuan; Zhou, Xiaojian; Qiu, Weiliu; Chen, Fangan; Chen, Wantao

2006-01-01

Cisplatin is widely used for chemotherapy of head and neck squamous cell carcinoma. However, details of the molecular mechanism responsible for cisplatin resistance are still unclear. The aim of this study was to identify the expression of genes related to cisplatin resistance in oral squamous cell carcinoma cells. A cisplatin-resistant cell line, Tca/cisplatin, was established from a cisplatin-sensitive cell line, Tca8113, which was derived from moderately-differentiated tongue squamous cell carcinoma. Global gene expression in this resistant cell line and its sensitive parent cell line was analyzed using Affymetrix HG-U95Av2 microarrays. Candidate genes involved in DNA repair, the MAP pathway and cell cycle regulation were chosen to validate the microarray analysis results. Cell cycle distribution and apoptosis following cisplatin exposure were also investigated. Cisplatin resistance in Tca/cisplatin cells was stable for two years in cisplatin-free culture medium. The IC50 for cisplatin in Tca/cisplatin was 6.5-fold higher than that in Tca8113. Microarray analysis identified 38 genes that were up-regulated and 25 that were down-regulated in this cell line. Some were novel candidates, while others are involved in well-characterized mechanisms that could be relevant to cisplatin resistance, such as RECQL for DNA repair and MAP2K6 in the MAP pathway; all the genes were further validated by Real-time PCR. The cell cycle-regulated genes CCND1 and CCND3 were involved in cisplatin resistance; 24-hour exposure to 10 μM cisplatin induced a marked S phase block in Tca/cisplatin cells but not in Tca8113 cells. The Tca8113 cell line and its stable drug-resistant variant Tca/cisplatin provided a useful model for identifying candidate genes responsible for the mechanism of cisplatin resistance in oral squamous cell carcinoma. Our data provide a useful basis for screening candidate targets for early diagnosis and further intervention in cisplatin resistance

Identification of genes associated with cisplatin resistance in human oral squamous cell carcinoma cell line

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Zhang Ping

2006-09-01

Full Text Available Abstract Background Cisplatin is widely used for chemotherapy of head and neck squamous cell carcinoma. However, details of the molecular mechanism responsible for cisplatin resistance are still unclear. The aim of this study was to identify the expression of genes related to cisplatin resistance in oral squamous cell carcinoma cells. Methods A cisplatin-resistant cell line, Tca/cisplatin, was established from a cisplatin-sensitive cell line, Tca8113, which was derived from moderately-differentiated tongue squamous cell carcinoma. Global gene expression in this resistant cell line and its sensitive parent cell line was analyzed using Affymetrix HG-U95Av2 microarrays. Candidate genes involved in DNA repair, the MAP pathway and cell cycle regulation were chosen to validate the microarray analysis results. Cell cycle distribution and apoptosis following cisplatin exposure were also investigated. Results Cisplatin resistance in Tca/cisplatin cells was stable for two years in cisplatin-free culture medium. The IC50 for cisplatin in Tca/cisplatin was 6.5-fold higher than that in Tca8113. Microarray analysis identified 38 genes that were up-regulated and 25 that were down-regulated in this cell line. Some were novel candidates, while others are involved in well-characterized mechanisms that could be relevant to cisplatin resistance, such as RECQL for DNA repair and MAP2K6 in the MAP pathway; all the genes were further validated by Real-time PCR. The cell cycle-regulated genes CCND1 and CCND3 were involved in cisplatin resistance; 24-hour exposure to 10 μM cisplatin induced a marked S phase block in Tca/cisplatin cells but not in Tca8113 cells. Conclusion The Tca8113 cell line and its stable drug-resistant variant Tca/cisplatin provided a useful model for identifying candidate genes responsible for the mechanism of cisplatin resistance in oral squamous cell carcinoma. Our data provide a useful basis for screening candidate targets for early diagnosis