Evaluation of the antitumor effects of vitamin K2 (menaquinone-7) nanoemulsions modified with sialic acid-cholesterol conjugate.

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Shi, Jia; Zhou, Songlei; Kang, Le; Ling, Hu; Chen, Jiepeng; Duan, Lili; Song, Yanzhi; Deng, Yihui

2018-02-01

Numerous studies have recently shown that vitamin K 2 (VK 2 ) has antitumor effects in a variety of tumor cells, but there are few reports demonstrating antitumor effects of VK 2 in vivo. The antitumor effects of VK 2 in nanoemulsions are currently not known. Therefore, we sought to characterize the antitumor potential of VK 2 nanoemulsions in S180 tumor cells in the present study. Furthermore, a ligand conjugate sialic acid-cholesterol, with enhanced affinity towards the membrane receptors overexpressed in tumors, was anchored on the surface of the nanoemulsions to increase VK 2 distribution to the tumor tissue. VK 2 was encapsulated in oil-in-water nanoemulsions, and the physical and chemical stability of the nanoemulsions were characterized during storage at 25 °C. At 25 °C, all nanoemulsions remained physically and chemically stable with little change in particle size. An in vivo study using syngeneic mice with subcutaneously established S180 tumors demonstrated that intravenous or intragastric administration of VK 2 nanoemulsions significantly suppressed the tumor growth. The VK 2 nanoemulsions modified with sialic acid-cholesterol conjugate showed higher tumor growth suppression than the VK 2 nanoemulsions, while neither of them exhibited signs of drug toxicity. In summary, VK 2 exerted effective antitumor effects in vivo, and VK 2 nanoemulsions modified with sialic acid-cholesterol conjugate enhanced the antitumor activity, suggesting that these VK 2 may be promising agents for the prevention or treatment of tumor in patients.

Antitumor efficacy of a novel CLA-PTX microemulsion against brain tumors: in vitro and in vivo findings.

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Li, Dan; Yang, Ke; Li, Jie-Si; Ke, Xi-Yu; Duan, Yu; Du, Ruo; Song, Ping; Yu, Ke-Fu; Ren, Wei; Huang, Dan; Li, Xing-Huo; Hu, Xin; Zhang, Xuan; Zhang, Qiang

2012-01-01

Considering the observations that linoleic acid conjugated with paclitaxel (CLA-PTX) possesses antitumor activity against brain tumors, is able to cross the blood-brain barrier, but has poor water solubility, the purpose of this study was to prepare a novel CLA-PTX microemulsion and evaluate its activity against brain tumors in vitro and in vivo. The in vitro cytotoxicity of a CLA-PTX microemulsion was investigated in C6 glioma cells. The in vivo antitumor activity of the CLA-PTX microemulsion was evaluated in tumor-bearing nude mice and rats. The pharmacokinetics of the CLA-PTX microemulsion were investigated in rats, and its safety was also evaluated in mice. The average droplet size of the CLA-PTX microemulsion was approximately 176.3 ± 0.8 nm and the polydispersity index was 0.294 ± 0.024. In vitro cytotoxicity results showed that the IC(50) of the CLA-PTX microemulsion was 1.61 ± 0.83 μM for a C6 glioma cell line, which was similar to that of free paclitaxel and CLA-PTX solution (P > 0.05). The antitumor activity of the CLA-PTX microemulsion against brain tumors was confirmed in our in vivo C6 glioma tumor-bearing nude mice as well as in a rat model. In contrast, Taxol(®) had almost no significant antitumor effect in C6 glioma tumor-bearing rats, but could markedly inhibit growth of C6 tumors in C6 glioma tumor-bearing nude mice. The pharmacokinetic results indicated that CLA-PTX in solution has a much longer circulation time and produces higher drug plasma concentrations compared with the CLA-PTX microemulsion. The results of the acute toxicity study showed that the LD(50) of CLA-PTX solution was 103.9 mg/kg. In contrast, the CLA-PTX microemulsion was well tolerated in mice when administered at doses up to 200 mg/kg. CLA-PTX microemulsion is a novel formulation with significant antitumor efficacy in the treatment of brain tumors, and is safer than CLA-PTX solution.

Antitumor Effect of KX-01 through Inhibiting Src Family Kinases and Mitosis.

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Kim, Seongyeong; Min, Ahrum; Lee, Kyung-Hun; Yang, Yaewon; Kim, Tae-Yong; Lim, Jee Min; Park, So Jung; Nam, Hyun-Jin; Kim, Jung Eun; Song, Sang-Hyun; Han, Sae-Won; Oh, Do-Youn; Kim, Jee Hyun; Kim, Tae-You; Hangauer, David; Lau, Johnson Yiu-Nam; Im, Kyongok; Lee, Dong Soon; Bang, Yung-Jue; Im, Seock-Ah

2017-07-01

KX-01 is a novel dual inhibitor of Src and tubulin. Unlike previous Src inhibitors that failed to show clinical benefit during treatment of breast cancer, KX-01 can potentially overcome the therapeutic limitations of current Src inhibitors through inhibition of both Src and tubulin. The present study further evaluates the activity and mechanism of KX-01 in vitro and in vivo . The antitumor effect of KX-01 in triple negative breast cancer (TNBC) cell lines was determined by MTT assay. Wound healing and immunofluorescence assays were performed to evaluate the action mechanisms of KX-01. Changes in the cell cycle and molecular changes induced by KX-01 were also evaluated. A MDA-MB-231 mouse xenograft model was used to demonstrate the in vivo effects. KX-01 effectively inhibited the growth of breast cancer cell lines. The expression of phospho-Src and proliferative-signaling molecules were down-regulated in KX-01-sensitive TNBC cell lines. In addition, migration inhibition was observed by wound healing assay. KX-01-induced G2/M cell cycle arrest and increased the aneuploid cell population in KX-01-sensitive cell lines. Multi-nucleated cells were significantly increased after KX-01 treatment. Furthermore, KX-01 effectively delayed tumor growth in a MDA-MB-231 mouse xenograft model. KX-01 effectively inhibited cell growth and migration of TNBC cells. Moreover, this study demonstrated that KX-01 showed antitumor effects through the inhibition of Src signaling and the induction of mitotic catastrophe. The antitumor effects of KX-01 were also demonstrated in vivo using a mouse xenograft model.

An experimental study on the antitumor effect of 131I-17-AAG in vitro and in vivo.

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Wenyong, Tu; Lu, Liu; Daozhen, Chen; Weidong, Yin; Ying, Huang

2009-02-01

To observe the antitumor effect of (131)I-17-allylamino-17-demethoxygeldanamycin ((131)I-17-AAG) in vitro/in vivo and explore its antitumor mechanism with a view to its potential therapeutic application. (131)I-17-AAG was prepared by the reaction of 17-AAG with Na [(131)I] in the presence of hydrogen peroxide. The effects of (131)17-AAG on cell growth inhibition and cell cycle distribution in vitro were studied in BEL-7402 cells lines. Following BEL-7402 tumor implantation by subcutaneous xenografts into nude mice, the reagents were injected through the tail vein, and the tumor volume was measured and analyzed. At the end of the experiment, tumor specimens were processed for histopathological analysis. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) was used to investigate apoptosis. The expression change of Akt2 was tested by Western-blot analysis. Methyl-thiazolyl-tetrazolium assay showed inhibition rates of 27.7 +/- 5.3%, 57.3 +/- 4.3%, and 63.7 +/- 3.1%, in Na(131)I group, 17-AAG group, and (131)I-17-AAG group, respectively. The inhibition rate in the (131)I-17-AAG group differed significantly between N(a131)I group and 17-AAG group (F = 229.49, P AAG group, and (131)I-17-AAG group, respectively. Following infusion for 32 days, the tumor volumes in the (131)I-17-AAG group were significantly smaller than those in the DMSO group (F = 24.18, P AAG inhibited the proliferation of tumor cells and induced apoptosis. The expression of Akt2 in (131)I-17-AAG was significantly lower than that in the DMSO group or (131)I group. (131)I-17-AAG can effectively inhibit the growth of BEL-7402 tumor cells in vitro and in vivo. (131)I-17-AAG is a promising agent for the treatment of BEL-7402 cell tumor.

An experimental study on the antitumor effect of 131I-17-AAG in vitro and in vivo

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Tu Wenyong; Liu Lu; Chen Daozhen; Huang Ying; Yin Weidong

2009-01-01

The objective of this study was to observe the antitumor effect of 131 I-17-allylamino-17-demethoxygeldanamycin ( 131 I-17-AAG) in vitro/in vivo and explore its antitumor mechanism with a view to its potential therapeutic application. 131 I-17-AAG was prepared by the reaction of 17-AAG with Na [ 131 I] in the presence of hydrogen peroxide. The effects of 131 17-AAG on cell growth inhibition and cell cycle distribution in vitro were studied in BEL-7402 cells lines. Following BEL-7402 tumor implantation by subcutaneous xenografts into nude mice, the reagents were injected through the tail vein, and the tumor volume was measured and analyzed. At the end of the experiment, tumor specimens were processed for histopathological analysis. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) was used to investigate apoptosis. The expression change of Akt2 was tested by Western-blot analysis. Methyl-thiazolyl-tetrazolium assay showed inhibition rates of 27.7±5.3%, 57.3±4.3%, and 63.7±3.1%, in Na 131 I group, 17-AAG group, and 131 I-17-AAG group, respectively. The inhibition rate in the 131 I-17-AAG group differed significantly between Na 131 I group and 17-AAG group (F=229.49, P 131 I group, 17-AAG group, and 131 I-17-AAG group, respectively. Following infusion for 32 days, the tumor volumes in the 131 I-17-AAG group were significantly smaller than those in the DMSO group (F=24.18, P 131 I group (F=20.68, P 131 I-17-AAG inhibited the proliferation of tumor cells and induced apoptosis. The expression of Akt2 in 131 I-17-AAG was significantly lower than that in the DMSO group or 131 I group. 131 I-17-AAG can effectively inhibit the growth of BEL-7402 tumor cells in vitro and in vivo. 131 I-17-AAG is a promising agent for the treatment of BEL-7402 cell tumor. (author)

The effect of high frequency steep pulsed electric fields on in vitro and in vivo antitumor efficiency of ovarian cancer cell line skov3 and potential use in electrochemotherapy

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Zheng Fei-Yun

2009-04-01

Full Text Available Abstract Background Patients received electrochemotherapy often associated with unpleasant sensations mainly result from low-frequency electric pulse induced muscle contractions. Increasing the repetition frequency of electric pulse can reduce unpleasant sensations. However, due to the specificity of SPEF, frequency related antitumor efficiency need to be further clarified. The aim of this study was to compare in vitro cytotoxic and in vivo antitumor effect on ovarian cancer cell line SKOV3 by SPEF with different repetition frequencies. Explore potential benefits of using high frequency SPEF in order to be exploitable in electrochemotherapy. Methods For in vitro experiment, SKOV3 cell suspensions were exposed to SPEF with gradient increased frequencies (1, 60, 1 000, 5 000 Hz and electric field intensity (50, 100, 150, 200, 250, 300, 350, 400 V/cm respectively. For in vivo test, SKOV3 subcutaneous implanted tumor in BALB/c nude mice (nu/nu were exposure to SPEF with gradient increased frequencies (1, 60, 1 000, 5 000 Hz and fixed electric field intensity (250 V/cm (7 mice for each frequency and 7 for control. Antitumor efficiency was performed by in vitro cytotoxic assay and in vivo tumor growth inhibition rate, supplemented by histological and TEM observations. Data were analyzed using one-way ANOVA followed by the comparisons of multiple groups. Results SPEF with a given frequency and appropriate electric field intensity could achieve similar cytotoxicity until reached a plateau of maximum cytotoxicity (approx. 100%. SPEF with different frequencies had significant antitumor efficiency in comparison to the control group (P 0.05. Histological and TEM observations demonstrated obvious cell damages in response to SPEF exposure. Furthermore, SPEF with 5 kHz could induce apoptosis under TEM observations both in vitro and in vivo. Conclusion SPEF with high frequency could also achieve similar antitumor efficiency which can be used to reduce

A novel compound NSC745885 exerts an anti-tumor effect on tongue cancer SAS cells in vitro and in vivo.

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Yuan-Wu Chen

Full Text Available Oral squamous cell carcinoma (OSCC is a prevalent cancer, especially in developing countries. Anthracyclines and their anthraquinone derivatives, such as doxorubicin, exhibit a cell growth inhibitory effect and have been used as anti-cancer drugs for many years. However, the cardiotoxicity of anthracycline antibiotics is a major concern in their clinical application. NSC745885 is a novel compound synthesized from 1,2-diaminoanthraquinone, which subsequently reacts with thionyl chloride and triethylamine. The present study aimed to investigate the anti-oral cancer potential and the safety of NSC745885.We investigated the anti-cancer potential of NSC745885 in oral squamous carcinoma cell lines and in an in vivo oral cancer xenograft mouse model. The expression of apoptotic related genes were evaluated by real-time RT-PCR and western bloting, and the in vivo assessment of apoptotic marker were measured by immunohistochemical staining. The anti-tumor efficiency and safety between doxorubicin and NSC745885 were also compared.Our results demonstrated that NSC745885 exhibits anti-oral cancer activity through the induction of apoptosis in cancer cells and in tumor-bearing mice, and this treatment did not induce marked toxicity in experimental mice. This compound also exhibits a comparable anti-tumor efficiency and a higher safety in experimental mice when compared to doxorubicin.The data of this study provide evidence for NSC745885 as a potential novel therapeutic drug for the treatment of human OSCC.

Characterization and anti-tumor effects of chondroitin sulfate-chitosan nanoparticles delivery system

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Hu, Chieh-Shen; Tang, Sung-Ling; Chiang, Chiao-Hsi; Hosseinkhani, Hossein; Hong, Po-Da; Yeh, Ming-Kung

2014-11-01

We prepared chondroitin sulfate (ChS)-chitosan (CS) nanoparticles (NPs) as a delivery carrier, and doxorubicin (Dox) was used as a model drug. The physicochemical properties and biological activities of the Dox-ChS-CS NPs including the release profile, cell cytotoxicity, cellular internalization, and in vivo anti-tumor effects were evaluated. The ChS-CS NPs and Dox-ChS-CS NPs had a mean size of 262.0 ± 15.0 and 369.4 ± 77.4 nm, and a zeta potential of 30.2 ± 0.9 and 20.6 ± 3.1 mV, respectively. In vitro release tests showed that the 50 % release time for the Dox-ChS-CS NPs was 20 h. Two hepatoma cell models, HepG2 and HuH6, were used for evaluating the cytotoxicity and cell uptake efficiency of the Dox-ChS-CS NPs. A significant difference was observed between doxorubicin solution and the Dox-ChS-CS NPs in the cellular uptake within 60 min ( p < 0.01). For the in vivo human xenograft-nude mouse model, the Dox-ChS-CS NPs were more effective with less body weight loss and anti-tumor growth suppression in comparison with the Dox solution. The prepared Dox-ChS-CS NPs offer a new effective targeting nanoparticle delivery system platform for anti-tumor therapy.

A Novel Paclitaxel Microemulsion Containing a Reduced Amount of Cremophor EL: Pharmacokinetics, Biodistribution, and In Vivo Antitumor Efficacy and Safety

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Wang, Ying; Wu, Ke-Chun; Zhao, Bing-Xiang; Zhao, Xin; Wang, Xin; Chen, Su; Nie, Shu-Fang; Pan, Wei-San; Zhang, Xuan; Zhang, Qiang

2011-01-01

The purpose of this study was to prepare a novel paclitaxel (PTX) microemulsion containing a reduced amount of Cremophor EL (CrEL) which had similar pharmacokinetics and antitumor efficacy as the commercially available PTX injection, but a significantly reduced allergic effect due to the CrEL. The pharmacokinetics, biodistribution, in vivo antitumor activity and safety of PTX microemulsion was evaluated. The results of pharmacokinetic and distribution properties of PTX in the microemulsion were similar to those of the PTX injection. The antitumor efficacy of the PTX microemulsion in OVCRA-3 and A 549 tumor-bearing animals was similar to that of PTX injection. The PTX microemulsion did not cause haemolysis, erythrocyte agglutination or simulative reaction. The incidence and degree of allergic reactions exhibited by the PTX microemulsion group, with or without premedication, were significantly lower than those in the PTX injection group (P microemulsion had similar pharmacokinetics and anti-tumor efficacy to the PTX injection, but a significantly reduced allergic effect due to CrEL, indicating that the PTX microemulsion overcomes the disadvantages of the conventional PTX injection and is one way of avoiding the limitations of current injection product while providing suitable therapeutic efficacy. PMID:21331356

Antitumor effects of Marginisporum crassissimum (Rhodophyceae), a marine red alga.

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Hiroishi, S; Sugie, K; Yoshida, T; Morimoto, J; Taniguchi, Y; Imai, S; Kurebayashi, J

2001-06-26

Marginisporum crassissimum (Yendo) Ganesan, a marine red alga found in the ordinal coastal sea around Japan, revealed antitumor (antimetastatic) effects in vitro and in vivo. In in vitro experiments, extracts of this alga inhibited not only the growth of several tumor cell lines, such as B16-BL6 (a mouse melanoma cell line), JYG-B (a mouse mammary carcinoma cell line) and KPL-1 (a human mammary carcinoma cell line), but also invasion of B16-BL6 cells in a culture system. In in vivo experiments, the lung metastasis of B16-BL6 cells inoculated to the tail vein of B57BL/6J mice was inhibited by intraperitoneal administration of an extract from the alga. In addition, life prolongation of B57BL/6J mice inoculated with B16-BL6 cells was also observed by the intraperitoneal administration of the extract. An effective substance showing B16-BL6 growth inhibition in vitro was partially purified by filtration and hydrophobic column chromatography, and was revealed to be sensitive to trypsin-digestion and heat-treatment. The molecular weight of the substance was greater than 100 kDa. This is the first study demonstrating antitumor (antimetastatic) effects of M. crassissimum.

Targeting tumor antigens to secreted membrane vesicles in vivo induces efficient antitumor immune responses.

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Zeelenberg, Ingrid S; Ostrowski, Matias; Krumeich, Sophie; Bobrie, Angélique; Jancic, Carolina; Boissonnas, Alexandre; Delcayre, Alain; Le Pecq, Jean-Bernard; Combadière, Béhazine; Amigorena, Sebastian; Théry, Clotilde

2008-02-15

Expression of non-self antigens by tumors can induce activation of T cells in vivo, although this activation can lead to either immunity or tolerance. CD8+ T-cell activation can be direct (if the tumor expresses MHC class I molecules) or indirect (after the capture and cross-presentation of tumor antigens by dendritic cells). The modes of tumor antigen capture by dendritic cells in vivo remain unclear. Here we examine the immunogenicity of the same model antigen secreted by live tumors either in association with membrane vesicles (exosomes) or as a soluble protein. We have artificially addressed the antigen to secreted vesicles by coupling it to the factor VIII-like C1C2 domain of milk fat globule epidermal growth factor-factor VIII (MFG-E8)/lactadherin. We show that murine fibrosarcoma tumor cells that secrete vesicle-bound antigen grow slower than tumors that secrete soluble antigen in immunocompetent, but not in immunodeficient, host mice. This growth difference is due to the induction of a more potent antigen-specific antitumor immune response in vivo by the vesicle-bound than by the soluble antigen. Finally, in vivo secretion of the vesicle-bound antigen either by tumors or by vaccination with naked DNA protects against soluble antigen-secreting tumors. We conclude that the mode of secretion can determine the immunogenicity of tumor antigens and that manipulation of the mode of antigen secretion may be used to optimize antitumor vaccination protocols.

Antitumor effect of the essential oil from leaves of Guatteria pogonopus (Annonaceae).

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do N Fontes, José Eraldo; Ferraz, Rosana P C; Britto, Anny C S; Carvalho, Adriana A; Moraes, Manoel O; Pessoa, Claudia; Costa, Emmanoel V; Bezerra, Daniel P

2013-04-01

Guatteria pogonopus Martius, a plant belonging to the Annonaceae family, is found in the remaining Brazilian Atlantic Forest. In this study, the chemical composition and antitumor effects of the essential oil isolated from leaves of G. pogonopus was investigated. The chemical composition of the oil was determined by GC-FID and GC/MS analyses. The in vitro cytotoxicity was evaluated against three different tumor cell lines (OVCAR-8, NCI-H358M, and PC-3M), and the in vivo antitumor activity was tested in mice bearing sarcoma 180 tumor. A total of 29 compounds was identified and quantified in the oil. The major compounds were γ-patchoulene (13.55%), (E)-caryophyllene (11.36%), β-pinene (10.37%), germacrene D (6.72%), bicyclogermacrene (5.97%), α-pinene (5.33%), and germacrene B (4.69%). The essential oil, but neither (E)-caryophyllene nor β-pinene, displayed in vitro cytotoxicity against all three tumor cell lines tested. The obtained average IC50 values ranged from 3.8 to 20.8 μg/ml. The lowest and highest values were obtained against the NCI-H358M and the OVCAR-8 cell lines, respectively. The in vivo tumor-growth-inhibition rates in the tumor-bearing mice treated with essential oil (50 and 100 mg/kg/d) were 25.3 and 42.6%, respectively. Hence, the essential oil showed significant in vitro and in vivo antitumor activity. Copyright © 2013 Verlag Helvetica Chimica Acta AG, Zürich.

In vitro and in vivo antitumor effects of doxorubicin loaded with bacterial magnetosomes (DBMs) on H22 cells: the magnetic bio-nanoparticles as drug carriers.

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Sun, Jian-Bo; Duan, Jin-Hong; Dai, Shun-Ling; Ren, Jun; Zhang, Yan-Dong; Tian, Jie-Sheng; Li, Ying

2007-12-08

Hepatocellular carcinoma (HCC) is the most common form of cancer although effective therapeutic strategy especially targeted therapy is lacking. We recently employed bacterial magnetosomes (BMs) as the magnetic-targeted drug carrier and found an antitumor effect of doxorubicin (DOX)-loaded BMs (DBMs) in EMT-6 and HL60 cell lines. The aim of this study was to evaluate the in vitro and in vivo anti-neoplastic effects of DBMs on hepatic cancer. DBMs, DOX and BMs displayed tumor suppression rates of 86.8%, 78.6% and 4.3%, respectively, in H22 cell-bearing mice. The mortality rates following administration of DBMs, DOX and BMs were 20%, 80% and 0%, respectively. Pathological examination of hearts and tumors revealed that both DBMs and DOX effectively inhibited tumor growth although DBMs displayed a much lower cardiac toxicity compared with DOX. The DBMs were cytotoxic to H22 cells manifested as inhibition of cell proliferation and c-myc expression, consistent with DOX. The IC(50) of DOX, DBMs and BMs in target cells were 5.309 +/- 0.010, 4.652 +/- 0.256 and 22.106 +/- 3.330 microg/ml, respectively. Our data revealed both in vitro and in vivo antitumor property of DBMs similar to that of DOX. More importantly, the adverse cardiac toxicity was significantly reduced in DBMs compared with DOX. Collectively, our study suggests the therapeutic potential of DBMs in target-therapy against liver cancer.

In vitro and in vivo studies of pharmacokinetics and antitumor efficacy of D07001-F4, an oral gemcitabine formulation.

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Hao, Wei-Hua; Wang, Jong-Jing; Hsueh, Shu-Ping; Hsu, Pei-Jing; Chang, Li-Chien; Hsu, Chang-Shan; Hsu, Kuang-Yang

2013-02-01

The chemotherapy agent gemcitabine is currently administered intravenously because the drug has poor oral bioavailability. In order to assess the pharmacokinetics and antitumor activity of D07001-F4, a new self-microemulsifying oral drug delivery system preparation of gemcitabine, this study was performed to compare the effect of D07001-F4 with administered gemcitabine in vitro and in vivo. D07001-F4 pharmacokinetics was examined by evaluation of in vitro deamination of D07001-F4 and gemcitabine hydrochloride by recombinant human cytidine deaminase (rhCDA) and in vivo evaluation of D07001-F4 pharmacokinetics in mice. Antitumor activity was evaluated by comparing the effect of D07001-F4 and gemcitabine hydrochloride in inhibiting growth in nine cancer cell lines and by examining the effect of D07001-F4 and gemcitabine in two xenograft tumor models in mice. In vitro deamination of D07001-F4 by rhCDA was 3.3-fold slower than deamination of gemcitabine hydrochloride. Growth inhibition by D07001-F4 of 7 of the 8 cancer cell lines was increased compared with that seen with gemcitabine hydrochloride, and D07001-F4 inhibited the growth of pancreatic and colon cancer xenografts. In vivo pharmacokinetics showed the oral bioavailability of D07001-F4 to be 34%. D07001-F4 was effective against several cancer types, was metabolized more slowly than gemcitabine hydrochloride, and exhibited enhanced oral bioavailability.

A new extract of the plant calendula officinalis produces a dual in vitro effect: cytotoxic anti-tumor activity and lymphocyte activation

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Collado Antonia

2006-05-01

Full Text Available Abstract Background Phytopharmacological studies of different Calendula extracts have shown anti-inflamatory, anti-viral and anti-genotoxic properties of therapeutic interest. In this study, we evaluated the in vitro cytotoxic anti-tumor and immunomodulatory activities and in vivo anti-tumor effect of Laser Activated Calendula Extract (LACE, a novel extract of the plant Calendula Officinalis (Asteraceae. Methods An aqueous extract of Calendula Officinalis was obtained by a novel extraction method in order to measure its anti-tumor and immunomodulatory activities in vitro. Tumor cell lines derived from leukemias, melanomas, fibrosarcomas and cancers of breast, prostate, cervix, lung, pancreas and colorectal were used and tumor cell proliferation in vitro was measured by BrdU incorporation and viable cell count. Effect of LACE on human peripheral blood lymphocyte (PBL proliferation in vitro was also analyzed. Studies of cell cycle and apoptosis were performed in LACE-treated cells. In vivo anti-tumor activity was evaluated in nude mice bearing subcutaneously human Ando-2 melanoma cells. Results The LACE extract showed a potent in vitro inhibition of tumor cell proliferation when tested on a wide variety of human and murine tumor cell lines. The inhibition ranged from 70 to 100%. Mechanisms of inhibition were identified as cell cycle arrest in G0/G1 phase and Caspase-3-induced apoptosis. Interestingly, the same extract showed an opposite effect when tested on PBLs and NKL cell line, in which in vitro induction of proliferation and activation of these cells was observed. The intraperitoneal injection or oral administration of LACE extract in nude mice inhibits in vivo tumor growth of Ando-2 melanoma cells and prolongs the survival day of the mice. Conclusion These results indicate that LACE aqueous extract has two complementary activities in vitro with potential anti-tumor therapeutic effect: cytotoxic tumor cell activity and lymphocyte activation

A new extract of the plant calendula officinalis produces a dual in vitro effect: cytotoxic anti-tumor activity and lymphocyte activation

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Jiménez-Medina, Eva; Garcia-Lora, Angel; Paco, Laura; Algarra, Ignacio; Collado, Antonia; Garrido, Federico

2006-01-01

Phytopharmacological studies of different Calendula extracts have shown anti-inflamatory, anti-viral and anti-genotoxic properties of therapeutic interest. In this study, we evaluated the in vitro cytotoxic anti-tumor and immunomodulatory activities and in vivo anti-tumor effect of Laser Activated Calendula Extract (LACE), a novel extract of the plant Calendula Officinalis (Asteraceae). An aqueous extract of Calendula Officinalis was obtained by a novel extraction method in order to measure its anti-tumor and immunomodulatory activities in vitro. Tumor cell lines derived from leukemias, melanomas, fibrosarcomas and cancers of breast, prostate, cervix, lung, pancreas and colorectal were used and tumor cell proliferation in vitro was measured by BrdU incorporation and viable cell count. Effect of LACE on human peripheral blood lymphocyte (PBL) proliferation in vitro was also analyzed. Studies of cell cycle and apoptosis were performed in LACE-treated cells. In vivo anti-tumor activity was evaluated in nude mice bearing subcutaneously human Ando-2 melanoma cells. The LACE extract showed a potent in vitro inhibition of tumor cell proliferation when tested on a wide variety of human and murine tumor cell lines. The inhibition ranged from 70 to 100%. Mechanisms of inhibition were identified as cell cycle arrest in G0/G1 phase and Caspase-3-induced apoptosis. Interestingly, the same extract showed an opposite effect when tested on PBLs and NKL cell line, in which in vitro induction of proliferation and activation of these cells was observed. The intraperitoneal injection or oral administration of LACE extract in nude mice inhibits in vivo tumor growth of Ando-2 melanoma cells and prolongs the survival day of the mice. These results indicate that LACE aqueous extract has two complementary activities in vitro with potential anti-tumor therapeutic effect: cytotoxic tumor cell activity and lymphocyte activation. The LACE extract presented in vivo anti-tumoral activity in nude

In vitro and in vivo antitumor activity of crude extracts obtained from Brazilian Chromobacterium sp isolates

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Menezes, C.B.A.; Silva, B.P. [Universidade Estadual de Campinas, Centro Pluridisciplinar de Pesquisas Químicas, Biológicas e Agrícolas, Campinas, SP (Brazil); Universidade de São Paulo, Interunidades em Biotecnologia, São Paulo, SP (Brazil); Sousa, I.M.O.; Ruiz, A.L.T.G.; Spindola, H.M. [Universidade Estadual de Campinas, Centro Pluridisciplinar de Pesquisas Químicas, Biológicas e Agrícolas, Campinas, SP (Brazil); Cabral, E.; Eberlin, M.N. [Instituto de Química, Universidade Estadual de Campinas, Laboratório Thomson Mass Spectrometry, Campinas, SP (Brazil); Tinti, S.V.; Carvalho, J.E. [Universidade Estadual de Campinas, Centro Pluridisciplinar de Pesquisas Químicas, Biológicas e Agrícolas, Campinas, SP (Brazil); Foglio, M.A.; Fantinatti-Garboggini, F. [Universidade Estadual de Campinas, Centro Pluridisciplinar de Pesquisas Químicas, Biológicas e Agrícolas, Campinas, SP (Brazil); Universidade de São Paulo, Interunidades em Biotecnologia, São Paulo, SP (Brazil)

2012-10-23

Natural products produced by microorganisms have been an important source of new substances and lead compounds for the pharmaceutical industry. Chromobacterium violaceum is a Gram-negative β-proteobacterium, abundant in water and soil in tropical and subtropical regions and it produces violacein, a pigment that has shown great pharmaceutical potential. Crude extracts of five Brazilian isolates of Chromobacterium sp (0.25, 2.5, 25, and 250 µg/mL) were evaluated in an in vitro antitumor activity assay with nine human tumor cells. Secondary metabolic profiles were analyzed by liquid chromatography and electrospray ionization mass spectrometry resulting in the identification of violacein in all extracts, whereas FK228 was detected only in EtCE 308 and EtCE 592 extracts. AcCE and EtCE 310 extracts showed selectivity for NCI/ADR-RES cells in the in vitro assay and were evaluated in vivo in the solid Ehrlich tumor model, resulting in 50.3 and 54.6% growth inhibition, respectively. The crude extracts of Chromobacterium sp isolates showed potential and selective antitumor activities for certain human tumor cells, making them a potential source of lead compounds. Furthermore, the results suggest that other compounds, in addition to violacein, deoxyviolacein and FK228, may be involved in the antitumor effect observed.

In vitro and in vivo antitumor activity of crude extracts obtained from Brazilian Chromobacterium sp isolates

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C.B.A. Menezes

2013-01-01

Full Text Available Natural products produced by microorganisms have been an important source of new substances and lead compounds for the pharmaceutical industry. Chromobacterium violaceum is a Gram-negative β-proteobacterium, abundant in water and soil in tropical and subtropical regions and it produces violacein, a pigment that has shown great pharmaceutical potential. Crude extracts of five Brazilian isolates of Chromobacterium sp (0.25, 2.5, 25, and 250 µg/mL were evaluated in an in vitro antitumor activity assay with nine human tumor cells. Secondary metabolic profiles were analyzed by liquid chromatography and electrospray ionization mass spectrometry resulting in the identification of violacein in all extracts, whereas FK228 was detected only in EtCE 308 and EtCE 592 extracts. AcCE and EtCE 310 extracts showed selectivity for NCI/ADR-RES cells in the in vitro assay and were evaluated in vivo in the solid Ehrlich tumor model, resulting in 50.3 and 54.6% growth inhibition, respectively. The crude extracts of Chromobacterium sp isolates showed potential and selective antitumor activities for certain human tumor cells, making them a potential source of lead compounds. Furthermore, the results suggest that other compounds, in addition to violacein, deoxyviolacein and FK228, may be involved in the antitumor effect observed.

In vitro and in vivo antitumor activity of crude extracts obtained from Brazilian Chromobacterium sp isolates

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Menezes, C.B.A.; Silva, B.P.; Sousa, I.M.O.; Ruiz, A.L.T.G.; Spindola, H.M.; Cabral, E.; Eberlin, M.N.; Tinti, S.V.; Carvalho, J.E.; Foglio, M.A.; Fantinatti-Garboggini, F.

2012-01-01

Natural products produced by microorganisms have been an important source of new substances and lead compounds for the pharmaceutical industry. Chromobacterium violaceum is a Gram-negative β-proteobacterium, abundant in water and soil in tropical and subtropical regions and it produces violacein, a pigment that has shown great pharmaceutical potential. Crude extracts of five Brazilian isolates of Chromobacterium sp (0.25, 2.5, 25, and 250 µg/mL) were evaluated in an in vitro antitumor activity assay with nine human tumor cells. Secondary metabolic profiles were analyzed by liquid chromatography and electrospray ionization mass spectrometry resulting in the identification of violacein in all extracts, whereas FK228 was detected only in EtCE 308 and EtCE 592 extracts. AcCE and EtCE 310 extracts showed selectivity for NCI/ADR-RES cells in the in vitro assay and were evaluated in vivo in the solid Ehrlich tumor model, resulting in 50.3 and 54.6% growth inhibition, respectively. The crude extracts of Chromobacterium sp isolates showed potential and selective antitumor activities for certain human tumor cells, making them a potential source of lead compounds. Furthermore, the results suggest that other compounds, in addition to violacein, deoxyviolacein and FK228, may be involved in the antitumor effect observed

Novel T cells with improved in vivo anti-tumor activity generated by RNA electroporation

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Xiaojun Liu

2017-05-01

Full Text Available ABSTRACT The generation of T cells with maximal anti-tumor activities will significantly impact the field of T-cell-based adoptive immunotherapy. In this report, we found that OKT3/IL-2-stimulated T cells were phenotypically more heterogeneous, with enhanced anti-tumor activity in vitro and when locally administered in a solid tumor mouse model. To further improve the OKT3/IL-2-based T cell manufacturing procedure, we developed a novel T cell stimulation and expansion method in which peripheral blood mononuclear cells were electroporated with mRNA encoding a chimeric membrane protein consisting of a single-chain variable fragment against CD3 and the intracellular domains of CD28 and 4-1BB (OKT3-28BB. The expanded T cells were phenotypically and functionally similar to T cells expanded by OKT3/IL-2. Moreover, co-electroporation of CD86 and 4-1BBL could further change the phenotype and enhance the in vivo anti-tumor activity. Although T cells expanded by the co-electroporation of OKT3-28BB with CD86 and 4-1BBL showed an increased central memory phenotype, the T cells still maintained tumor lytic activities as potent as those of OKT3/IL-2 or OKT3-28BB-stimulated T cells. In different tumor mouse models, T cells expanded by OKT3-28BB RNA electroporation showed anti-tumor activities superior to those of OKT3/IL-2 T cells. Hence, T cells with both a less differentiated phenotype and potent tumor killing ability can be generated by RNA electroporation, and this T cell manufacturing procedure can be further optimized by simply co-delivering other splices of RNA, thus providing a simple and cost-effective method for generating high-quality T cells for adoptive immunotherapy.

Curcuma increasing antitumor effect of Rhizoma paridis saponins through absorptive enhancement of paridis saponins.

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Man, Shuli; Li, Yuanyuan; Fan, Wei; Gao, Wenyuan; Liu, Zhen; Li, Nan; Zhang, Yao; Liu, Changxiao

2013-09-15

Rhizoma paridis saponins (RPS) played a good antitumor role in many clinical applications. However, low oral bioavailability limited its application. In this research, water extract of Curcuma (CW) significantly increased antitumor effect of Rhizoma paridis saponins (RPS). GC-MS was used to identify its polar composition. HPLC was applied for determination of the content of curcuminoids in CW. As a result, 47 analytes with 0.65% of curcuminoids were identified in CW. According to the in vivo anti-tumor data, the best proportion of curcuminoids in CW with RPS was 16:500 (w/w). Using this ratio, curcuminoids significantly increased absorption of RPS in the everted rat duodenum sac system. In addition, curcuminoids decreased the promotion of RPS on rhodamine 123 efflux. The effect of curcuminoids was similar to that of the P-gp inhibitor, cyclosporin A in combination with RPS. In conclusion, drug combination of water extract of Curcuma with RPS was a good method to increase the antitumor effect of RPS. This combination would be a potent anticancer agent used in the prospective application. Crown Copyright © 2013. Published by Elsevier B.V. All rights reserved.

[The Antitumor Effects of Fisetin on Ovarian Cancer in vitro and in vivo.

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Meng, Yi-Bo; Xiao, Chao; Chen, Xin-Lian; Bai, Peng; Yao, Yuan; Wang, He; Xiao, Xue

2016-11-01

We attempted to survey the inhibit effect of fisetin with human ovarian cancer cell line SKOV3 and the xenograft and the mechanism of the effect. The ovarian cancer cell line SKOV3 treated by fisetin were observed directly under the transmission electronmicroscope (TEM);MTT assay was used to determine cell viability.Flow cytometry was used to analyze the apoptosis in ovarian cancer cell line SKOV3.In addition,we established an ovarian cancer athymicnude rat model.We observed the neoplasia and progression after fisetin treatment.The proliferation and apoptosis of athymic nude rat model were evaluated by testing Bcl-2,Bax and poly-ADP-ribose polyerase (PARP) expression through Western blot. The chromatin were brought together and the apoptotic bodies were detected in SKOV3 cells under transmission electron microscope after the treatment by fisetin.MTT assay indicated that fisetin inhibited ovarian cancer cell proliferation in a dose-dependent manner.The flow cytometry data demonstrated that the apoptosis might induct in SKOV3 cells after treatment by fisetin.In athymic rude rat model,under the influence of fisetin,tumor volume and tumor mass were significantly decreased.Western blot demonstrated that treatment with higher concentration of fisetin resulted in a significant decrease of Bcl-2 and a significant increase of Bax.The apoptosis proteins PARP was cut apparently. The results provided the first insight into antitumor anti-proliferative and the induction of apoptosis efficacy of fisetin against ovarian cancer in vitro and in vivo .All data suggested a safe promising therapeutic potential of fisetin in ovarian cancer treatment.

Antitumor Effects of Saffron-Derived Carotenoids in Prostate Cancer Cell Models

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Claudio Festuccia

2014-01-01

Full Text Available Crocus sativus L. extracts (saffron are rich in carotenoids. Preclinical studies have shown that dietary intake of carotenoids has antitumor effects suggesting their potential preventive and/or therapeutic roles. We have recently reported that saffron (SE and crocin (CR exhibit anticancer activity by promoting cell cycle arrest in prostate cancer (PCa cells. It has also been demonstrated that crocetin esters are produced after SE gastrointestinal digestion by CR hydrolysis. The aim of the present report was to investigate if SE, crocetin (CCT, and CR affected in vivo tumor growth of two aggressive PCa cell lines (PC3 and 22rv1 which were xenografted in male nude mice treated by oral gavage with SE, CR, and CCT. We demonstrated that the antitumor effects of CCT were higher when compared to CR and SE and treatments reverted the epithelial-mesenchymal transdifferentiation (EMT as attested by the significant reduction of N-cadherin and beta-catenin expression and the increased expression of E-cadherin. Additionally, SE, CR, and CCT inhibited PCa cell invasion and migration through the downmodulation of metalloproteinase and urokinase expression/activity suggesting that these agents may affect metastatic processes. Our findings suggest that CR and CCT may be dietary phytochemicals with potential antitumor effects in biologically aggressive PCa cells.

Study on fluorouracil–chitosan nanoparticle preparation and its antitumor effect

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Gaimin Chen

2016-05-01

Full Text Available To successfully prepare fluorouracil–chitosan nanoparticles, and further analyze its anti-tumor activity mechanism, this paper makes a comprehensive study of existing preparation prescription and makes a detailed analysis of fluorouracil–chitosan in vitro release and pharmacodynamic behavior of animals. Two-step synthesis method is adopted to prepare 5-FU–CS–mPEG prodrugs, and infrared, 1H NMR and differential thermal analysis are adopted to analyze characterization synthetic products of prepared drugs. To ensure clinical efficacy of prepared drugs, UV spectrophotometry is adopted for determination of drug loading capacity of prepared drugs, transmission electron microscopy is adopted to observe the appearance, dynamic dialysis method is used to observe in vitro drug release of prepared drugs and fitting of various release models is done. Anti-tumor effect is studied via level of animal pharmacodynamics. After the end of the experiment, tumor inhibition rate, spleen index and thymus index of drugs are calculated. Experimental results show that the prepared drugs are qualified in terms of regular shape, dispersion, drug content, etc. Animal pharmacodynamics experiments have shown that concentration level of drug loading capacity of prepared drugs has a direct impact on anti-tumor rate. The higher the concentration, the higher the anti-tumor rate. Results of pathological tissue sections of mice show that the prepared drugs cause varying degrees of damage to receptor cells, resulting in cell necrosis or apoptosis problem. It can thus be concluded that ion gel method is an effective method to prepare drug-loading nanoparticles, with prepared nanoparticles evenly distributed in regular shape which demonstrate good slow-release characteristics in receptor vitro and vivo. At the same time, after completion of drug preparation, relatively strong anti-tumor activity can be generated for the receptor, so this mode of preparation enjoys broad

Antioxidants impair anti-tumoral effects of Vorinostat, but not anti-neoplastic effects of Vorinostat and caspase-8 downregulation.

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Bergadà, Laura; Yeramian, Andree; Sorolla, Annabel; Matias-Guiu, Xavier; Dolcet, Xavier

2014-01-01

We have recently demonstrated that histone deacetylase inhibitor, Vorinostat, applied as a single therapy or in combination with caspase-8 downregulation exhibits high anti-tumoral activity on endometrial carcinoma cell lines. In the present study, we have assessed the signalling processes underlying anti-tumoral effects of Vorinostat. Increasing evidence suggests that reactive oxygen species are responsible for histone deacetylase inhibitor-induced cell killing. We have found that Vorinostat induces formation of reactive oxygen species and DNA damage. To investigate the role of oxidative stress as anti-neoplastic mechanism, we have evaluated the effects of different antioxidants (Bha, Nac and Tiron) on endometrial carcinoma cell line Ishikawa treated with Vorinostat. We show that Bha, Nac and Tiron markedly inhibited the cytotoxic effects of Vorinostat, increasing cell viability in vitro. We found that all three antioxidants did not inhibited accumulation of acetyl Histone H4, so that antioxidants did not inhibit Vorinostat activity. Finally, we have evaluated the effects of antioxidants on anti-tumoral activity of Vorinostat as monotherapy or in combination with caspase-8 downregulation in vivo. Interestingly, antioxidants blocked the reduction of tumour growth caused by Vorinostat, but they were unable to inhibit anti-tumoral activity of Vorinostat plus caspase-8 inhibition.

Antitumor effects evaluation of a novel porphyrin derivative in photodynamic therapy.

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Li, Jian-Wei; Wu, Zhong-Ming; Magetic, Davor; Zhang, Li-Jun; Chen, Zhi-Long

2015-12-01

In this paper, the antitumor activity of a novel porphyrin-based photosensitizer 5,10,15,20-tetrakis[(5-diethylamino)pentyl] porphyrin (TDPP) was reported in vitro and in vivo. The photophysical and cellular properties of TDPP were investigated. The singlet oxygen generation quantum yield of TDPP was detected; it showed a high singlet oxygen quantum yield of 0.52. The intracellular distribution of photosensitizer was detected with laser scanning confocal microscopy. The efficiency of TDPP-photodynamic therapy (PDT) in vitro was analyzed by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay and in situ trypan blue exclusion test. Treated with a 630-nm laser, TDPP can kill cultured human esophageal cancer cell line (Eca-109) cells and reduce the growth of Eca-109 xenograft tumors significantly in BABL/c nude mice. And histopathological study was also used to confirm the antitumor effect. It has the perspective to be developed as a new antitumor drug in photodynamic therapy and deserves further investigation.

Antitumor Activity of Kielmeyera Coriacea Leaf Constituents in Experimental Melanoma, Tested in Vitro and in Vivo in Syngeneic Mice

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Carlos Rogério Figueiredo

2014-10-01

Full Text Available Purpose: The antitumor activity of Kielmeyera coriacea (Clusiaceae, a medicinal plant used in the treatment of parasitic, as well as fungal and bacterial infections by the Brazilian Cerrado population, was investigated. Methods: A chloroform extract (CE of K. coriacea was tested in the murine melanoma cell line (B16F10-Nex2 and a panel of human tumor cell lines. Tumor cell migration was determined by the wound-healing assay and the in vivo antitumor activity of CE was investigated in a melanoma cell metastatic model. 1H NMR and GC/MS were used to determine CE chemical composition. Results: We found that CE exhibited strong cytotoxic activity against murine melanoma cells and a panel of human tumor cell lines in vitro. CE also inhibited growth of B16F10-Nex2 cells at sub lethal concentrations, inducing cell cycle arrest at S phase, and inhibition of tumor cell migration. Most importantly, administration of CE significantly reduced the number of melanoma metastatic nodules in vivo. Chemical analysis of CE indicated the presence of the long chain fatty compounds, 1-eicosanol, 1-docosanol, and 2-nonadecanone as main constituents. Conclusion: These results indicate that K. coriacea is a promising medicinal plant in cancer therapy exhibiting antitumor activity both in vitro and in vivo against different tumor cell lines.

Vitamins K2, K3 and K5 exert antitumor effects on established colorectal cancer in mice by inducing apoptotic death of tumor cells.

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Ogawa, Mutsumi; Nakai, Seiji; Deguchi, Akihiro; Nonomura, Takako; Masaki, Tsutomu; Uchida, Naohito; Yoshiji, Hitoshi; Kuriyama, Shigeki

2007-08-01

Although a number of studies have shown that vitamin K possesses antitumor activities on various neoplastic cell lines, there are few reports demonstrating in vivo antitumor effects of vitamin K, and the antitumor effect on colorectal cancer (CRC) remains to be examined. Therefore, antitumor effects of vitamin K on CRC were examined both in vitro and in vivo. Vitamins K2, K3 and K5 suppressed the proliferation of colon 26 cells in a dose-dependent manner, while vitamin K1 did not. On flow cytometry, induction of apoptosis by vitamins K2, K3 and K5 was suggested by population in sub-G1 phase of the cell cycle. Hoechst 33342 staining and a two-color flow cytometric assay using fluorescein isothiocyanate-conjugated annexin V and propidium iodide confirmed that vitamins K2, K3 and K5 induced apoptotic death of colon 26 cells. Enzymatic activity of caspase-3 in colon 26 cells was significantly up-regulated by vitamins K2, K3 and K5. The pan-caspase inhibitor, benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone, substantially prevented vitamin K-mediated apoptosis. In vivo study using syngeneic mice with subcutaneously established colon 26 tumors demonstrated that intravenous administration of vitamins K2, K3 and K5 significantly suppressed the tumor growth. The number of apoptotic tumor cells was significantly larger in the vitamin K-treated groups than in the control group. These results suggest that vitamins K2, K3 and K5 exerted effective antitumor effects on CRC in vitro and in vivo by inducing caspase-dependent apoptotic death of tumor cells, suggesting that these K vitamins may be promising agents for the treatment of patients with CRC.

In vitro and in vivo antitumor effects of 50 to 100-KDa components from B16 melanoma culture supernatant.

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Qin, Ying-Song; Zhang, X U; Zhang, Xiang-Yu

2015-07-01

The development of immunological therapies for melanoma has been of considerable concern in recent years. Whole tumor cell lysates have been used to develop antitumor vaccines, but the effective components of the lysates have not been identified. In the present study, protein elements were purified from the B16 supernatant to analyze the in vitro chemotaxis towards mouse spleen lymphocytes using a Boyden chamber. Prior to establishing a B16 melanoma model, C57BL/6 mice were vaccinated with these proteins, and melanoma growth, tumor appearance time and behavioral changes were observed. Next, the cytotoxicity and subsets of the tumor infiltrating lymphocytes, and the histological characteristics of the melanoma were analyzed. The isolated purified fragments of B16 melanoma culture supernatant had strong antitumor effects. The possible antitumor mechanism was delineated, and was identified to possibly be through the activation of cluster of differentiation 8-positive T cells and the promotion of B16 cell differentiation. These methods will provide a novel insight into understanding antitumor immunological mechanisms and provide a potential avenue for immunotherapy.

The antitumor activity of a doxorubicin loaded, iRGD-modified sterically-stabilized liposome on B16-F10 melanoma cells: in vitro and in vivo evaluation

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Yu KF

2013-07-01

Full Text Available Ke-Fu Yu,1 Wei-Qiang Zhang,1 Li-Min Luo,1 Ping Song,1 Dan Li,1 Ruo Du,1 Wei Ren,1 Dan Huang,1 Wan-Liang Lu,1,2 Xuan Zhang,1 Qiang Zhang1,2 1Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing, People’s Republic of China; 2State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, People’s Republic of China Abstract: Considering the fact that iRGD (tumor-homing peptide demonstrates tumor-targeting and tumor-penetrating activity, and that B16-F10 (murine melanoma cells overexpress both αv integrin receptor and neuropilin-1 (NRP-1, the purpose of this study was to prepare a novel doxorubicin (DOX-loaded, iRGD-modified, sterically-stabilized liposome (SSL (iRGD-SSL-DOX in order to evaluate its antitumor activity on B16-F10 melanoma cells in vitro and in vivo. The iRGD-SSL-DOX was prepared using a thin-film hydration method. The characteristics of iRGD-SSL-DOX were evaluated. The in vitro leakage of DOX from iRGD-SSL-DOX was tested. The in vitro tumor-targeting and tumor-penetrating characteristics of iRGD-modified liposomes on B16-F10 cells were investigated. The in vivo tumor-targeting and tumor-penetrating activities of iRGD-modified liposomes were performed in B16-F10 tumor-bearing nude mice. The antitumor effect of iRGD-SSL-DOX was evaluated in B16-F10 tumor-bearing C57BL/6 mice in vivo. The average particle size of the iRGD-SSL-DOX was found to be 91 nm with a polydispersity index (PDI of 0.16. The entrapment efficiency of iRGD-SSL-DOX was 98.36%. The leakage of DOX from iRGD-SSL-DOX at the 24-hour time point was only 7.5%. The results obtained from the in vitro flow cytometry and confocal microscopy, as well as in vivo biodistribution and confocal immunofluorescence microscopy experiments, indicate that the tumor-targeting and tumor-penetrating activity of the iRGD-modified SSL was higher than that of unmodified SSL. In vivo antitumor activity

Preparation, Characterization, and In Vitro and Vivo Antitumor Activity of Oridonin-Conjugated Multiwalled Carbon Nanotubes Functionalized with Carboxylic Group

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Chuanjin Wang

2016-01-01

Full Text Available Carbon nanotubes have shown great potential in tumor therapy. Oridonin (ORI is a poorly water-soluble diterpenoid compound (C20H28O6 used in the treatment of esophageal and hepatic carcinoma for decades. For the purpose of enhancing the antitumor potency and reducing cytotoxicity of ORI, multiwalled carbon nanotubes functionalized with carboxylic group (MWCNTs-COOH were used as ORI carrier. ORI was noncovalently encapsulated into (or onto the functionalized carbon nanotubes (MWCNTs-ORI. The obtained MWCNTs-ORI has been characterized. The ORI loading efficiency in MWCNTs-COOH carrier was studied to be about 82.6% (w/w. In vitro cytotoxicity assay on MWCNTs-ORI gave IC50 of 7.29±0.5 μg/mL and ORI-F gave IC50 of 14.5±1.4 μg/mL. The antitumor effect studies in vivo showed that MWCNTs-ORI improved antitumor activity of ORI in comparison with ORI-F. The tumor inhibition ratio for MWCNTs-ORI (1.68×10-2 g·Kg−1·d−1 was 86.4%, higher than that of ORI-F (1.68×10-2 g·Kg−1·d−1 which was 39.2%. This can greatly improve the pharmaceutical efficiency and reduce potential side effects.

Enhanced antitumor activities of (-)-epigallocatechin-3-O-gallate fatty acid monoester derivatives in vitro and in vivo

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Matsumura, Kazuaki; Kaihatsu, Kunihiro; Mori, Shuichi; Cho, Han Hee; Kato, Nobuo; Hyon, Suong Hyu

2008-01-01

(-)-Epigallocatechin-3-O-gallate (EGCG) monoesters modified with butanoyl (EGCG-C4), octanoyl (EGCG-C8), palmitoyl groups (EGCG-C16) were synthesized by a lipase-catalyzed transesterification method and their antitumor activities were investigated in vitro and in vivo. The in vitro antitumor activities of EGCG-monoester derivatives increased in an alkyl chain length-dependent manner. The cytotoxicity of EGCG, EGCG-C4, EGCG-C8 was mainly caused by H 2 O 2 which was generated with their oxidation. On the other hand, EGCG-C16 was more stable than EGCG and it did not generate H 2 O 2 in the cell culture medium. Furthermore, EGCG-C16 inhibited cell proliferation and induced apoptosis in the presence of catalase. EGCG-C16 was found to inhibit the phosphorylation of the epidermal growth factor receptor (EGFR), which is related to various types of tumor growth. EGCG-C16 suppressed tumor growth in vivo in colorectal tumor bearing mice in comparison to an untreated control, vector control (DMSO) and EGCG.

Antitumor activity and systemic effects of PVM/MA-shelled selol nanocapsules in lung adenocarcinoma-bearing mice

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De Souza, Ludmilla Regina; Muehlmann, Luis Alexandre; Matos, Lívia Carneiro; Lacava, Zulmira Guerreiro Marques; Báo, Sônia Nair; Azevedo, Ricardo Bentes; Simón-Vázquez, Rosana; González-Fernández, África; De-Paula, Alfredo Maurício Batista; Mosiniewicz-Szablewska, Ewa; Suchocki, Piotr; Morais, Paulo César

2015-01-01

Selol is a semi-synthetic compound containing selenite that is effective against cancerous cells and safer for clinical applications in comparison with other inorganic forms of selenite. Recently, we have developed a formulation of poly(methyl vinyl ether-co-maleic anhydride)-shelled selol nanocapsules (SPN), which reduced the proliferative activity of lung adenocarcinoma cells and presented little deleterious effects on normal cells in in vitro studies. In this study, we report on the antitumor activity and systemic effects induced by this formulation in chemically induced lung adenocarcinoma-bearing mice. The in vivo antitumor activity of the SPN was verified by macroscopic quantification, immunohistochemistry and morphological analyses. Toxicity analyses were performed by evaluations of the kidney, liver, and spleen; analyses of hemogram and plasma levels of alanine aminotransferase, aspartate transaminase, urea, and creatinine; and DNA fragmentation and cell cycle activity of the bone marrow cells. Furthermore, we investigated the potential of the SPN formulation to cause hemolysis, activate the complement system, provoke an inflammatory response and change the conformation of the plasma proteins. Our results showed that the SPN reduced the area of the surface tumor nodules but not the total number of tumor nodules. The biochemical and hematological findings were suggestive of the low systemic toxicity of the SPN formulation. The surface properties of the selol nanocapsules point to characteristics that are consistent with the treatment of the tumors in vivo: low hemolytic activity, weak inflammatory reaction with no activation of the complement system, and mild or absent conformational changes of the plasma proteins. In conclusion, this report suggests that the SPN formulation investigated herein exhibits anti-tumoral effects against lung adenocarcinoma in vivo and is associated with low systemic toxicity and high biocompatibility. (paper)

Increasing antitumor effects of chemoradiotherapy by drug efflux inhibition with encapsulated anti-RLIP-76

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Harada, Satoshi; Ehara, Shigeru; Ishii, Keizo

2011-01-01

Microencapsulated anti-RLIP76 was tested in vivo using C3He/J mice to determine the increasing of antitumor effects by chemotherapeutic agent efflux inhibition during chemoradiotherapy. Microcapsules were produced by spraying a mixture of 3.0% hyaluronic acid, 2.0% alginate, 3.0% H 2 O 2 , and 0.3 mmol carboplatin onto a mixture of 0.3 mol FeCl 2 and 0.15 mol CaCl 2 . Microcapsules were subcutaneously injected into MM46 tumors previously inoculated into the left hind legs of C3He/J mice. Subsequent radiotherapy consisted of tumor irradiation with 10 Gy or 20 Gy 60 Co. The antitumor effects of microcapsules were tested by measuring tumor size and monitoring tumor growth. Three types of adverse effects were considered: fuzzy hair, loss of body weight, and mortality. Carboplatin levels were monitored using particle-induced X-ray emission (PIXE) and a micro-PIXE camera. Anti-RLIP76 inhibited the efflux of carboplatin from tumor tissue, which led to an increase in the concentration of carboplatin. Higher carboplatin concentration significantly increased the combined antitumor effect of radiation and chemotherapy. A significant decrease in adverse effects was also observed with microencapsulated anti-RLIP76. (author)

In vitro and in vivo antitumor efficacy of berberine-nanostructured lipid carriers against H22 tumor

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Wang, Zhi-ping; Wu, Jun-biao; Chen, Tong-sheng; Zhou, Qun; Wang, Yi-fei

2015-03-01

Hepatocarcinoma, a malignant cancer, threaten human life badly. It is a current issue to seek the effective natural remedy from plant to treat cancer due to the resistance of the advanced hepatocarcinoma to chemotherapy. Berberine (Ber), an isoquinoline derivative alkaloid, has a wide range of pharmacological properties and is considered to have anti-hepatocarcinoma effects. However its low oral bioavailability restricts its wide application. In this report, Ber loaded nanostructured lipid carriers (Ber-NLC) was prepared by hot melting and then high pressure homogenization technique. Both in vitro and in vivo anti-hepatocarcinoma effects of Ber-NLC relative to efficacy of bulk Ber were evaluated. The particle size and zeta potential of Ber-NLC were 189.3 nm and -19.3 mV, respectively. MTT assay showed that Ber-NLC effectively inhibited the proliferation of H22 cells, and the corresponding IC50 values were 6.3 μg/ml (22.1 μg/ml of bulk Ber). In vivo studies also showed higher antitumor efficacy, and inhibition rates was 68.3 % (41.4 % of bulk Ber) at 100 mg/kg intragastric administration in the H22 solid tumor bearing mice. These results suggest that the delivery of Ber-NLC is a promising approach for treating tumors.

Antitumor Properties of Modified Detonation Nanodiamonds and Sorbed Doxorubicin on the Model of Ehrlich Ascites Carcinoma.

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Medvedeva, N N; Zhukov, E L; Inzhevatkin, E V; Bezzabotnov, V E

2016-01-01

We studied antitumor properties of modified detonation nanodiamonds loaded with doxorubicin on in vivo model of Ehrlich ascites carcinoma. The type of tumor development and morphological characteristics of the liver, kidneys, and spleen were evaluated in experimental animals. Modified nanodiamonds injected intraperitoneally produced no antitumor effect on Ehrlich carcinoma. However, doxorubicin did not lose antitumor activity after sorption on modified nanodiamonds.

Targeting Gene-Viro-Therapy with AFP driving Apoptin gene shows potent antitumor effect in hepatocarcinoma

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Zhang Kang-Jian

2012-02-01

Full Text Available Abstract Background Gene therapy and viral therapy are used for cancer therapy for many years, but the results are less than satisfactory. Our aim was to construct a new recombinant adenovirus which is more efficient to kill hepatocarcinoma cells but more safe to normal cells. Methods By using the Cancer Targeting Gene-Viro-Therapy strategy, Apoptin, a promising cancer therapeutic gene was inserted into the double-regulated oncolytic adenovirus AD55 in which E1A gene was driven by alpha fetoprotein promoter along with a 55 kDa deletion in E1B gene to form AD55-Apoptin. The anti-tumor effects and safety were examined by western blotting, virus yield assay, real time polymerase chain reaction, 3-(4,5-dimethylthiazol-2-yl-2, 5-diphenyltetrazolium bromide assay, Hoechst33342 staining, Fluorescence-activated cell sorting, xenograft tumor model, Immunohistochemical assay, liver function analysis and Terminal deoxynucleotidyl transferase mediated dUTP Nick End Labeling assay. Results The recombinant virus AD55-Apoptin has more significant antitumor effect for hepatocelluar carcinoma cell lines (in vitro than that of AD55 and even ONYX-015 but no or little impair on normal cell lines. Furthermore, it also shows an obvious in vivo antitumor effect on the Huh-7 liver carcinoma xenograft in nude mice with bigger beginning tumor volume till about 425 mm3 but has no any damage on the function of liver. The induction of apoptosis is involved in AD55-Apoptin induced antitumor effects. Conclusion The AD55-Apoptin can be a potential anti-hepatoma agent with remarkable antitumor efficacy as well as higher safety in cancer targeting gene-viro-therapy system.

In Vitro and In Vivo Antitumor Activity of [Pt(O,O'-acac)(γ-acac)(DMS)] in Malignant Pleural Mesothelioma.

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Muscella, Antonella; Vetrugno, Carla; Cossa, Luca Giulio; Antonaci, Giovanna; De Nuccio, Francesco; De Pascali, Sandra Angelica; Fanizzi, Francesco Paolo; Marsigliante, Santo

2016-01-01

Malignant pleural mesothelioma (MPM) is an aggressive malignancy highly resistant to chemotherapy. There is an urgent need for effective therapy inasmuch as resistance, intrinsic and acquired, to conventional therapies is common. Among Pt(II) antitumor drugs, [Pt(O,O'-acac)(γ-acac)(DMS)] (Ptac2S) has recently attracted considerable attention due to its strong in vitro and in vivo antiproliferative activity and reduced toxicity. The purpose of this study was to examine the efficacy of Ptac2S treatment in MPM. We employed the ZL55 human mesothelioma cell line in vitro and in a murine xenograft model in vivo, to test the antitumor activity of Ptac2S. Cytotoxicity assays and Western blottings of different apoptosis and survival proteins were thus performed. Ptac2S increases MPM cell death in vitro and in vivo compared with cisplatin. Ptac2S was more efficacious than cisplatin also in inducing apoptosis characterized by: (a) mitochondria depolarization, (b) increase of bax expression and its cytosol-to-mitochondria translocation and decrease of Bcl-2 expression, (c) activation of caspase-7 and -9. Ptac2S activated full-length PKC-δ and generated a PKC-δ fragment. Full-length PKC-δ translocated to the nucleus and membrane, whilst PKC-δ fragment concentrated to mitochondria. Ptac2S was also responsible for the PKC-ε activation that provoked phosphorylation of p38. Both PKC-δ and PKC-ε inhibition (by PKC-siRNA) reduced the apoptotic death of ZL55 cells. Altogether, our results confirm that Ptac2S is a promising therapeutic agent for malignant mesothelioma, providing a solid starting point for its validation as a suitable candidate for further pharmacological testing.

Anti-tumor efficacy of lymphokine-activated killer cells and recombinant interleukin 2 in vivo

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Mule, J.J.; Shu, S.; Rosenberg, S.A.

1985-01-01

The authors showed previously that adoptive immunotherapy with the combination of LAK cells and recombinant IL 2 (RIL 2) can markedly reduce pulmonary micrometastases from multiple sarcomas established 3 days after the i.v. injection of syngeneic tumor cells in C57BL/6 mice. In this report, they analyzed the factors required for successful therapy. Titration analysis in vivo revealed an inverse relationship between the number of pulmonary metastases remaining after treatment and both the number of LAK cells and the amount of RIL 2 administered. Fresh or unstimulated splenocytes had no anti-tumor effect; a 2- to 3-day incubation of splenocytes in RIL 2 was required. LAK cells generated from allogeneic DBA (H-2d) splenocytes were as effective in vivo as syngeneic, C57BL/6 (H-2b) LAK cells. The anti-metastatic capacity of LAK cells was significantly reduced or eliminated when irradiated with 3000 rad before adoptive transfer. The combined therapy of LAK cells plus RIL 2 was shown to be highly effective in mice immunosuppressed by 500 rad total body irradiation and in treating macrometastases established in the lung 10 days after the i.v. injection of sarcoma cells. Further, reduction of both micrometastases and macrometastases could also be achieved by RIL 2 alone when administered at higher levels than were required with LAK cells. The value of LAK cell transfer and of IL 2 administration for the treatment of tumors established at other sites is currently under investigation

Melittin exerts an antitumor effect on non‑small cell lung cancer cells.

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Zhang, Su-Fang; Chen, Zhe

2017-09-01

Lung cancer accounts for a significant percentage of all cancer‑associated mortalities in men and women, with non‑small cell lung cancer being the most frequently occurring type of lung cancer. Melittin is the principal active component of apitoxin (bee venom) that has been reported to exert anti‑chronic inflammatory and anti‑cancer effects. In the present study, the antitumor effect of melittin was evaluated using in vivo and in vitro analyses. The results demonstrated that melittin significantly inhibited the epidermal growth factor‑induced invasion and migration of non‑small cell lung cancer cells. Subcutaneous injection of melittin at doses of 1 and 10 mg/kg significantly suppressed non‑small cell lung cancer tumor growth by 27 and 61%, respectively. In addition, melittin significantly inhibited the secretion of vascular endothelial growth factor (VEGF) in non‑small cell lung cancer cells. Furthermore, melittin decreased the protein expression of VEGF and hypoxia‑inducible factor 1‑α. Therefore, the antitumor activity of melittin may be associated with the anti‑angiogenic actions of inhibiting the VEGF and hypoxia‑inducible factor signaling pathways.

Ficus umbellata Vahl. (Moraceae Stem Bark Extracts Exert Antitumor Activities In Vitro and In Vivo

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Kevine Kamga Silihe

2017-05-01

Full Text Available A Ficus umbellata is used to treat cancer. The present work was therefore designed to assess antitumor potentials of F. umbellata extracts in nine different cell lines. Cell cycle, apoptosis, cell migration/invasion, levels of reactive oxygen species (ROS, mitochondrial membrane potential (MMP, caspases activities as well as Bcl-2 and Bcl-xL protein content were assessed in MDA-MB-231 cells. The 7,12-dimethylbenz(aanthracene (DMBA-induced carcinogenesis in rats were also used to investigate antitumor potential of F. umbellata extracts. The F. umbellata methanol extract exhibited a CC50 of 180 μg/mL in MDA-MB-231 cells after 24 h. It induced apoptosis in MCF-7 and MDA-MB-231 cells, while it did not alter their cell cycle phases. Further, it induced a decrease in MMP, an increase in ROS levels and caspases activities as well as a downregulation in Bcl-2 and Bcl-xL protein contents in MDA-MB-231 cells. In vivo, F. umbellata aqueous (200 mg/kg and methanol (50 mg/kg extracts significantly (p < 0.001 reduced ovarian tumor incidence (10%, total tumor burden (58% and 46%, respectively, average tumor weight (57.8% and 45.6%, respectively as compared to DMBA control group. These results suggest antitumor potential of F. umbellata constituents possibly due to apoptosis induction mediated through ROS-dependent mitochondrial pathway.

In vitro and in vivo antitumor activity of the halogenated boroxine dipotassium-trioxohydroxytetrafluorotriborate (K2[B3O3F4OH]).

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Ivankovic, Sinisa; Stojkovic, Ranko; Galic, Zoran; Galic, Borivoj; Ostojic, Jelena; Marasovic, Maja; Milos, Mladen

2015-06-01

Dipotassium-trioxohydroxytetrafluorotriborate K2[B3O3F4OH] was listed as a promising new therapeutic for cancer diseases. For in vitro and in vivo investigation of its antitumor effects 4T1 mammary adenocarcinoma, B16F10 melanoma and squamous cell carcinoma SCCVII were used. The detailed in vitro investigation undoubtedly showed that K2[B3O3F4OH] affects the growth of cancer cells. The proliferation of cells depends on the concentration so that aqueous solution of K2[B3O3F4OH], the concentrations of 10(-4) M and less, does not affect cell growth, but the concentrations of 10(-3) M or more, significantly slows cells growth. B16F10 and SCCVII cells show higher sensitivity to the cytotoxic effects of K2[B3O3F4OH] compared to 4T1 cells. Under in vivo conditions, K2[B3O3F4OH] slows the growth of all three tumors tested compared to the control, and the inhibitory effect was most pronounced during the application of the substance. There is almost no difference if K2[B3O3F4OH] was applied intraperitoneally, intratumor, peroral or as ointment. Addition of 5-FU did not further increase the antitumor efficacy of K2[B3O3F4OH].

A marginal anticancer effect of regorafenib on pancreatic carcinoma cells in vitro, ex vivo, and in vivo.

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Mayer, Barbara; Karakhanova, Svetlana; Bauer, Nathalie; Liu, Li; Zhu, Yifan; Philippov, Pavel P; Werner, Jens; Bazhin, Alexandr V

2017-11-01

Activation of receptor tyrosine kinases is recognized as a hallmark of cancer. Vascular endothelial growth factor (VEGF) and its receptor VEGFR are the prominent players in the induction of tumor neoangiogenesis. Strategies to inhibit VEGF and VEGFR are under intensive investigation in preclinical and clinical settings. Regorafenib is a multikinase inhibitor targeting some VEGFR and other receptor kinases. Preclinical results led to the FDA approval of regorafenib for treatment of metastatic colorectal cancer patients. Effects of this drug in pancreatic ductal adenocarcinoma (PDAC) have not been investigated yet. Gene expression was assessed with real-time PCR analysis. In vitro cell viability, proliferation, apoptosis, necrosis, migration, and invasion of the PDAC cells were assessed after regorafenib treatment. Ex vivo anti-tumor effects of regorafenib were investigated in a spheroid model of PDAC. In vivo anti-tumor effects of the drug were evaluated in a fertilized chicken egg model. In this work, we have demonstrated only a marginal anticancer effect of regorafenib in PDAC in vitro and ex vivo. However, in the egg model of PDAC, this drug reduced tumor volume. Besides, regorafenib is capable of modulating the expression of cancer stem cell (CSC) markers and epithelial-to-mesenchymal transition (EMT) markers on PDAC cells. We found out that effects of regorafenib on the expression of CSC and EMT markers are very heterogeneous and depend obviously on original expression of these markers. We concluded that regorafenib might be a potential drug for PDAC and it should be investigated in future clinical trials.

Evaluation of antitumor, immunomodulatory and free radical scavenging effects of a new herbal prescription seaweed complex preparation

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Liu, Xin; Shao, Changlun; Kong, Wenwen; Fang, Yuchun; Wang, Changyun

2013-09-01

Seaweed Complex Preparation (SCP) is a clinical traditional Chinese medicine preparation which is composed of seven traditional Chinese herbs, and it has been used for treatment of lung cancer, liver cancer and digestive cancer. However, little information is available about the pharmacodynamic basis. The antitumor, immunomodulatory and free radical scavenging effects of SCP were evaluated in this study. Transplanted tumor in vivo method was used to determine the antitumor effect. The effects on splenocyte proliferation and phagocytosis of macrophages in tumor-bearing mice were measured by the MTT method and the phagocytizing cock red blood cell (CRBC) method respectively. The scavenging activities of SCP on DPPH and hydroxyl radicals in vitro were investigated. It was found that the medium-dose and high-dose of SCP could significantly inhibit the growth of transplanted hepatic tumor of murine hepatocarcinoma cell line H22, and promote proliferation of splenocytes and phagocytosis of macrophages. SCP possessed noticeable scavenging activities on DPPH and hydroxyl radicals. The antitumor effects of SCP might be achieved by improving immune system and scavenging free radicals, which is in accordance with the viewpoint of traditional Chinese medicine in promoting the body resistance and eliminating pathogenic factors for cancer treatment.

Structurally related antitumor effects of flavanones in vitro and in vivo: involvement of caspase 3 activation, p21 gene expression, and reactive oxygen species production

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Shen, S.-C.; Ko, C.H.; Tseng, S.-W.; Tsai, S.-H.; Chen, Y.-C.

2004-01-01

Flavonoids exist extensively in plants and Chinese herbs, and several biological effects of flavonoids have been demonstrated. The antitumor effects in colorectal carcinoma cells (HT29, COLO205, and COLO320HSR) of eight flavanones including flavanone, 2'-OH flavanone, 4'-OH flavanone, 6-OH flavanone, 7-OH flavanone, naringenin, nargin, and taxifolin were investigated. Results of the MTT assay indicate that 2'-OH flavanone showed the most potent cytotoxic effect on these three cells, and cell death induced by 2'-OH flavanone was via the occurrence of DNA ladders, apoptotic bodies, and hypodiploid cells, all characteristics of apoptosis. Induction of caspase 3 protein processing and enzyme activity associated with cleavage of poly(ADP-ribose) polymerase (PARP) was identified in 2'-OH flavanone-treated cells, and a peptidyl inhibitor (Ac-DEVD-FMK) of caspase 3 attenuated the cytotoxicity of 2'-OH flavanone in COLO205 and HT-29 cells. Elevation of p21 (but not p53) and a decrease in Mcl-1 protein were found in 2'-OH flavanone-treated COLO205 and HT-29 cells. Elevation of intracellular reactive oxygen species (ROS) was detected in 2'-OH flavanone-treated cells by the 2',7'-dichlorodihydrofluorescein diacetate (DCHF-DA) assay, and ROS scavengers including 4,5-dihydro-1,3-benzene disulfonic acid (tiron), catalase, superoxide dismutase (SOD), and pyrrolidine dithiocarbamate (PDTC) suppressed the 2'-OH flavanone-induced cytotoxic effect. Subcutaneous injection of COLO205 induced tumor formation in nude mice, and 2'-OH flavanone showed a significant inhibitory effect on tumor formation. The appearance of apoptotic cells with H and E staining, and an increase in p21, but not p53, protein by immunohistochemistry were observed in tumor tissues under 2'-OH flavanone treatment. Primary tumor cells (COLO205-X) derived from a tumor specimen elicited by COLO205 were established, and 2'-OH flavanone showed an significant apoptotic effect in COLO205-X cells in accordance with the

Anti-tumor activities of luteolin and silibinin in glioblastoma cells: overexpression of miR-7-1-3p augmented luteolin and silibinin to inhibit autophagy and induce apoptosis in glioblastoma in vivo.

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Chakrabarti, Mrinmay; Ray, Swapan K

2016-03-01

Glioblastoma is the deadliest brain tumor in humans. High systemic toxicity of conventional chemotherapies prompted the search for natural compounds for controlling glioblastoma. The natural flavonoids luteolin (LUT) and silibinin (SIL) have anti-tumor activities. LUT inhibits autophagy, cell proliferation, metastasis, and angiogenesis and induces apoptosis; while SIL activates caspase-8 cascades to induce apoptosis. However, synergistic anti-tumor effects of LUT and SIL in glioblastoma remain unknown. Overexpression of tumor suppressor microRNA (miR) could enhance the anti-tumor effects of LUT and SIL. Here, we showed that 20 µM LUT and 50 µM SIL worked synergistically for inhibiting growth of two different human glioblastoma U87MG (wild-type p53) and T98G (mutant p53) cell lines and natural combination therapy was more effective than conventional chemotherapy (10 µM BCNU or 100 µM TMZ). Combination of LUT and SIL caused inhibition of growth of glioblastoma cells due to induction of significant amounts of apoptosis and complete inhibition of invasion and migration. Further, combination of LUT and SIL inhibited rapamycin (RAPA)-induced autophagy, a survival mechanism, with suppression of PKCα and promotion of apoptosis through down regulation of iNOS and significant increase in expression of the tumor suppressor miR-7-1-3p in glioblastoma cells. Our in vivo studies confirmed that overexpression of miR-7-1-3p augmented anti-tumor activities of LUT and SIL in RAPA pre-treated both U87MG and T98G tumors. In conclusion, our results clearly demonstrated that overexpression of miR-7-1-3p augmented the anti-tumor activities of LUT and SIL to inhibit autophagy and induce apoptosis for controlling growth of different human glioblastomas in vivo.

Decreasing size of radiosensitive capsules from micro to nano, and its increased antitumor effect and decreasing adverse effect

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Harada, S.; Ehara, S.; Ishii, K.; Yamazaki, H.; Matsuyama, S.; Sato, Takahiro; Kamiya, Tomihiro; Sera, K.; Saito, Y.

2012-01-01

We have been developing microcapsules that release anticancer drug with response to radiation. We attempted to decrease the diameter of capsules. Then, two categories were tested in VIVO in C3He mice: (1) the antitumor effect in combination with radiation and subcutaneously injected nanocapsules, (2) the kidnetics of nanocapsules when they were injected intravenously. Microcapsules were produced by spraying a mixture of 3.0 % hyaluronic acid, 2.0 % alginate, 3.0 % H 2 O 2 , and 0.3 mmol carboplatin (Pt containing anticancer drug) onto a mixture of vibrated 0.3 mol FeCl 2 and 0.15 mol CaCl 2 . The antitumor effect was measured by measuring tumor diameter every day. The kinetics of microcapsules were expressed as the numbers of capsules in 5 views (25 x 25 μm) of micro PIXE camera and Pt concentration of quantiative PIXE. The generated microcapsules 752 ± 64 nm, which were significantly downsized relative to previous capsules. The accumulations of capsules in lungs, liver, and kidneys were decreased by downsizing, whereas those of tumors were increased. By adjusting Pt concentration in tumor, there were no significant differences in antitumor effect between not downsized and downsized microcapsules with combination with radiation. Decreased trapping of downsized microcapsules to lungs, liver, and kidneys, also increased trapping in tumors will lead to new targeted chemoradiotherapy via intravenous injection of microcapsules. (author)

Anti-tumor effect of bisphosphonate (YM529 on non-small cell lung cancer cell lines

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Date Hiroshi

2007-01-01

Full Text Available Abstract Background YM529 is a newly developed nitrogen-containing bisphosphonate (BP classified as a third-generation BP that shows a 100-fold greater potency against bone resorption than pamidronate, a second-generation BP. This agent is, therefore expected to be extremely useful clinically for the treatment of osteoporosis and hypercalcemia. Recently, YM529 as well as other third-generation BPs have also been shown to exert anti-tumor effects against various types of cancer cells both in vitro or/and in vivo. In this study, we investigate the anti-tumor effect of YM529 on non-small cell lung cancer (NSCLC. Methods Direct anti-tumor effect of YM529 against 8 NSCLC cell lines (adenocarcinoma: H23, H1299, NCI-H1819, NCI-H2009, H44, A549, adenosquamous cell carcinoma: NCI-H125, squamous cell carcinoma: NCI-H157 were measured by MTS assay and calculated inhibition concentration 50 % (IC50 values. YM529 induced apoptosis of NCI-H1819 was examined by DNA fragmentation of 2 % agarose gel electrophoresis and flowcytometric analysis (sub-G1 method. We examined where YM529 given effect to apoptosis of NSCLC cells in signaling pathway of the mevalonate pathway by western blotting analysis. Results We found that there was direct anti-tumor effect of YM529 on 8 NSCLC cell lines in a dose-dependent manner and their IC50 values were 2.1 to 7.9 μM and YM529 induced apoptosis and G1 arrest cell cycle with dose-dependent manner and YM529 caused down regulation of phospholyration of ERK1/2 in signaling pathways of NSCLC cell line (NCI-H1819. Conclusion Our study demonstrate that YM529 showed direct anti-tumor effect on NSCLC cell lines in vitro, which supports the possibility that third-generation BPs including YM529 can be one of therapeutic options for NSCLC.

The novel fusion proteins, GnRH-p53 and GnRHIII-p53, expression and their anti-tumor effect.

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Peiyuan Jia

Full Text Available p53, one of the most well studied tumor suppressor factor, is responsible to a variety of damage owing to the induction of apoptosis and cell cycle arrest in the tumor cells. More than 50% of human tumors contain mutation or deletion of p53. Gonadotrophin-releasing hormone (GnRH, as the ligand of Gonadotrophin-releasing hormone receptor (GnRH-R, was used to deliver p53 into tumor cells. The p53 fusion proteins GnRH-p53 and GnRH iii-p53 were expressed and their targeted anti-tumor effects were determined. GnRH mediates its fusion proteins transformation into cancer cells. The intracellular delivery of p53 fusion proteins exerted the inhibition of the growth of H1299 cells in vitro and the reduction of tumor volume in vivo. Their anti-tumor effect was functioned by the apoptosis and cell cycle arrest induced by p53. Hence, the fusion protein could be a novel protein drug for anti-tumor therapy.

Antioxidant Activity, Antitumor Effect, and Antiaging Property of Proanthocyanidins Extracted from Kunlun Chrysanthemum Flowers

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Siqun Jing

2015-01-01

Full Text Available The objective of the present study was to evaluate the antioxidant activity, antitumor effect, and antiaging property of proanthocyanidins from Kunlun Chrysanthemum flowers (PKCF grown in Xinjiang. In vitro antioxidant experiments results showed that the total antioxidant activity and the scavenging capacity of hydroxyl radicals (•OH and 1,1-diphenyl-2-picrylhydrazyl (DPPH• radicals increased in a concentration-dependent manner and were stronger than those of vitamin C. To investigate the antioxidant activity of PKCF in vivo, we used serum, liver, and kidney from mouse for the measurement of superoxide dismutase (SOD, malondialdehyde (MDA, and total antioxidant capacity (T-AOC. Results indicated that PKCF had antioxidative effect in vivo which significantly improved the activity of SOD and T-AOC and decreased MDA content. To investigate the antitumor activity of PKCF, we used H22 cells, HeLa cells, and Eca-109 cells with Vero cells as control. Inhibition ratio and IC50 values were measured by 3-(4,5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide (MTT assay; PKCF showed great inhibitory activity on H22 cells and HeLa cells. We also used fruit flies as a model for analyzing the anti-aging property of PKCF. Results showed that PKCF has antiaging effect on Drosophila. Results of the present study demonstrated that PKCF could be a promising agent that may find applications in health care, medicine, and cosmetics.

Effect of immunomodifier on radiation-induced antitumor immunity following local irradiation to tumor, 2

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Mukae, Shiro; Norimura, Toshiyuki; Tsuchiya, Takehiko

1988-01-01

This study was carried out to clarify whether or not the antitumor cell-mediated immunity of host is more effectively induced by the combined use of mouse interferon-α/β (MuIFN-α/β) with local irradiation than by simple local irradiation to tumor. C3H/He female mice, MM46 tumor cells and mouse interferon-α/β (MuIFN-α/β) were used in the experiment. Antitumor activity in mice was evaluated by the inhibition of tumor growth and mean survival days after treatment. Spleen cell killing activity to MM46 tumor cells was measured to evaluate the antitumor activity in vitro. In the case of single use of MuIFN-α/β, tumor growth was more rapid than in the non-treated group (control) in vivo. The mean survival days were also reduced. There was no siginificant difference in tumor growth inhibition between combined therapy using X-irradiation and MuIFN-α/β, and single therapy by local irradiation. However, in the case of administration of MuIFN-α/β after irradiation, the mean survival days was significantly increased compared with the group receiving X-ray irradiation only. (author)

The Therapeutic Effect of the Antitumor Drug 11 Beta and Related Molecules on Polycystic Kidney Disease

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2017-10-01

models (Somlo, Yale). Preparation work to assemble a collection of probes specific for oxidative stress genes and other PKD specific genes (as part... Worked : 6 Contribution to Project: Performance of experiments including those related to mitochondrial biology in vivo and unfolded protein...1 AWARD NUMBER: W81XWH-15-1-0364 TITLE: THE THERAPEUTIC EFFECT OF THE ANTITUMOR DRUG 11 BETA AND RELATED MOLECULES ON POLYYSTIC KIDNEY DISEASE

Clinical pharmacology of CAR-T cells: Linking cellular pharmacodynamics to pharmacokinetics and antitumor effects.

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Norelli, M; Casucci, M; Bonini, C; Bondanza, A

2016-01-01

Adoptive cell transfer of T cells genetically modified with tumor-reactive chimeric antigen receptors (CARs) is a rapidly emerging field in oncology, which in preliminary clinical trials has already shown striking antitumor efficacy. Despite these premises, there are still a number of open issues related to CAR-T cells, spanning from their exact mechanism of action (pharmacodynamics), to the factors associated with their in vivo persistence (pharmacokinetics), and, finally, to the relative contribution of each of the two in determining the antitumor effects and accompanying toxicities. In light of the unprecedented curative potential of CAR-T cells and of their predicted wide availability in the next few years, in this review we will summarize the current knowledge on the clinical pharmacology aspects of what is anticipated to be a brand new class of biopharmaceuticals to join the therapeutic armamentarium of cancer doctors. Copyright © 2015. Published by Elsevier B.V.

Vaccination with OK-432 followed by TC-1 tumor lysate leads to significant antitumor effects.

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Chen, I-Ju; Yen, Chih-Feng; Lin, Kun-Ju; Lee, Chyi-Long; Soong, Yung-Kuei; Lai, Chyong-Huey; Lin, Cheng-Tao

2011-07-01

Human papillomavirus (HPV) infects large numbers of women worldwide and is present in more than 99% of all cervical cancer. TC-1 cell is a cell line with high expression of E7 antigen of HPV type 16 and its cell lysate has been demonstrated as an ideal inducer of E7-specific, antitumor immunity. OK-432 (Picibanil), a penicillin-killed Streptococcus pyogenes, has been reported with potent immunomodulation properties in cancer treatment by stimulating the maturation of dendritic cells (DCs) and secretion of Th-1 type cytokines. The current study demonstrated that a protocol to immunize the C57BL/6 mice with OK-432 followed by treatment with TC-1 lysate can generate markedly increased immune responses of E7-specific CD4(+) T cells and a moderate increase of natural killer (NK) cell, as well as a satisfactorily protective and therapeutic antitumor effect by triggering the DCs to prime T cells. Depletion of lymphocyte subset in vivo suggested that the antitumor effects could be dominantly executed by CD8+ T cells and followed by NK cells, and both of these reactions were induced by the generation of robust E7-specific CD4(+) T helper cell response. These findings warrant OK-432 combination with tumor-lysate as an effective and safe vaccine in future clinical application of cervical cancer.

Antitumor and Immunomodulatory Effects of Polysaccharides from Broken-Spore of Ganoderma lucidum

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Peng-Yun eWang

2012-07-01

Full Text Available The antitumor activity of Gl-BSP, a polysaccharide isolated from boiling water extract of the broken-spores of Ganoderma lucidum (Leyss ex Fr Karst. and its possible mechanism were investigated in vivo and in vitro. It was showed that Gl-BSP (50, 100, 200 mg/kg exhibited antitumor effect against Sarcoma 180 (S180 in BALB/c mice. The Gl-BSP was not cytotoxicity in S180 cells and PG cells (human lung carcinoma cell in vitro. However, Gl-BSP-treated serum potently inhibited S180 cells and PG cells proliferation in vitro. Moreover, Gl-BSP could promote the splenic lymphocyte proliferation induced by Con A or LPS, enhance nature killer cell (NK cell cytotoxic activity, augment the percentage of neutral red (NR phagocytosis by macrophages, and increase the percentage of the CD4+ or CD8+ subset in S180-bearing BALB/c mice. The level of IFN-γ, TNF-α and NO of serum apparently was increased by Gl-BSP. Gl-BSP also showed immunomodulatory activities in tumor-bearing mice. Furthermore，It was proved that neutralization with anti-TNF-α and/or anti-IFN-γ significantly diminished growth inhibition induced by Gl-BSP –treated serum in S180 or PG cells. Blocking effect was noted in the combination of anti-TNF-α and anti-IFN-γ. These observations suggest that the antitumor activity of Gl-BSP may mainly relate to the activation of the immune response of the host organism by the stimulation of NK cells, T cells, and macrophages.

Evaluation of antitumor efficacy and toxicity of novel 6-nitro-2-(3-chloropropyl-1H-benz[de]isoquinoline-1,3-dione in vivo in mouse

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Asama Mukherjee

2013-01-01

Full Text Available Aim: This study was aimed to assess the in vivo anti-tumoral potency of the novel 6-nitro-2-(3-chloropropyl-1H-benz[de]isoquinoline-1,3-dione [Compound 1] that has earlier demonstrated excellent cytotoxicity in 15 out of 17 human tumor cell lines tested. Materials and Methods: Two murine tumors namely Sarcoma-180 (S-180 and Ehrlich ascites carcinoma (EAC were used to measure its in vivo anti-tumor activity through the increase in median survival times (MST of drug treated (T over untreated control (C mice. Drug-induced toxicity in respect of hematological parameters, femoral bone marrow and splenic cellularity as well as biochemical parameters and histopathology of liver and kidney were assessed in vivo in normal and S-180 bearing mice sequentially on days 9, 14 and 19 following drug treatment at the optimum dose of 60 mg/kg administered from day 1 to 7. Results: Results revealed significant tumor regression effects in S-180 and EAC as T/C max values of 138 and 189 were obtained at its optimum dose of 60 mg/kg for QD 1-7 . Toxicity assay indicated no significant cardiotoxicity, hepatotoxicity or nephrotoxicity of the compound in normal and S-180 bearing mice. An initial hyposplenic cellularity and the femoral bone marrow suppression effect observed on day 9 reached normalcy by day 19. HPLC analysis revealed that it has appreciable stability (half-life ~ 3 h in murine blood plasma in vitro. Conclusion: Above results justify potential candidature of the compound for further drug development.

Low dose radiation enhance the anti-tumor effect of high dose radiation on human glioma cell U251

International Nuclear Information System (INIS)

Wang Chang; Wang Guanjun; Tan Yehui; Jiang Hongyu; Li Wei

2008-01-01

Objective: To detect the effect on the growth of human glioma cell U251 induced by low dose irradiation and low dose irradiation combined with large dose irradiation. Methods: Human glioma cell line U251 and nude mice carried with human glioma were used. The tumor cells and the mice were treated with low dose, high dose, and low dose combined high dose radiation. Cells growth curve, MTT and flow cytometry were used to detect the proliferation, cell cycle and apoptosis of the cells; and the tumor inhibition rate was used to assess the growth of tumor in vivo. Results: After low dose irradiation, there was no difference between experimental group and control group in cell count, MTT and flow cytometry. Single high dose group and low dose combined high dose group both show significantly the suppressing effect on tumor cells, the apoptosis increased and there was cell cycle blocked in G 2 period, but there was no difference between two groups. In vivo apparent anti-tumor effect in high dose radiation group and the combining group was observed, and that was more significant in the combining group; the prior low dose radiation alleviated the injury of hematological system. There was no difference between single low dose radiation group and control. Conclusions: There is no significant effect on human glioma cell induced by low dose radiation, and low dose radiation could not induce adaptive response. But in vivo experience, low dose radiation could enhance the anti-tumor effect of high dose radiation and alleviated the injury of hematological system. (authors)

Antitumor effect of iRGD-modified liposomes containing conjugated linoleic acid–paclitaxel (CLA-PTX on B16-F10 melanoma

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Du R

2014-06-01

Full Text Available Ruo Du,1 Ting Zhong,1 Wei-Qiang Zhang,1 Ping Song,1 Wen-Ding Song,1 Yang Zhao,1 Chao-Wang,1 Yi-Qun Tang,3 Xuan Zhang,1,2 Qiang Zhang1,2 1Department of Pharmaceutics, 2State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 3Department of Clinical Pharmacy, China Pharmaceutical University, Nanjing, People’s Republic of China Abstract: In the present study, we prepared a novel delivery system of iRGD (CRGDK/RGPD/EC-modified sterically stabilized liposomes (SSLs containing conjugated linoleic acid–paclitaxel (CLA-PTX. The anti-tumor effect of iRGD-SSL-CLA-PTX was investigated on B16-F10 melanoma in vitro and in vivo. The in vitro targeting effect of iRGD-modified SSLs was investigated in a real-time confocal microscopic analysis experiment. An endocytosis-inhibition assay was used to evaluate the endocytosis pathways of the iRGD-modified SSLs. In addition, the in vitro cellular uptake and in vitro cytotoxicity of iRGD-SSL-CLA-PTX were evaluated in B16-F10 melanoma cells. In vivo biodistribution and in vivo antitumor effects of iRGD-SSL-CLA-PTX were investigated in B16-F10 tumor-bearing mice. The induction of apoptosis by iRGD-SSL-CLA-PTX was evaluated in tumor-tissue sections. Real-time confocal microscopic analysis results indicated that the iRGD-modified SSLs internalized into B16-F10 cells faster than SSLs. The identified endocytosis pathway of iRGD-modified SSLs indicated that energy- and lipid raft-mediated endocytosis played a key role in the liposomes’ cellular uptake. The results of the cellular uptake experiment indicated that the increased cellular uptake of CLA-PTX in the iRGD-SSL-CLA-PTX-treated group was 1.9-, 2.4-, or 2.1-fold compared with that in the CLA-PTX group after a 2-, 4-, or 6-hour incubation, respectively. In the biodistribution test, the CLA-PTX level in tumor tissues from iRGD-SSL-CLA-PTX-treated mice at 1 hour (1.84±0.17 µg/g and 4 hours (1.17±0

Expression of microRNA-15b and the glycosyltransferase GCNT3 correlates with antitumor efficacy of Rosemary diterpenes in colon and pancreatic cancer.

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Margarita González-Vallinas

Full Text Available Colorectal and pancreatic cancers remain important contributors to cancer mortality burden and, therefore, new therapeutic approaches are urgently needed. Rosemary (Rosmarinus officinalis L. extracts and its components have been reported as natural potent antiproliferative agents against cancer cells. However, to potentially apply rosemary as a complementary approach for cancer therapy, additional information regarding the most effective composition, its antitumor effect in vivo and its main molecular mediators is still needed. In this work, five carnosic acid-rich supercritical rosemary extracts with different chemical compositions have been assayed for their antitumor activity both in vivo (in nude mice and in vitro against colon and pancreatic cancer cells. We found that the antitumor effect of carnosic acid together with carnosol was higher than the sum of their effects separately, which supports the use of the rosemary extract as a whole. In addition, gene and microRNA expression analyses have been performed to ascertain its antitumor mechanism, revealing that up-regulation of the metabolic-related gene GCNT3 and down-regulation of its potential epigenetic modulator miR-15b correlate with the antitumor effect of rosemary. Moreover, plasmatic miR-15b down-regulation was detected after in vivo treatment with rosemary. Our results support the use of carnosic acid-rich rosemary extract as a complementary approach in colon and pancreatic cancer and indicate that GCNT3 expression may be involved in its antitumor mechanism and that miR-15b might be used as a non-invasive biomarker to monitor rosemary anticancer effect.

Evaluation of antitumor activity and in vivo antioxidant status of Anthocephalus cadamba on Ehrlich ascites carcinoma treated mice.

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Dolai, Narayan; Karmakar, Indrajit; Suresh Kumar, R B; Kar, Biswakanth; Bala, Asis; Haldar, Pallab Kanti

2012-08-01

Anthocephalus cadamba (Roxb.) Miq. (Family: Rubiaceae) is commonly known as "Kadamba" in Sanskrit and Hindi in India. Various parts of this plant have been used as a folk medicine for the treatment of tumor, wound healing, inflammation and as a hypoglycemic agent. The purpose of this investigation was to evaluate the antitumor activity and antioxidant status of defatted methanol extract of A. cadamba (MEAC) on Ehrlich ascites carcinoma (EAC) treated mice. In vitro cytotoxicity assay has been evaluated by using the trypan blue method. The determination of in vivo antitumor activity was performed by using different EAC cells (2 × 10(6) cells, i.p.) inoculated mice groups (n=12). The groups were treated for 9 consecutive days with MEAC at the doses of 200 and 400 mg/kg b.w. respectively. After 24h of last dose and 18 h of fasting, half of the mice were sacrificed and the rest were kept alive for assessment of increase in life span. The antitumor potential of MEAC was assessed by evaluating tumor volume, viable and nonviable tumor cell count, tumor weight, hematological parameters and biochemical estimations. Furthermore, antioxidant parameters were assayed by estimating liver and kidney tissue enzymes. MEAC showed direct cytotoxicity on EAC cell line in a dose dependant manner. MEAC exhibited significant (P<0.01) decrease in the tumor volume, viable cell count, tumor weight and elevated the life span of EAC tumor bearing mice. The hematological profile, biochemical estimations and tissue antioxidant assay were reverted to normal level in MEAC treated mice. Experimental results revealed that MEAC possesses potent antitumor and antioxidant properties. Further research is going on to find out the active principle(s) of MEAC for better understanding of mechanism of its antitumor and antioxidant activity. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Anti-tumor effect in human breast cancer by TAE226, a dual inhibitor for FAK and IGF-IR in vitro and in vivo

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Kurio, Naito [Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, 700-8525 (Japan); Shimo, Tsuyoshi, E-mail: shimotsu@md.okayama-u.ac.jp [Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, 700-8525 (Japan); Fukazawa, Takuya; Takaoka, Munenori [Department of General Surgery, Kawasaki Medical School, Okayama, 700-0821 (Japan); Okui, Tatsuo; Hassan, Nur Mohammad Monsur; Honami, Tatsuki [Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, 700-8525 (Japan); Hatakeyama, Shinji [Novartis Institutes for BioMedical Research, Basel (Switzerland); Ikeda, Masahiko [Department of Surgery, Fukuyama City Hospital, Fukuyama, 720-8511 (Japan); Naomoto, Yoshio [Department of General Surgery, Kawasaki Medical School, Okayama, 700-0821 (Japan); Sasaki, Akira [Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, 700-8525 (Japan)

2011-05-01

Focal adhesion kinase (FAK) is a 125-kDa non-receptor type tyrosine kinase that localizes to focal adhesions. FAK overexpression is frequently found in invasive and metastatic cancers of the breast, colon, thyroid, and prostate, but its role in osteolytic metastasis is not well understood. In this study, we have analyzed anti-tumor effects of the novel FAK Tyr{sup 397} inhibitor TAE226 against bone metastasis in breast cancer by using TAE226. Oral administration of TAE226 in mice significantly decreased bone metastasis and osteoclasts involved which were induced by MDA-MB-231 breast cancer cells and increased the survival rate of the mouse models of bone metastasis. TAE226 also suppressed the growth of subcutaneous tumors in vivo and the proliferation and migration of MDA-MB-231 cells in vitro. Significantly, TAE226 inhibited the osteoclast formation in murine pre-osteoclastic RAW264.7 cells, and actin ring and pit formation in mature osteoclasts. Moreover, TAE226 inhibited the receptor activator for nuclear factor {kappa} B Ligand (RANKL) gene expression induced by parathyroid hormone-related protein (PTHrP) in bone stromal ST2 cells and blood free calcium concentration induced by PTHrP administration in vivo. These findings suggest that FAK was critically involved in osteolytic metastasis and activated in tumors, pre-osteoclasts, mature osteoclasts, and bone stromal cells and TAE226 can be effectively used for the treatment of cancer induced bone metastasis and other bone diseases.

HDAC inhibitor L-carnitine and proteasome inhibitor bortezomib synergistically exert anti-tumor activity in vitro and in vivo.

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Hongbiao Huang

Full Text Available Combinations of proteasome inhibitors and histone deacetylases (HDAC inhibitors appear to be the most potent to produce synergistic cytotoxicity in preclinical trials. We have recently confirmed that L-carnitine (LC is an endogenous HDAC inhibitor. In the current study, the anti-tumor effect of LC plus proteasome inhibitor bortezomib (velcade, Vel was investigated both in cultured hepatoma cancer cells and in Balb/c mice bearing HepG2 tumor. Cell death and cell viability were assayed by flow cytometry and MTS, respectively. Gene, mRNA expression and protein levels were detected by gene microarray, quantitative real-time PCR and Western blot, respectively. The effect of Vel on the acetylation of histone H3 associated with the p21(cip1 gene promoter was examined by using ChIP assay and proteasome peptidase activity was detected by cell-based chymotrypsin-like (CT-like activity assay. Here we report that (i the combination of LC and Vel synergistically induces cytotoxicity in vitro; (ii the combination also synergistically inhibits tumor growth in vivo; (iii two major pathways are involved in the synergistical effects of the combinational treatment: increased p21(cip1 expression and histone acetylation in vitro and in vivo and enhanced Vel-induced proteasome inhibition by LC. The synergistic effect of LC and Vel in cancer therapy should have great potential in the future clinical trials.

Silybin-mediated inhibition of Notch signaling exerts antitumor activity in human hepatocellular carcinoma cells.

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Song Zhang

Full Text Available Hepatocellular carcinoma (HCC is a global health burden that is associated with limited treatment options and poor patient prognoses. Silybin (SIL, an antioxidant derived from the milk thistle plant (Silybum marianum, has been reported to exert hepatoprotective and antitumorigenic effects both in vitro and in vivo. While SIL has been shown to have potent antitumor activity against various types of cancer, including HCC, the molecular mechanisms underlying the effects of SIL remain largely unknown. The Notch signaling pathway plays crucial roles in tumorigenesis and immune development. In the present study, we assessed the antitumor activity of SIL in human HCC HepG2 cells in vitro and in vivo and explored the roles of the Notch pathway and of the apoptosis-related signaling pathway on the activity of SIL. SIL treatment resulted in a dose- and time-dependent inhibition of HCC cell viability. Additionally, SIL exhibited strong antitumor activity, as evidenced not only by reductions in tumor cell adhesion, migration, intracellular glutathione (GSH levels and total antioxidant capability (T-AOC but also by increases in the apoptotic index, caspase3 activity, and reactive oxygen species (ROS. Furthermore, SIL treatment decreased the expression of the Notch1 intracellular domain (NICD, RBP-Jκ, and Hes1 proteins, upregulated the apoptosis pathway-related protein Bax, and downregulated Bcl2, survivin, and cyclin D1. Notch1 siRNA (in vitro or DAPT (a known Notch1 inhibitor, in vivo further enhanced the antitumor activity of SIL, and recombinant Jagged1 protein (a known Notch ligand in vitro attenuated the antitumor activity of SIL. Taken together, these data indicate that SIL is a potent inhibitor of HCC cell growth that targets the Notch signaling pathway and suggest that the inhibition of Notch signaling may be a novel therapeutic intervention for HCC.

Antitumor Activity of Ethanolic Extract of Dendrobium formosum in T-Cell Lymphoma: An In Vitro and In Vivo Study

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Ritika Prasad

2014-01-01

Full Text Available Dendrobium, a genus of orchid, was found to possess useful therapeutic activities like anticancer, hypoglycaemic, antimicrobial, immunomodulatory, hepatoprotective, antioxidant, and neuroprotective activities. The study was aimed to evaluate the anticancer property of the ethanolic extract of Dendrobium formosum on Dalton’s lymphoma. In vitro cytotoxicity was determined by MTT assay, apoptosis was determined by fluorescence microscopy, and cell cycle progression was analysed using flow cytometry; in vivo antitumor activity was performed in Dalton’s lymphoma bearing mice. The IC50 value of ethanolic extract was obtained at 350 μg/mL in Dalton’s lymphoma cells. Fluorescence microscopy analysis showed significant increase in apoptotic cell death in dose- and time-dependent manner which was further confirmed through the resulting DNA fragmentation. Further, flow cytometry analysis showed that the ethanolic extract arrests the cells in G2/M phase of the cell cycle. The in vivo anticancer activity study illustrates significant increase in the survival time of Dalton’s lymphoma bearing mice on treatment with ethanolic extract when compared to control. These results substantiate the antitumor properties of ethanolic extract of Dendrobium formosum and suggest an alternative in treatment of cancer. Further studies are required regarding the isolation and characterization of bioactive components along with the analysis of molecular mechanism involved.

Antitumor Activity of Ethanolic Extract of Dendrobium formosum in T-Cell Lymphoma: An In Vitro and In Vivo Study

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Prasad, Ritika; Koch, Biplob

2014-01-01

Dendrobium, a genus of orchid, was found to possess useful therapeutic activities like anticancer, hypoglycaemic, antimicrobial, immunomodulatory, hepatoprotective, antioxidant, and neuroprotective activities. The study was aimed to evaluate the anticancer property of the ethanolic extract of Dendrobium formosum on Dalton's lymphoma. In vitro cytotoxicity was determined by MTT assay, apoptosis was determined by fluorescence microscopy, and cell cycle progression was analysed using flow cytometry; in vivo antitumor activity was performed in Dalton's lymphoma bearing mice. The IC50 value of ethanolic extract was obtained at 350 μg/mL in Dalton's lymphoma cells. Fluorescence microscopy analysis showed significant increase in apoptotic cell death in dose- and time-dependent manner which was further confirmed through the resulting DNA fragmentation. Further, flow cytometry analysis showed that the ethanolic extract arrests the cells in G2/M phase of the cell cycle. The in vivo anticancer activity study illustrates significant increase in the survival time of Dalton's lymphoma bearing mice on treatment with ethanolic extract when compared to control. These results substantiate the antitumor properties of ethanolic extract of Dendrobium formosum and suggest an alternative in treatment of cancer. Further studies are required regarding the isolation and characterization of bioactive components along with the analysis of molecular mechanism involved. PMID:24959588

Chimeric HCMV/HSV-1 and Δγ134.5 oncolytic herpes simplex virus elicit immune mediated antigliomal effect and antitumor memory

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Mohammed G. Ghonime

2018-02-01

Full Text Available Malignant gliomas are the most common primary brain tumor and are characterized by rapid and highly invasive growth. Because of their poor prognosis, new therapeutic strategies are needed. Oncolytic virotherapy (OV is a promising strategy for treating cancer that incorporates both direct viral replication mediated and immune mediated mechanisms to kill tumor cells. C134 is a next generation Δγ134.5 oHSV-1 with improved intratumoral viral replication. It remains safe in the CNS environment by inducing early IFN signaling which restricts its replication in non-malignant cells. We sought to identify how C134 performed in an immunocompetent tumor model that restricts its replication advantage over first generation viruses. To achieve this we identified tumors that have intact IFN signaling responses that restrict C134 and first generation virus replication similarly. Our results show that both viruses elicit a T cell mediated anti-tumor effect and improved animal survival but that subtle difference exist between the viruses effect on median survival despite equivalent in vivo viral replication. To further investigate this we examined the anti-tumor activity in immunodeficient mice and in syngeneic models with re-challenge. These studies show that the T cell response is integral to C134 replication independent anti-tumor response and that OV therapy elicits a durable and circulating anti-tumor memory. The studies also show that repeated intratumoral administration can extend both OV anti-tumor effects and induce durable anti-tumor memory that is superior to tumor antigen exposure alone.

Purification and characterization of an antitumor polysaccharide from Portulaca oleracea L.

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Shen, Huan; Tang, Guo; Zeng, Guang; Yang, Yongjin; Cai, Xingwei; Li, Dongli; Liu, Hongchen; Zhou, Ningxin

2013-04-02

In the present study, we purified a unique polysaccharide component (POP) from Portulaca oleracea and found that it had pronounced anti-tumor effects in vivo model. Tumor weight, immune organ index and T lymphocyte subsets were employed to detect the immunoregulatory and antitumor effects of POP after administration. Hematological and biochemical analyses were also investigated in order to evaluate the toxicological aspects related to POP treatment. POP could significantly inhibit the growth of transplantable sarcoma 180 and potentiate the animal's immune responses including an increase in the number of white blood cell (WBC) and CD4(+) T-lymphocytes, as well as the ratio of CD4(+)/CD8(+). Furthermore the serum aspartate transanimase (AST), alanine transaminase (ALT), urea nitrogen (BUN), and creatinine levels in S180-bearing mice were significantly reversed by POP. Considering all these results, it is suggested that the anti-tumor effect elicited by POP could be associated with its immunostimulating properties. Copyright © 2012 Elsevier Ltd. All rights reserved.

In vitro and in vivo anti-tumor effect of metformin as a novel therapeutic agent in human oral squamous cell carcinoma

International Nuclear Information System (INIS)

Luo, Qingqiong; Hu, Dan; Hu, Shuiqing; Yan, Ming; Sun, Zujun; Chen, Fuxiang

2012-01-01

Metformin, which is widely used as an antidiabetic agent, has recently been reported to reduce cancer risk and improve prognosis in certain malignancies. However, the specific mechanisms underlying the effect of metformin on the development and progression of several cancers including oral squamous cell carcinoma (OSCC) remain unclear. In the present study, we investigated the effects of metformin on OSCC cells in vitro and in vivo. OSCC cells treated with or without metformin were counted using a hemocytometer. The clonogenic ability of OSCC cells after metformin treatment was determined by colony formation assay. Cell cycle progression and apoptosis were assessed by flow cytometry, and the activation of related signaling pathways was examined by immunoblotting. The in vivo anti-tumor effect of metformin was examined using a xenograft mouse model. Immunohistochemistry and TUNEL staining were used to determine the expression of cyclin D1 and the presence of apoptotic cells in tumors from mice treated with or without metformin. Metformin inhibited proliferation in the OSCC cell lines CAL27, WSU-HN6 and SCC25 in a time- and dose-dependent manner, and significantly reduced the colony formation of OSCC cells in vitro. Metformin induced an apparent cell cycle arrest at the G0/G1 phase, which was accompanied by an obvious activation of the AMP kinase pathway and a strongly decreased activation of mammalian target of rapamycin and S6 kinase. Metformin treatment led to a remarkable decrease of cyclin D1, cyclin-dependent kinase (CDK) 4 and CDK6 protein levels and phosphorylation of retinoblastoma protein, but did not affect p21 or p27 protein expression in OSCC cells. In addition, metformin induced apoptosis in OSCC cells, significantly down-regulating the anti-apoptotic proteins Bcl-2 and Bcl-xL and up-regulating the pro-apoptotic protein Bax. Metformin also markedly reduced the expression of cyclin D1 and increased the numbers of apoptotic cells in vivo, thus inhibiting

In Vitro and In Vivo Antitumor Effect of Anti-CD33 Chimeric Receptor-Expressing EBV-CTL against CD33+ Acute Myeloid Leukemia

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A. Dutour

2012-01-01

Full Text Available Genetic engineering of T cells with chimeric T-cell receptors (CARs is an attractive strategy to treat malignancies. It extends the range of antigens for adoptive T-cell immunotherapy, and major mechanisms of tumor escape are bypassed. With this strategy we redirected immune responses towards the CD33 antigen to target acute myeloid leukemia. To improve in vivo T-cell persistence, we modified human Epstein Barr Virus-(EBV- specific cytotoxic T cells with an anti-CD33.CAR. Genetically modified T cells displayed EBV and HLA-unrestricted CD33 bispecificity in vitro. In addition, though showing a myeloablative activity, they did not irreversibly impair the clonogenic potential of normal CD34+ hematopoietic progenitors. Moreover, after intravenous administration into CD33+ human acute myeloid leukemia-bearing NOD-SCID mice, anti-CD33-EBV-specific T cells reached the tumor sites exerting antitumor activity in vivo. In conclusion, targeting CD33 by CAR-modified EBV-specific T cells may provide additional therapeutic benefit to AML patients as compared to conventional chemotherapy or transplantation regimens alone.

The Targeted Antitumor Effects of C- PC/CMC-CD59sp Nanoparticles on HeLa Cells in Vitro and in Vivo.

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Wang, Yujuan; Jiang, Liangqian; Yin, Qifeng; Liu, Huihui; Liu, Guoxiang; Zhu, Guoteng; Li, Bing

2017-01-01

The novel C-PC/CMC-CD59sp-NPs were made by carbocymethyl chitosan (CMC) loading C-phycocyanin (C-PC) with the lead of CD59 specific ligand peptide (CD59sp) for targeting, and the characteristics and targeted anti-tumor mechanism were explored in order to realize the targeted therapy of C-PC on the growth of HeLa cells both in vitro and vivo . The targeting nanoparticles were synthesized by ionic-gelation method, and the optimal condition was selected out by orthogonal analysis. The properties of nanoparticles were observed by laser particle analyzer and dynamic light scattering (DLS) and Fourier Transform Infrared Spectrometer (FTIR). The effects of nanoparticles on the proliferation of HeLa cells in vitro were assessed by MTT assay. The mice model with tumor was constructed by subcutaneous injection of HeLa cells into the left axilla of NU/NU mice. The weight of tumor and the spleen were tested. The expression quantities of cleaved caspase-3, Bcl-2 were determined by western blot and immunofluorescent staining. Results showed the morphology of the finally prepared nanoparticles was well distributed with a diameter distribution of 200±11.3 nm and zeta potential of -19.5±4.12mV. Under the guidance of CD59sp, the targeting nanoparticles could targetedly and efficiently arrive at the surface of HeLa cells, and had obvious inhibitory effect on HeLa cells proliferation both in vitro and vivo. Moreover, the nanoparticles could induce cell apoptosis by up-regulation of cleaved caspase-3 proteins expression, but down-regulation of Bcl-2 and cyclinD1 proteins. Our study provided a new idea for the research and development of marine drugs, and supplied a theoretical support for the target therapy of anticancer drug.

Antitumor effects and mechanisms of Ganoderma extracts and spores oil

OpenAIRE

Chen, Chun; Li, Peng; Li, Ye; Yao, Guan; Xu, Jian-Hua

2016-01-01

Ganoderma lucidum is a popular herbal medicine used in China to promote health. Modern studies have disclosed that the active ingredients of Ganoderma can exhibit several effects, including antitumor effects and immunomodulation. The present study evaluated the antitumor effects of self-prepared Ganoderma extracts and spores oil, and investigated the possible underlying mechanisms by observing the effects of the extracts and oil on topoisomerases and the cell cycle. The results showed that Ga...

In vivo antitumor and antimetastatic effects of flavokawain B in 4T1 breast cancer cell-challenged mice

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Abu N

2015-03-01

Full Text Available Nadiah Abu,1,2 Nurul Elyani Mohamed,2 Swee Keong Yeap,3 Kian Lam Lim,4 M Nadeem Akhtar,5 Aimi Jamil Zulfadli,3 Beh Boon Kee,2 Mohd Puad Abdullah,2 Abdul Rahman Omar,3 Noorjahan Banu Alitheen2 1Bright Sparks Unit, Universiti Malaya, Kuala Lumpur, Malaysia; 2Department of Cell and Molecular Biology, Faculty of Biotechnology and Biomolecular Sciences, 3Institute of Bioscience, Universiti Putra Malaysia, Serdang, Selangor Darul Ehsan, Malaysia; 4Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Lot PT, Jalan Sungai Long, Bandar Sungai Long, Cheras, Selangor, Malaysia; 5Faculty of Industrial Sciences and Technology, Universiti Malaysia Pahang, Lebuhraya Tun Razak, Kuantan Pahang, Malaysia Abstract: Flavokawain B (FKB is a naturally occurring chalcone that can be isolated through the root extracts of the kava-kava plant (Piper methysticum. It can also be synthesized chemically to increase the yield. This compound is a promising candidate as a biological agent, as it is reported to be involved in a wide range of biological activities. Furthermore, FKB was reported to have antitumorigenic effects in several cancer cell lines in vitro. However, the in vivo antitumor effects of FKB have not been reported on yet. Breast cancer is one of the major causes of cancer-related deaths in the world today. Any potential treatment should not only impede the growth of the tumor, but also modulate the immune system efficiently and inhibit the formation of secondary tumors. As presented in our study, FKB induced apoptosis in 4T1 tumors in vivo, as evidenced by the terminal deoxynucleotidyl transferase dUTP nick end labeling and hematoxylin and eosin staining of the tumor. FKB also regulated the immune system by increasing both helper and cytolytic T-cell and natural killer cell populations. In addition, FKB also enhanced the levels of interleukin 2 and interferon gamma but suppressed interleukin 1B. Apart from that, FKB was also found to inhibit

Antitumor activity of Portulaca oleracea L. polysaccharides against cervical carcinoma in vitro and in vivo.

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Zhao, Rui; Gao, Xu; Cai, Yaping; Shao, Xingyue; Jia, Guiyan; Huang, Yulan; Qin, Xuegong; Wang, Jingwei; Zheng, Xiaoliang

2013-07-25

Portulaca oleracea L. has been used as folk medicine in different countries to treat different ailments in humans. P. oleracea L. polysaccharide (POL-P), extracted from P. oleracea L., is found to have bioactivities such as hypoglycemic and hypolipidemic activities, antioxidant and antitumor activities. In our study, a water-soluble polysaccharide (POL-P3b) was successfully purified from Galium verum L. by DEAE cellulose and Sephadex G-200 column chromatography. To evaluate the anticancer efficacy and associated mechanisms of POL-P3b on cervical cancer in vitro and in vivo, we showed that treatment of HeLa cell with POL-P3b inhibited cell proliferation. In addition, POL-P3b significantly inhibited tumor growth in U14-bearing mice. Further analysis indicated that POL-P3b possesses the activity of inhibiting cervical cancer cell growth in vitro and in vivo at a concentration- and time-dependent manner, and the mechanisms were associated with Sub-G1 phase cell cycle arrest, triggering DNA damage and inducing apoptosis. Copyright © 2013 Elsevier Ltd. All rights reserved.

Oral JS-38, a metabolite from Xenorhabdus sp., has both anti-tumor activity and the ability to elevate peripheral neutrophils.

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Liu, Min-Yu; Xiao, Lin; Chen, Geng-Hui; Wang, Yong-Xiang; Xiong, Wei-Xia; Li, Fei; Liu, Ying; Huang, Xiao-Ling; Deng, Yi-Fang; Zhang, Zhen; Sun, Hai-Yan; Liu, Quan-Hai; Yin, Ming

2014-10-01

JS-38 (mitothiolore), a synthetic version of a metabolite isolated from Xenorhabdus sp., was evaluated for its anti-tumor and white blood cell (WBC) elevating activities. These anti-proliferative activities were assessed in vitro using a panel of ten cell lines. The anti-tumor activities were tested in vivo using B16 allograft mouse models and xenograft models of A549 human lung carcinoma and QGY human hepatoma in nude mice. The anti-tumor interactions of JS-38 and cyclophosphamide (CTX) or 5-fluorouracil (5-Fu) were studied in a S180 sarcoma model in ICR mice. Specific stimulatory effects were determined on peripheral neutrophils in normal and CTX- and 5-Fu-induced neutropenic mice. The IC50 values ranged from 0.1 to 2.0 μmol·L(-1). JS-38 (1 μmol·L(-1)) caused an increase in A549 tumor cell apoptosis. Multi-daily gavage of JS-38 (15, 30, and 60 mg·kg(-1)·d(-1)) inhibited in vivo tumor progression without a significant effect on body weight. JS-38 additively enhanced the in vivo anti-tumor effects of CTX or 5-Fu. JS-38 increased peripheral neutrophil counts and neutrophil rates in normal BALB/c mice almost as effectively as granulocyte colony-stimulating factor (G-CSF). In mice with neutropenia induced by CTX or 5-Fu, JS-38 rapidly restored neutrophil counts. These results suggest that JS-38 has anti-tumor activity, and also has the ability to increase peripheral blood neutrophils. Copyright © 2014 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.

Evaluation of in vitro and in vivo antitumor effects of gambogic acid-loaded layer-by-layer self-assembled micelles.

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Ke, Zhongcheng; Yang, Lei; Wu, Hao; Li, Zihao; Jia, Xiaobin; Zhang, Zhenghai

2018-04-11

This study aimed to develop a novel type of multilayer micelle using protamine (PRM) and hyaluronic acid (HA) for the delivery of gambogic acid (GA). GA-loaded micelles (GA-M) were simply andrapidly prepared using lecithin/solutol HS15 using a film-dispersion method. PRM and HA were added in sequence to form layer-by-layer self-assembled micelles (HA-PRM-GA-M), in which particle size, zeta potential, particle morphology, drug loading, encapsulation efficiency, and in vitro release were investigated. Surface charge reversal demonstrated that rapid HA detachment exposed PRM, leading to activation of a "protonsponge"effect in the hyaluronidase (HAase)-rich tumor microenvironment. Compared with coumarin 6-loaded micelles (C6-M), more efficient intracellular trafficking was observed for HA-PRM-C6-M, which is associated with the endosomal/lysosomal escaping ability of the exposed PRM. In vivo imaging showed increased enrichment of near infrared fluorescent dye (DIR)-loaded HA-PRM-DIR-M at the tumor site, suggesting that HA enhanced the active tumor targeting of GA. Furthermore, HA-PRM-GA-M showed the stronger antitumor activity than GA and GA-M against human lung adenocarcinoma (A549) tumor xenografts in nude mice. In summary, our findings show the potential of HA-PRM-GA-M as a novel intravenous drug carrier for the treatment of lung cancer. Copyright © 2018. Published by Elsevier B.V.

The anti-tumor effect and biological activities of the extract JMM6 ...

African Journals Online (AJOL)

Juglans mandshurica Maxim is a traditional herbal medicines in China, and its anti-tumor bioactivities are of research interest. Bioassay-guided fractionation method was employed to isolate anti-tumor compounds from the stem barks of the Juglans mandshurica Maxim. The anti-tumor effect and biological activities of the ...

Antitumor efficacy of α-solanine against pancreatic cancer in vitro and in vivo.

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Chongqing Lv

Full Text Available α-solanine, a steroidal glycoalkaloid in potato, was found to have proliferation-inhibiting and apoptosis-promoting effect on multiple cancer cells, such as clone, liver, melanoma cancer cells. However, the antitumor efficacy of α-solanine on pancreatic cancer has not been fully evaluated. In this study, we inquired into the anti-carcinogenic effect of α-solanine against human pancreatic cancer cells. In the present study, we investigated the anti-carcinogenic effect of α-solanine against human pancreatic cancer cells. In vitro, α-solanine inhibited proliferation of PANC-1, sw1990, MIA PaCa-2 cells in a dose-dependent manner, as well as cell migration and invasion with atoxic doses. The expression of MMP-2/9, extracellular inducer of matrix metalloproteinase (EMMPRIN, CD44, eNOS and E-cadherin were suppressed by α-solanine in PANC-1 cells. Moreover, significantly decreased vascular endothelial growth factor (VEGF expression and tube formation of endothelial cells were discerned following α-solanine treatment. Suppressed phosphorylation of Akt, mTOR, and Stat3, and strengthen phosphorylation of β-catenin was found, along with markedly decreased tran-nuclear of NF-κB, β-catenin and TCF-1. Following the administration of α-solanine (6 µg/g for 2 weeks in xenograft model, tumor volume and weight were decreased by 61% and 43% (p<0.05 respectively, showing decreased MMP-2/9, PCNA and VEGF expression. In conclusion, α-solanine showed beneficial effects on pancreatic cancer in vitro and in vivo, which may via suppressing the pathway proliferation, angiogenesis and metastasis.

The antitumor effect of arsenic trioxide on hepatocellular carcinoma is enhanced by andrographolide.

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Duan, Xuhua; Li, Tengfei; Han, Xinwei; Ren, Jianzhuang; Chen, Pengfei; Li, Hao; Gong, Shaojun

2017-10-31

High concentrations of arsenic trioxide (As 2 O 3 ) are used to treat acute promyelocytic leukemia and solid tumors, with negative side effects to normal cells. Andrographolide is a traditional Chinese medicine that exerts anti-cancer, anti-inflammatory, anti-virus, and anti-diabetic effects. Here, we tested the effects of combined andrographolide with As 2 O 3 against hepatocellular carcinoma (HCC). We found that by increasing apoptosis, andrographolide synergistically enhanced the anti-tumor effects of As2O3 in HepG2 cells in vitro and in vivo . Furthermore, results from our microarray assays and experiments with mouse xenografts showed that EphB4 was downregulated by the combination of As 2 O 3 plus andrographolide. These findings suggest that the combination of andrographolide and As 2 O 3 could yield therapeutic benefits in the treatment of HCC.

Antitumor Activity of a 5-Hydroxy-1H-Pyrrol-2-(5H-One-Based Synthetic Small Molecule In Vitro and In Vivo.

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Yunyun Geng

Full Text Available Alternative chemo-reagents are in great demand because chemotherapy resistance is one of the major challenges in current cancer treatment. 5-hydoxy-1H-pyrrol-2-(5H-one is an important N-heterocyclic scaffold that is present in natural products and medicinal chemistry. However, its antitumor activity has not been systematically explored. In this study, we screened a panel of 5-hydoxy-1H-pyrrol-2-(5H-one derivatives and identified compound 1d as possessing strong anti-proliferative activity in multiple cancer cell lines. Cell cycle analysis revealed that 1d can induce S-phase cell cycle arrest and that HCT116 was sensitive to 1d-induced apoptosis. Further analysis indicated that 1d preferentially induced DNA damage and p53 activation in HCT116 cells and that 1d-induced apoptosis is partly dependent on p53. Furthermore, we showed that 1d significantly suppressed tumor growth in xenograft tumor models in vivo. Taken together, our results suggest that 5-hydoxy-1H-pyrrol-2-(5H-one derivatives bear potential antitumor activity and that 1d is an effective agent for cancer treatment.

Antisense oligonucleotides and all-trans retinoic acid have a synergistic anti-tumor effect on oral squamous cell carcinoma

International Nuclear Information System (INIS)

Xu, Qin; Zhang, Zhiyuan; Zhang, Ping; Chen, Wantao

2008-01-01

Antisense oligonucleotides against hTR (As-ODN-hTR) have shown promising results as treatment strategies for various human malignancies. All-trans retinoic acid (ATRA) is a signalling molecule with important roles in differentiation and apoptosis. Biological responses to ATRA are currently used therapeutically in various human cancers. The aim of this study was to evaluate the anti-tumor effects of As-ODN-hTR combined with ATRA in vivo. In situ human oral squamous cell carcinoma (OSCC) models were established by subcutaneous injection of Tca8113 cells. Mice were treated with sense oligonucleotides against hTR(S-ODN-hTR) alone, As-ODN-hTR alone, ATRA alone, As-ODN-hTR plus ATRA, or S-ODN-hTR plus ATRA. Tumor size and weight were assessed in the mice. Telomerase activity was detected by a TRAP assay, apoptotic cells were evaluated with a Tunel assay, the expression of apoptosis-related proteins (Bcl-2 and Bax) was evaluated by immunohistochemistry and ultrastructural morphological changes in the tumor specimen were examined. Both As-ODN-hTR and ATRA can significantly inhibit tumor growth in this OSCC xenograft solid-tumor model, and the combination of the two agents had a synergistic anti-tumorogenic effect. We also demonstrated that this anti-tumor effect correlated with inhibition of telomerase activity. Furthermore, significant increases in the number of apoptotic cells, typical apoptotic morphology and a downregulation of the anti-apoptotic protein, bcl-2 were observed in the treated tissues. The combination of As-ODN-hTR and ATRA has a synergistic anti-tumor effect. This anti-tumor effect can be mainly attributed to apoptosis induced by a decrease in telomerase activity. Bcl-2 plays an important role in this process. Therefore, combining As-ODN-hTR and ATRA may be an approach for the treatment of human oral squamous cell carcinoma

Modification of carcinogenic and antitumor radiation effects (biomedical aspects)

International Nuclear Information System (INIS)

Vilenchik, M.M.

1985-01-01

In the book the data on modification of carcinogenic radiation effects by physiologicaly active compounds (caffeine, hormones, promoters and others) as well as on potentiation of antitumor radiation effects by means of hyperthermia are systematized. It is shown that as a basis of synergetic (superadditive) carcinogenic or antitumor radiation effects combined with other factor can be the inhibiting effects of the latter on the reparation process of radiation-induced DNA injuries. The results of experimental investigations and the data on quantitative analysis can be used as a theoretical basis for improvement of the ways and means of the prophylaxis of tumor diseases as well as for increasing the efficiency of radiotherapy

Studies on photodynamic mechanism of a novel chlorine derivative (TDPC and its antitumor effect for photodynamic therapy in vitro and in vivo

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Ying Ye

2015-01-01

Full Text Available Photodynamic therapy (PDT represents a promising method for treatment of cancerous tumors. The chemical and physical properties of used photosensitizer (PS play key roles in the treatment efficacy. In this study, a novel PS, 5,10,15,20-tetrakis((5-dipropylaminopentyl-chlorin (TDPC which displayed a characteristic long wavelength absorption peak at 650 nm were synthesized. It also shows a singlet oxygen generation rate of 4.257 min-1. Generally, TDPC is localized in mitochondria and nucleus of cell. After light irradiation with 650 nm laser, it can kill many types of cell, in addition, TDPC–PDT can destroy ECA-109 tumor in nude mice and a necrotic scab was formed eventually. The expression levels of many genes which regulated cell growth and apoptosis were determined by RT-PCR following TDPC–PDT. The results showed that it either increased or decreased, among which, the expression level of TNFSF13, a member of tumor necrosis factor superfamily, increased significantly. In general, TDPC is an effective antitumor PS in vitro and in vivo and is worthy of further study as a new drug candidate. TNFSF13 will be an important molecular target for the discovery of new PSs.

Ethacrynic acid improves the antitumor effects of irreversible epidermal growth factor receptor tyrosine kinase inhibitors in breast cancer.

Science.gov (United States)

Liu, Bing; Huang, XinPing; Hu, YunLong; Chen, TingTing; Peng, BoYa; Gao, NingNing; Jin, ZhenChao; Jia, TieLiu; Zhang, Na; Wang, ZhuLin; Jin, GuangYi

2016-09-06

Prolonged treatment of breast cancer with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) often results in acquired resistance and a narrow therapeutic index. One strategy to improve the therapeutic effects of EGFR TKIs is to combine them with drugs used for other clinical indications. Ethacrynic acid (EA) is an FDA approved drug that may have antitumor effects and may enhance the cytotoxicity of chemotherapeutic agents by binding to glutathione and inhibiting WNT signaling. While the α,β-unsaturated-keto structure of EA is similar to that of irreversible TKIs, the mechanism of action of EA when combined with irreversible EGFR TKIs in breast cancer remains unknown. We therefore investigated the combination of irreversible EGFR TKIs and EA. We found that irreversible EGFR TKIs and EA synergistically inhibit breast cancer both in vitro and in vivo. The combination of EGFR TKIs and EA induces necrosis and cell cycle arrest and represses WNT/β-catenin signaling as well as MAPK-ERK1/2 signaling. We conclude that EA synergistically enhances the antitumor effects of irreversible EGFR TKIs in breast cancer.

The translocator protein radioligand 18F-DPA-714 monitors antitumor effect of erufosine in a rat 9L intracranial glioma model

International Nuclear Information System (INIS)

Awde, Ali R.; Boisgard, Raphael; Theze, Benoit; Dubois, Albertine; Zheng, Jinzi; Winkeler, Alexandra; Dolle, Frederic; Jacobs, Andreas H.; Tavitian, Bertrand

2013-01-01

On the one hand, the translocator protein (TSPO) radioligand N,N-diethyl-2-(2-(4-(2- 18 F-fluoroethoxy)phenyl)-5,7-dimethylpyrazolo[1,5-a] pyrimidin-3-yl)acetamide ( 18 F-DPA-714) has been suggested to serve as an alternative radiotracer to image human glioma, and on the other hand the alkyl-phosphocholine erufosine (ErPC3) has been reported to induce apoptosis in otherwise highly apoptosis resistant glioma cell lines. The induction of apoptosis by ErPC3 requires TSPO, a mitochondrial membrane protein highly expressed in malignant gliomas. In this preclinical study, we monitored the effect of ErPC3 treatment in vivo using 18 F-DPA-714 PET. Methods: In vitro studies investigated the antitumor effect of ErPC3 in 9L rat gliosarcoma cells. In vivo, glioma-bearing rats were imaged with 18 F-DPA-714 for the time of treatment. Results: A significant decrease in 9L cell proliferation and viability and a significant increase in apoptosis and caspase-3 activation were demonstrated on ErPC3 treatment in cell culture. In the rat model, ErPC3 administration resulted in significant changes in 18 F-DPA-714 tumor uptake over the course of the treatment. Immunohistochemistry revealed reduced tumor volume and increased cell death in ErPC3-treated animals accompanied by infiltration of the tumor core by CD11b-positive micro-glia/macrophages and glial fibrillary acidic protein-positive astrocytes. Conclusion: Our findings demonstrate a potent antitumor effect of ErPC3 in vitro, in vivo, and ex vivo. PET imaging of TSPO expression using 18 F-DPA-714 allows effective monitoring and quantification of disease progression and response to ErPC3 therapy in intracranial 9L gliomas. (authors)

Potent antitumor activities of recombinant human PDCD5 protein in combination with chemotherapy drugs in K562 cells

International Nuclear Information System (INIS)

Shi, Lin; Song, Quansheng; Zhang, Yingmei; Lou, Yaxin; Wang, Yanfang; Tian, Linjie; Zheng, Yi; Ma, Dalong; Ke, Xiaoyan; Wang, Ying

2010-01-01

Conventional chemotherapy is still frequently used. Programmed cell death 5 (PDCD5) enhances apoptosis of various tumor cells triggered by certain stimuli and is lowly expressed in leukemic cells from chronic myelogenous leukemia patients. Here, we describe for the first time that recombinant human PDCD5 protein (rhPDCD5) in combination with chemotherapy drugs has potent antitumor effects on chronic myelogenous leukemia K562 cells in vitro and in vivo. The antitumor efficacy of rhPDCD5 protein with chemotherapy drugs, idarubicin (IDR) or cytarabine (Ara-C), was examined in K562 cells in vitro and K562 xenograft tumor models in vivo. rhPDCD5 protein markedly increased the apoptosis rates and decreased the colony-forming capability of K562 cells after the combined treatment with IDR or Ara-C. rhPDCD5 protein by intraperitoneal administration dramatically improved the antitumor effects of IDR treatment in the K562 xenograft model. The tumor sizes and cell proliferation were significantly decreased; and TUNEL positive cells were significantly increased in the combined group with rhPDCD5 protein and IDR treatment compared with single IDR treatment groups. rhPDCD5 protein, in combination with IDR, has potent antitumor effects on chronic myelogenous leukemia K562 cells and may be a novel and promising agent for the treatment of chronic myelogenous leukemia.

Anti-tumor activity of N-hydroxy-7-(2-naphthylthio) heptanomide, a novel histone deacetylase inhibitor

International Nuclear Information System (INIS)

Kim, Dong Hoon; Lee, Jiyong; Kim, Kyung Noo; Kim, Hye Jin; Jeung, Hei Cheul; Chung, Hyun Cheol; Kwon, Ho Jeong

2007-01-01

Histone deacetylase (HDAC), a key enzyme in gene expression and carcinogenesis, is considered an attractive target molecule for cancer therapy. Here, we report a new synthetic small molecule, N-hydroxy-7-(2-naphthylthio) heptanomide (HNHA), as a HDAC inhibitor with anti-tumor activity both in vitro and in vivo. The compound inhibited HDAC enzyme activity as well as proliferation of human fibrosarcoma cells (HT1080) in vitro. Treatment of cells with HNHA elicited histone hyperacetylation leading to an up-regulation of p21 transcription, cell cycle arrest, and an inhibition of HT1080 cell invasion. Moreover, HNHA effectively inhibited the growth of tumor tissue in a mouse xenograph assay in vivo. Together, these data demonstrate that this novel HDAC inhibitor could be developed as a potential anti-tumor agent targeting HDAC

Docetaxel-loaded single-wall carbon nanohorns using anti-VEGF antibody as a targeting agent: characterization, in vitro and in vivo antitumor activity

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Zhao, Qian; Li, Nannan; Shu, Chang; Li, Ruixin; Ma, Xiaona; Li, Xuequan; Wang, Ran; Zhong, Wenying

2015-05-01

A novel antitumor drug delivery system, docetaxel (DTX)-loaded oxidized single-wall carbon nanohorns (oxSWNHs) with anti-VEGF monoclonal antibody (mAb) as a target agent was constructed. DTX was absorbed onto the oxSWNHs via the physical adsorption or π-π interaction. DSPE-PEG-COOH was non-covalently wrapped to the hydrophobic surface of oxSWNHs to improve its water solubility and biocompatibility. The mAb was bonded to the PEG through amide bond. The DTX@oxSWNHs-PEG-mAb (DDS) exhibited suitable particle size (191.2 ± 2.1 nm), good particle size distribution (PDI: 0.196), and negative zeta potential (-24.3 ± 0.85 mV). These features enhanced permeability and retention (EPR) effect and reduced the drug molecule uptake by the reticuloendothelial system. The in vitro drug release followed non-Fickian diffusion ( n = 0.6857, R = 0.9924) with the cumulative release of DTX 59 ± 1.35 % at 72 h. Compared with free DTX, the DDS enhanced the cytotoxicity in MCF-7 cell lines in vitro efficiently (IC50: 2.96 ± 0.6 μg/ml), and provided higher antitumor efficacy (TGI: 69.88 %) in vivo. The histological analysis indicated that the DDS had no significant side effect. Therefore, the new DDS is promising to attain higher pharmaceutical efficacy and lower side effects than free DTX for cancer therapy. The research demonstrated that DTX@oxSWNHs-PEG-mAb might have promising biomedical applications for future cancer therapy.

Antitumor and immunomodulatory activity of Inonotus obliquus

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Staniszewska Justyna

2017-06-01

Full Text Available The article presents the antitumor and immunomodulatory activity of compounds and extracts from Inonotus obliquus. Polysaccharides isolated from sclerotium have a direct antitumor effect due to protein synthesis inhibition in tumor cells. Polysaccharides derived from the mycelium function by activating the immune system. Due to the limited toxicity of these substances, both extracts as well as isolated and purified chemicals may be a good alternative to current chemotherapy and play a role in cancer prevention. In vitro experiments have shown the inhibition of inflammation with the influence of action of I. obliquus extracts; however, in vivo experiments on animals implanted with tumor cells of different types have shown the activation of the host immune system. This led to decrease in tumor mass and prolonged survival. The immunomodulatory mechanism of action is complex and it seems that stimulation of macrophages and induction of apoptosis in cancer cells is of great importance.

Hydroxyurea derivatives of irofulven with improved antitumor efficacy.

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Staake, Michael D; Kashinatham, Alisala; McMorris, Trevor C; Estes, Leita A; Kelner, Michael J

2016-04-01

Irofulven is a semi-synthetic derivative of Illudin S, a toxic sesquiterpene isolated from the mushroom Omphalotus illudens. Irofulven has displayed significant antitumor activity in various clinical trials but displayed a limited therapeutic index. A new derivative of irofulven was prepared by reacting hydroxyurea with irofulven under acidic conditions. Acetylation of this new compound with acetic anhydride produced a second derivative. Both of these new derivatives displayed significant antitumor activity in vitro and in vivo comparable to or exceeding that of irofulven. Copyright © 2016 Elsevier Ltd. All rights reserved.

Enhancement of hypoxia-activated prodrug TH-302 anti-tumor activity by Chk1 inhibition.

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Meng, Fanying; Bhupathi, Deepthi; Sun, Jessica D; Liu, Qian; Ahluwalia, Dharmendra; Wang, Yan; Matteucci, Mark D; Hart, Charles P

2015-05-21

The hypoxia-activated prodrug TH-302 is reduced at its nitroimidazole group and selectively under hypoxic conditions releases the DNA cross-linker bromo-isophosphoramide mustard (Br-IPM). Here, we have explored the effect of Chk1 inhibition on TH-302-mediated pharmacological activities. We employed in vitro cell viability, DNA damage, cellular signaling assays and the in vivo HT29 human tumor xenograft model to study the effect of Chk1inhibition on TH-302 antitumor activities. TH-302 cytotoxicity is greatly enhanced by Chk1 inhibition in p53-deficient but not in p53-proficient human cancer cell lines. Chk1 inhibitors reduced TH-302-induced cell cycle arrest via blocking TH-302-induced decrease of phosphorylation of histone H3 and increasing Cdc2-Y15 phosphorylation. Employing the single-cell gel electrophoresis (comet) assay, we observed a potentiation of the TH-302 dependent tail moment. TH-302 induced γH2AX and apoptosis were also increased upon the addition of Chk1 inhibitor. Potentiation of TH-302 cytotoxicity by Chk1 inhibitor was only observed in cell lines proficient in, but not deficient in homology-directed DNA repair. We also show that combination treatment led to lowering of Rad51 expression levels as compared to either agent alone. In vivo data demonstrate that Chk1 inhibitor enhances TH-302 anti-tumor activity in p53 mutant HT-29 human tumor xenografts, supporting the hypothesis that these in vitro results can translate to enhanced in vivo efficacy of the combination. TH-302-mediated in vitro and in vivo anti-tumor activities were greatly enhanced by the addition of Chk1 inhibitors. The preclinical data presented in this study support a new approach for the treatment of p53-deficient hypoxic cancers by combining Chk1 inhibitors with the hypoxia-activated prodrug TH-302.

Antitumor Activities of Kushen: Literature Review

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Mingyu Sun

2012-01-01

Full Text Available To discover and develop novel natural compounds with therapeutic selectivity or that can preferentially kill cancer cells without significant toxicity to normal cells is an important area in cancer chemotherapy. Kushen, the dried roots of Sophora flavescens Aiton, has a long history of use in traditional Chinese medicine to treat inflammatory diseases and cancer. Kushen alkaloids (KS-As and kushen flavonoids (KS-Fs are well-characterized components in kushen. KS-As containing oxymatrine, matrine, and total alkaloids have been developed in China as anticancer drugs. More potent antitumor activities were identified in KS-Fs than in KS-As in vitro and in vivo. KS-Fs may be developed as novel antitumor agents.

Antitumor effects of traditional Chinese medicine targeting the cellular apoptotic pathway

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Xu HL

2015-05-01

Full Text Available Huanli Xu,1 Xin Zhao,2 Xiaohui Liu,1 Pingxiang Xu,1 Keming Zhang,2 Xiukun Lin11Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, 2Department of Hepatobiliary Surgery, 302 Hospital of Chinese People’s Liberation Army, Beijing, People’s Republic of ChinaAbstract: Defects in apoptosis are common phenomena in many types of cancer and are also a critical step in tumorigenesis. Targeting the apoptotic pathway has been considered an intriguing strategy for cancer therapy. Traditional Chinese medicine (TCM has been used in the People’s Republic of China for thousands of years, and many of the medicines have been confirmed to be effective in the treatment of a number of tumors. With increasing cancer rates worldwide, the antitumor effects of TCMs have attracted more and more attention globally. Many of the TCMs have been shown to have antitumor activity through multiple targets, and apoptosis pathway-related targets have been extensively studied and defined to be promising. This review focuses on several antitumor TCMs, especially those with clinical efficacy, based on their effects on the apoptotic signaling pathway. The problems with and prospects of development of TCMs as anticancer agents are also presented.Keywords: traditional Chinese medicine, antitumor effects, apoptotic pathway

Triterpene-loaded microemulsion using Coix lacryma-jobi seed extract as oil phase for enhanced antitumor efficacy: preparation and in vivo evaluation

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Qu D

2013-12-01

Full Text Available Ding Qu, Junjie He, Congyan Liu, Jing Zhou, Yan ChenKey Laboratory of New Drug Delivery System of Chinese Materia Medica, Jiangsu Provincial Academy of Chinese Medicine, Jiangsu, People’s Republic of ChinaAbstract: Ganoderma lucidum triterpene-loaded microemulsions (TMEs using Coix lacryma-jobi (adlay seed oil as oil phase were prepared, characterized, and evaluated for enhanced antitumor activity. Ternary phase diagrams for the TMEs were constructed and the optimal preparation was developed. Transmission electron microscopy and dynamic light scattering showed that this formulation had a well defined spherical shape, a homogeneous distribution, a small size, and a narrow polydispersity index. The drug-loading rate was determined to be 9.87% by ultraviolet spectrophotometry, and acceptable stability under various stimulations in vitro was confirmed. Importantly, the TME formulation showed a significantly greater antiproliferative effect towards human lung carcinoma (A549 cells and murine lung tumor (Lewis cells in comparison with suspension formulations containing triterpene and adlay seed oil as a positive control. The half-maximal inhibitory concentration of the TMEs was about 0.62 mg crude drug per mL, being 2.5-fold improved relative to that of the corresponding suspension formulation, but no significant cytotoxicity was observed for the bare microemulsion in A549 cells and Lewis cells. In vivo, the TME formulation showed markedly enhanced antitumor efficacy in a xenograft model of Lewis lung cancer after intragastric administration. Compared with cyclophosphamide, the TME formulation showed similar antitumor activity but less general toxicity. These results indicate the feasibility of using a microemulsion to increase the solubility of triterpene and adlay. TMEs hold promise as an efficient drug delivery system for the treatment of lung cancer.Keywords: microemulsion, Ganoderma lucidum, triterpene, adlay seed oil, lung cancer

Ukrain, a plant derived semi-synthetic compound, exerts antitumor effects against murine and human breast cancer and induce protective antitumor immunity in mice.

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Bozeman, E N; Srivatsan, S; Mohammadi, H; Daniels, D; Shashidharamurthy, R; Selvaraj, P

2012-12-01

Despite the recent advances in anti-cancer therapies, breast cancer accounts for the highest percentage of estimated new cases among female cancer patients. The anti-cancer drug Ukrain, a plant-derived semi-synthetic compound, has been shown to be effective in a variety of tumor models including colon, brain, ovarian, melanoma and lymphoma. However, the direct cytotoxic effects of Ukrain have yet to be investigated in breast cancer models. Herein, we investigated the in vitro and in vivo cytotoxicity of Ukrain using murine (4T07 and TUBO) and human (SKBR-3) breast cancer cell lines. Cells were treated with varying concentrations of Ukrain for up to 72 h and analyzed for viability by trypan blue exclusion, apoptosis by intracellular caspase 3 and Annexin V staining, and proliferative potential by a clonogenic assay. Female BALB/c mice were challenged subcutaneously (s.c.) with 4T07-RG cells and administered 5 mg/kg or 12.5 mg/kg body weight Ukrain intravenously (i.v.) on the same day and 3 days later. Protective immune responses were determined following re-challenge of tumor-free mice 35 days post primary challenge. Ukrain exposure induced apoptosis in a dose and time-dependent manner with 50 µg/mL Ukrain leading to >50% cell death after 48 h exposure for all three breast cancer cell lines. Ukrain administration (12.5 mg/kg) led to significant inhibition of 4T07 tumor growth in vivo and sustained protective anti-tumor immunity following secondary challenge. Our findings demonstrate the in vitro and in vivo cytotoxic effects of Ukrain on breast cancer cells and may provide insight into designing Ukrain-based therapies for breast cancer patients.

Immunotherapy with Dendritic Cells Modified with Tumor-Associated Antigen Gene Demonstrates Enhanced Antitumor Effect Against Lung Cancer

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Tao Jiang

2017-04-01

Full Text Available BACKGROUND: Immunotherapy using dendritic cell (DC vaccine has the potential to overcome the bottleneck of cancer therapy. METHODS: We engineered Lewis lung cancer cells (LLCs and bone marrow–derived DCs to express tumor-associated antigen (TAA ovalbumin (OVA via lentiviral vector plasmid encoding OVA gene. We then tested the antitumor effect of modified DCs both in vitro and in vivo. RESULTS: The results demonstrated that in vitro modified DCs could dramatically enhance T-cell proliferation (P < .01 and killing of LLCs than control groups (P < .05. Moreover, modified DCs could reduce tumor size and prolong the survival of LLC tumor-bearing mice than control groups (P < .01 and P < .01, respectively. Mechanistically, modified DCs demonstrated enhanced homing to T-cell–rich compartments and triggered more naive T cells to become cytotoxic T lymphocytes, which exhibited significant infiltration into the tumors. Interestingly, modified DCs also markedly reduced tumor cells harboring stem cell markers in mice (P < .05, suggesting the potential role on cancer stem-like cells. CONCLUSION: These findings suggested that DCs bioengineered with TAA could enhance antitumor effect and therefore represent a novel anticancer strategy that is worth further exploration.

[Structural analysis and anti-tumor activity in vivo of polysaccharide APS-2a from Angelica sinensis].

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Cao, Wei; Li, Xiao-Qiang; Hou, Ying; Fan, Hui-Ting; Zhang, Xiao-Nan; Mei, Qi-Bing

2008-02-01

The polysaccharide APS-2a was isolated from Angelica sinensis (Oliv.) Diels through water extraction, deprotein, ethanol precipitation and DEAE-sephades A-25 column chromatography respectively,and was further purified by Sephacryl S-400 and Sephadex G-100 column chromatography. The phenol-sulfuric acid assay and Bradford method were used to determine the contents of carbohydrate and protein, respectively. The molecular weight was carried out with high-performance size exclusion chromatography (HPSEC) combined with a differential refractometer detector. The monosaccharide compositions were determined by gas chromatography after complete hydrolysis with acid. The models of mice transplanted sarcoma S-180 were used to study the anti-tumor effects in vivo. Thymus indexes, spleen indexes were determined. The HPSEC result showed the APS-2a was a single homogeneous component and its weight average molecular weight was 7.4 x 10(5) Da. The monosaccharide composition of APS-2a was glucose, galactose, arabinose, rhamnose, galcturonic acid. Furthermore, APS-2a (20.50 mg/kg) could inhibit the proliferation of tumor cells in mice transplanted S-180. The thymus indexes and spleen indexes in the groups treated with APS-2a were higher than control group.

Anti-tumor effect of polysaccharides isolated from Taraxacum ...

African Journals Online (AJOL)

The effects of extraction temperature, liquid-solid ratio and extraction time on the yield of PTM were investigated using a Box-Behnken design (BBD). The in vitro anti-tumor effect of PTM on MCF-7 cells was investigated by methylthiazolyldiphenyl-tetrazolium bromide (MTT) assay, while the mechanism of PTM-induced ...

Simultaneous, But Not Consecutive, Combination With Folinate Salts Potentiates 5-Fluorouracil Antitumor Activity In Vitro and In Vivo.

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Di Paolo, Antonello; Orlandi, Paola; Di Desidero, Teresa; Danesi, Romano; Bocci, Guido

2017-08-07

The combination of folinate salts to 5-fluoruracil (5-FU)-based schedules is an established clinical routine in the landscape of colorectal cancer treatment. The aim of this study was to investigate the pharmacological differences between the sequential administration of folinate salts (1 h before, as in clinical routine) followed by 5-FU and the simultaneous administration of both drugs. Proliferation and apoptotic assays were performed on human colon cancer cells exposed to 5-FU, calcium (CaLV), or disodium (NaLV) levofolinate or their simultaneous and sequential combination for 24 and 72 h. TYMS and SLC19A1 gene expression was performed with real-time PCR. In vivo experiments were performed in xenografted nude mice, which were treated with 5-FU escalating doses and CaLV or NaLV alone or in simultaneous and sequential combination. The simultaneous combination of folinate salts and 5-FU was synergistic (NaLV) or additive (CaLV) in a 24-h treatment in both cell lines. In contrast, the sequential combination of both folinate salts and 5-FU was antagonistic at 24 and 72 h. The simultaneous combination of 5-FU and NaLV or CaLV inhibited TYMS gene expression at 24 h, whereas the sequential combination reduced SLC19A1 gene expression. In vivo experiments confirmed the enhanced antitumor activity of the 5-FU + NaLV simultaneous combination with a good toxicity profile, whereas the sequential combination with CaLV failed to potentiate 5-FU activity. In conclusion, only the simultaneous, but not the consecutive, in vitro and in vivo combination of 5-FU and both folinate salt formulations potentiated the antiproliferative effects of the drugs.

Antitumor Effects of Palladium-α-Lipoic Acid Complex Formulation as an Adjunct in Radiotherapy.

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Veena, Ravindran Kalathil; Ajith, Thekkuttuparambil Ananthanarayanan; Janardhanan, Kainoor Krishnankutty; Antonawich, Francis

2016-01-01

Several investigations have been initiated to enhance the antitumor effect of radiation and ameliorate its adverse effects such as reducing blood cell counts and causing DNA damage in normal cells. Compounds that enhance the antitumor activity of radiation without reducing blood cell counts or damaging DNA in normal cells can be of immense use as an adjunct in radiotherapy. We evaluated the antitumor effect of a specific set of minerals, vitamins, and amino acids (Poly-MVA) (2 mL/kg, per os), with and without radiation, against Dalton's lymphoma ascites (DLA) and Ehrlich's ascites carcinoma (EAC) cell lines that were transplanted in a solid-tumor model. Whole-body γ-radiation exposure (2 Gy) was performed using 60Co. Poly-MVA enhanced the antitumor effect of radiation when administered beforehand. Furthermore, Poly-MVA administered once daily for 2 wk, immediately after 4 Gy irradiation, protected DNA damage in peripheral blood. It also rendered protection against the radiation-induced reduction of platelet count. The unique electronic and redox properties of palladium-α-lipoic acid complex in Poly-MVA appear to be responsible for the exhibited effect. The results conclude that the antitumor-enhancing and normal cell-protective effect of Poly-MVA warrants additional studies for its potential clinical application.

CRA-024781: a novel synthetic inhibitor of histone deacetylase enzymes with antitumor activity in vitro and in vivo.

Science.gov (United States)

Buggy, Joseph J; Cao, Z Alexander; Bass, Kathryn E; Verner, Erik; Balasubramanian, Sriram; Liu, Liang; Schultz, Brian E; Young, Peter R; Dalrymple, Stacie A

2006-05-01

CRA-024781 is a novel, broad spectrum hydroxamic acid-based inhibitor of histone deacetylase (HDAC) that shows antitumor activity in vitro and in vivo preclinically and is under evaluation in phase I clinical trials for cancer. CRA-024781 inhibited pure recombinant HDAC1 with a K(i) of 0.007 mumol/L, and also inhibited the other HDAC isozymes HDAC2, HDAC3/SMRT, HDAC6, HDAC8, and HDAC10 in the nanomolar range. Treatment of cultured tumor cell lines grown in vitro with CRA-024781 resulted in the accumulation of acetylated histone and acetylated tubulin, resulting in an inhibition of tumor cell growth and the induction of apoptosis. CRA-024781 parenterally administered to mice harboring HCT116 or DLD-1 colon tumor xenografts resulted in a statistically significant reduction in tumor growth at doses that were well tolerated as measured by body weight. Inhibition of tumor growth was accompanied by an increase in the acetylation of alpha-tubulin in peripheral blood mononuclear cells, and an alteration in the expression of many genes in the tumors, including several involved in apoptosis and cell growth. These results reveal CRA-024781 to be a novel HDAC inhibitor with potent antitumor activity.

Cytotoxic, Antitumor and Immunomodulatory Effects of the Water-Soluble Polysaccharides from Lotus (Nelumbo nucifera Gaertn. Seeds

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Yafeng Zheng

2016-11-01

Full Text Available Lotus is an edible and medicinal plant, and the extracts from its different parts exhibit various bioactivities. In the present study, the hot water–soluble polysaccharides from lotus seeds (LSPS were evaluated for their cancer cell cytotoxicity, immunomodulatory and antitumor activities. LSPS showed significant inhibitory effects on the mouse gastric cancer MFC cells, human liver cancer HuH-7 cells and mouse hepatocarcinoma H22 cells. The animal studies showed that LSPS inhibited tumor growth in H22 tumor-bearing mice with the highest inhibition rate of 45.36%, which is comparable to that induced by cyclophosphamide (30 mg/kg treatment (50.79%. The concentrations of white blood cells were significantly reduced in cyclophosphamide-treated groups (p < 0.01, while LSPS showed much fewer side effects according to the hematology analysis. LSPS improved the immune response in H22 tumor-bearing mice by enhancing the spleen and thymus indexes, and increasing the levels of serum cytokines including tumor necrosis factor-α and interleukin-2. Moreover, LSPS also showed in vivo antioxidant activity by increasing superoxide dismutase activity, thus reducing the malondialdehyde level in the liver tissue. These results suggested that LSPS can be used as an antitumor and immunomodulatory agent.

Cholesterol negatively regulates IL-9-producing CD8+ T cell differentiation and antitumor activity.

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Ma, Xingzhe; Bi, Enguang; Huang, Chunjian; Lu, Yong; Xue, Gang; Guo, Xing; Wang, Aibo; Yang, Maojie; Qian, Jianfei; Dong, Chen; Yi, Qing

2018-05-09

CD8 + T cells can be polarized into IL-9-secreting (Tc9) cells. We previously showed that adoptive therapy using tumor-specific Tc9 cells generated stronger antitumor responses in mouse melanoma than classical Tc1 cells. To understand why Tc9 cells exert stronger antitumor responses, we used gene profiling to compare Tc9 and Tc1 cells. Tc9 cells expressed different levels of cholesterol synthesis and efflux genes and possessed significantly lower cholesterol content than Tc1 cells. Unique to Tc9, but not other CD8 + or CD4 + T cell subsets, manipulating cholesterol content in polarizing Tc9 cells significantly affected IL-9 expression and Tc9 differentiation and antitumor response in vivo. Mechanistic studies showed that IL-9 was indispensable for Tc9 cell persistence and antitumor effects, and cholesterol or its derivatives inhibited IL-9 expression by activating liver X receptors (LXRs), leading to LXR Sumoylation and reduced p65 binding to Il9 promoter. Our study identifies cholesterol as a critical regulator of Tc9 cell differentiation and function. © 2018 Ma et al.

Anti-tumor Study of Chondroitin Sulfate-Methotrexate Nanogels

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Wang, Jinyu; Zhao, Weibo; Chen, Haixiao; Qin, An; Zhu, Peizhi

2017-10-01

Self-assembly nanogels (NGs) were formed by bioconjugating methotrexate (MTX) with chondroitin sulfate (CS). MTX-CS NGs can greatly enhance the solubility and improve the delivery efficacy of MTX due to the CD44 binding property of CS. Vivo experiments revealed that MTX-CS NGs showed less toxicity than MTX. MTX-CS NGs can improve the anti-tumor effect while reducing the side effects of MTX. Due to their CD44 binding property, chondroitin sulfate-drug conjugates could be a promising and efficient platform for improving the solubility of sparingly soluble drug molecules as well as targeted delivery to cancer cells and tumor tissues.

Comparison of the fibronectin-binding ability and antitumor efficacy of various mycobacteria.

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Hudson, M A; Ritchey, J K; Catalona, W J; Brown, E J; Ratliff, T L

1990-07-01

Although the mechanism by which Bacillus Calmette-Guerin (BCG) exerts an antitumor effect on superficial bladder tumors is not fully understood, recent evidence has implicated binding of BCG organisms to fibronectin (FN) as requisite for this antitumor efficacy. Various substrains of BCG and other mycobacteria were tested in vitro for their relative capacities to bind both matrix and soluble FN. A substrain of Mycobacterium kansasii, designated the "high-binding strain," was found to bind FN more readily (P less than 0.05) in in vitro studies, when compared to commercially available substrains of BCG (Tice, Connaught, and Armand Frappier). The binding by the three commercial strains of BCG to FN in vitro appeared to be equivalent. The high-binding strain was further demonstrated to attach more readily in vivo to the acutely injured murine bladder (P less than 0.005) than the Armand Frappier substrain. Finally, using the MB49 murine bladder tumor model, an enhanced antitumor effect (P less than 0.05) was noted in mice treated with intravesical high-binding strain, in comparison to the Armand Frappier substrain, during five weekly treatments. It appears not only that the commercial substrains of BCG bind FN in an equivalent manner but also that the relative binding capacities of the substrains correlate directly with antitumor activity. A substrain of M. kansasii appears to have been identified which may prove more clinically effective than the currently available strains of BCG.

Anti-tumor effects of dehydroaltenusin, a specific inhibitor of mammalian DNA polymerase α

International Nuclear Information System (INIS)

Maeda, Naoki; Kokai, Yasuo; Ohtani, Seiji; Sahara, Hiroeki; Kuriyama, Isoko; Kamisuki, Shinji; Takahashi, Shunya; Sakaguchi, Kengo; Sugawara, Fumio; Yoshida, Hiromi; Sato, Noriyuki; Mizushina, Yoshiyuki

2007-01-01

In the screening of selective inhibitors of eukaryotic DNA polymerases (pols), dehydroaltenusin was found to be an inhibitor of pol α from a fungus (Alternaria tennuis). We succeeded in chemically synthesizing dehydroaltenusin, and the compound inhibited only mammalian pol α with IC 50 value of 0.5 μM, and did not influence the activities of other replicative pols such as pols δ and ε, but also showed no effect on pol α activity from another vertebrate, fish, or from a plant species. Dehydroaltenusin also had no influence on the other pols and DNA metabolic enzymes tested. The compound also inhibited the proliferation of human cancer cells with LD 50 values of 38.0-44.4 μM. In an in vivo anti-tumor assay on nude mice bearing solid tumors of HeLa cells, dehydroaltenusin was shown to be a promising suppressor of solid tumors. Histopathological examination revealed that increased tumor necrosis and decreased mitotic index were apparently detected by the compound in vivo. Therefore, dehydroaltenusin could be of interest as not only a mammalian pol α-specific inhibitor, but also as a candidate drug for anti-cancer treatment

Amplexicaule A exerts anti-tumor effects by inducing apoptosis in human breast cancer

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Shu, Guangwen; Wan, Dingrong; He, Feng; Loaec, Morgann; Ding, Yali; Li, Jun; Dovat, Sinisa; Yang, Gaungzhong; Song, Chunhua

2016-01-01

Chemotherapy is the main treatment for patients with breast cancer metastases, but natural alternatives have been receiving attention for their potential as novel anti-tumor reagents. Amplexicaule A (APA) is a flavonoid glucoside isolated from rhizomes of Polygonum amplexicaule D. Don var. sinense Forb (PADF). We found that APA has anti-tumor effects in a breast cancer xenograft mouse model and induces apoptosis in breast cancer cell lines. APA increased levels of cleaved caspase-3,-8,-9 and PARP, which resulted from suppression of MCL-1 and BCL-2 expression in the cells. APA also inactivated the Akt/mTOR pathway in breast cancer cells. Thus, APA exerts a strong anti-tumor effect on breast cancer cells, most likely through induction of apoptosis. Our study is the first to identify this novel anti-tumor compound and provides a new strategy for isolation and separation of single compounds from herbs. PMID:26943775

Antitumor effects of cannabidiol, a nonpsychoactive cannabinoid, on human glioma cell lines.

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Massi, Paola; Vaccani, Angelo; Ceruti, Stefania; Colombo, Arianna; Abbracchio, Maria P; Parolaro, Daniela

2004-03-01

Recently, cannabinoids (CBs) have been shown to possess antitumor properties. Because the psychoactivity of cannabinoid compounds limits their medicinal usage, we undertook the present study to evaluate the in vitro antiproliferative ability of cannabidiol (CBD), a nonpsychoactive cannabinoid compound, on U87 and U373 human glioma cell lines. The addition of CBD to the culture medium led to a dramatic drop of mitochondrial oxidative metabolism [3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H tetrazolium bromide test] and viability in glioma cells, in a concentration-dependent manner that was already evident 24 h after CBD exposure, with an apparent IC(50) of 25 microM. The antiproliferative effect of CBD was partially prevented by the CB2 receptor antagonist N-[(1S)-endo-1,3,3-trimethylbicyclo[2,2,1]heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide (SR144528; SR2) and alpha-tocopherol. By contrast, the CB1 cannabinoid receptor antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboximide hydrochloride (SR141716; SR1), capsazepine (vanilloid receptor antagonist), the inhibitors of ceramide generation, or pertussis toxin did not counteract CBD effects. We also show, for the first time, that the antiproliferative effect of CBD was correlated to induction of apoptosis, as determined by cytofluorimetric analysis and single-strand DNA staining, which was not reverted by cannabinoid antagonists. Finally, CBD, administered s.c. to nude mice at the dose of 0.5 mg/mouse, significantly inhibited the growth of subcutaneously implanted U87 human glioma cells. In conclusion, the nonpsychoactive CBD was able to produce a significant antitumor activity both in vitro and in vivo, thus suggesting a possible application of CBD as an antineoplastic agent.

The anti-tumor effect of bee honey in Ehrlich ascite tumor model of mice is coincided with stimulation of the immune cells.

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Attia, W Y; Gabry, M S; El-Shaikh, K A; Othman, G A

2008-01-01

Honey is thought to exhibit a broad spectrum of therapeutic properties including antibacterial, antifungal, cytostatic and anti-inflammatory activity and has been used for the treatment of gastric ulcers, burns, and for storage of skin grafts. The present study investigated the antitumor effect of bee honey against Ehrlich ascites tumor in mice and the possible mode of antitumor action. Peroral administration of mice with honey (10, 100 or 1000 mg/ 100 g BW) every other day for 4 weeks before intraperitoneal inoculation with Ehrlich ascites tumor (EAT, 1 x 10(6) cells) increased the number bone marrow cells as well as peritoneal macrophages, but not peripheral blood leukocytes nor splenocytes. The phagocytic function of macrophages as well as the T- and B-cell functions were also increased. Honey pre-treatment also recovered the total lipids, total proteins, as well as liver and kidney enzyme activities in EAT-bearing mice. In vitro studies on EAT cells demonstrated inhibitory effect of honey on tumor cell proliferation, viability % of tumor cells as well as the size of solid tumor. The present results indicate that the preventive treatment with honey is considerably effective against EAT in mice both in vivo and in vitro. The antitumor activity of honey may occur through the activation of macrophages, T-cells and B-cells.

Docetaxel-loaded single-wall carbon nanohorns using anti-VEGF antibody as a targeting agent: characterization, in vitro and in vivo antitumor activity

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Zhao, Qian; Li, Nannan; Shu, Chang; Li, Ruixin; Ma, Xiaona; Li, Xuequan; Wang, Ran; Zhong, Wenying, E-mail: wyzhong@cpu.edu.cn [China Pharmaceutical University, Department of Analytical Chemistry (China)

2015-05-15

A novel antitumor drug delivery system, docetaxel (DTX)-loaded oxidized single-wall carbon nanohorns (oxSWNHs) with anti-VEGF monoclonal antibody (mAb) as a target agent was constructed. DTX was absorbed onto the oxSWNHs via the physical adsorption or π–π interaction. DSPE–PEG–COOH was non-covalently wrapped to the hydrophobic surface of oxSWNHs to improve its water solubility and biocompatibility. The mAb was bonded to the PEG through amide bond. The DTX@oxSWNHs-PEG-mAb (DDS) exhibited suitable particle size (191.2 ± 2.1 nm), good particle size distribution (PDI: 0.196), and negative zeta potential (−24.3 ± 0.85 mV). These features enhanced permeability and retention (EPR) effect and reduced the drug molecule uptake by the reticuloendothelial system. The in vitro drug release followed non-Fickian diffusion (n = 0.6857, R = 0.9924) with the cumulative release of DTX 59 ± 1.35 % at 72 h. Compared with free DTX, the DDS enhanced the cytotoxicity in MCF-7 cell lines in vitro efficiently (IC{sub 50}: 2.96 ± 0.6 μg/ml), and provided higher antitumor efficacy (TGI: 69.88 %) in vivo. The histological analysis indicated that the DDS had no significant side effect. Therefore, the new DDS is promising to attain higher pharmaceutical efficacy and lower side effects than free DTX for cancer therapy. The research demonstrated that DTX@oxSWNHs-PEG-mAb might have promising biomedical applications for future cancer therapy.

Comparative study of nanosecond electric fields in vitro and in vivo on hepatocellular carcinoma indicate macrophage infiltration contribute to tumor ablation in vivo.

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Xinhua Chen

Full Text Available BACKGROUND AND AIM: Recurrence and metastasis are associated with poor prognosis in hepatocellular carcinoma even in the patients who have undergone radical resection. Therefore, effective treatment is urgently needed for improvement of patients' survival. Previously, we reported that nanosecond pulse electric fields (nsPEFs can ablate melanoma by induction of apoptosis and inhibition of angiogenesis. This study aims to investigate the in vivo ablation strategy by comparing the dose effect of nanosecond electric fields in vitro and in vivo on hepatocellular carcinoma. MATERIALS AND METHODS: Four hepatocellular carcinoma cell lines HepG2, SMMC7721, Hep1-6, and HCCLM3 were pulsed to test the anti-proliferation and anti-migration ability of 100 ns nsPEFs in vitro. The animal model of human subdermal xenograft HCCLM3 cells into BALB/c nude mouse was used to test the anti-tumor growth and macrophage infiltration in vivo. RESULTS: In vitro assays showed anti-tumor effect of nsPEFs is dose-dependant. But the in vivo study showed the strategy of low dose and multiple treatments is superior to high dose single treatment. The macrophages infiltration significantly increased in the tumors which were treated by multiple low dose nsPEFs. CONCLUSION: The low dose multiple nsPEFs application is more efficient than high dose single treatment in inhibiting the tumor volume in vivo, which is quite different from the dose-effect relationship in vitro. Beside the electric field strength, the macrophage involvement must be considered to account for effect variability and toxicology in vivo.

The Antitumor Activity of the Novel Compound Jesridonin on Human Esophageal Carcinoma Cells.

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Cong Wang

Full Text Available Jesridonin, a small molecule obtained through the structural modification of Oridonin, has extensive antitumor activity. In this study, we evaluated both its in vitro activity in the cancer cell line EC109 and its in vivo effect on tumor xenografts in nude mice. Apoptosis induced by Jesridonin was determined using an MTT assay, Annexin-V FITC assay and Hoechest 33258 staining. Apoptosis via mitochondrial and death receptor pathways were confirmed by detecting the regulation of MDM2, p53, and Bcl-2 family members and by activation of caspase-3/-8/-9. In addition, vena caudalis injection of Jesridonin showed significant inhibition of tumor growth in the xenograft model, and Jesridonin-induced cell apoptosis in tumor tissues was determined using TUNEL. Biochemical serum analysis of alkaline phosphatase (ALP, alanine transaminase (ALT, aspartate transaminase (AST, gamma-glutamyl transferase (GGT, total protein (TP and albumin (ALB indicated no obvious effects on liver function. Histopathological examination of the liver, kidney, lung, heart and spleen revealed no signs of JD-induced toxicity. Taken together, these results demonstrated that Jesridonin exhibits antitumor activity in human esophageal carcinomas EC109 cells both in vitro and in vivo and demonstrated no adverse effects on major organs in nude mice. These studies provide support for new drug development.

Antitumor Properties of the Essential Oil From the Leaves of Duguetia gardneriana.

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Rodrigues, Ana Carolina B C; Bomfim, Larissa M; Neves, Sara P; Menezes, Leociley R A; Dias, Rosane B; Soares, Milena B P; Prata, Ana Paula N; Rocha, Clarissa A Gurgel; Costa, Emmanoel V; Bezerra, Daniel P

2015-07-01

Duguetia gardneriana, popularly known in the Brazilian northeast as "jaquinha", is a species belonging to the family Annonaceae. The aim of this work was to assess the chemical composition and antitumor properties of the essential oil from the leaves of D. gardneriana in experimental models. The chemical composition of the essential oil was analyzed via gas chromatography-flame ionization detector and gas chromatography-mass spectrometry. In vitro cytotoxic activity was determined in cultured tumor cells, and in vivo antitumor activity was assessed in B16-F10-bearing mice. The identified compounds were β-bisabolene (80.99%), elemicin (8.04%), germacrene D (4.15%), and cyperene (2.82%). The essential oil exhibited a cytotoxic effect, with IC50 values of 16.89, 19.16, 13.08, and 19.33 µg/mL being obtained for B16-F10, HepG2, HL-60, and K562 cell lines, respectively. On the other hand, β-bisabolene was inactive in all of the tested tumor cell lines (showing IC50 values greater than 25 µg/mL). The in vivo analysis revealed tumor growth inhibition rates of 5.37-37.52% at doses of 40 and 80 mg/kg/day, respectively. Herein, the essential oil from the leaves of D. gardneriana presented β-bisabolene as the major constituent and showed cytotoxic and antitumor potential. Georg Thieme Verlag KG Stuttgart · New York.

Colloidally stable surface-modified iron oxide nanoparticles: Preparation, characterization and anti-tumor activity

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Macková, Hana [Institute of Macromolecular Chemistry, AS CR, Heyrovsky Sq. 2, 162 06 Prague 6 (Czech Republic); Horák, Daniel, E-mail: horak@imc.cas.cz [Institute of Macromolecular Chemistry, AS CR, Heyrovsky Sq. 2, 162 06 Prague 6 (Czech Republic); Donchenko, Georgiy Viktorovich; Andriyaka, Vadim Ivanovich; Palyvoda, Olga Mikhailovna; Chernishov, Vladimir Ivanovich [Palladin Institute of Biochemistry, NASU, 9 Leontovich St., 01601 Kiev (Ukraine); Chekhun, Vasyl Fedorovich; Todor, Igor Nikolaevich [R. E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology, NASU, 45 Vasylkivska St., 03022 Kiev (Ukraine); Kuzmenko, Oleksandr Ivanovich [Palladin Institute of Biochemistry, NASU, 9 Leontovich St., 01601 Kiev (Ukraine)

2015-04-15

Maghemite (γ-Fe{sub 2}O{sub 3}) nanoparticles were obtained by co-precipitation of Fe(II) and Fe(III) chlorides and subsequent oxidation with sodium hypochlorite and coated with poly(N,N-dimethylacrylamide-co-acrylic acid) [P(DMAAm-AA)]. They were characterized by a range of methods including transmission electron microscopy (TEM), elemental analysis, dynamic light scattering (DLS) and zeta potential measurements. The effect of superparamagnetic P(DMAAm-AA)-γ-Fe{sub 2}O{sub 3} nanoparticles on oxidation of blood lipids, glutathione and proteins in blood serum was detected using 2-thiobarbituric acid and the ThioGlo fluorophore. Finally, mice received magnetic nanoparticles administered per os and the antitumor activity of the particles was tested on Lewis lung carcinoma (LLC) in male mice line C57BL/6 as an experimental in vivo metastatic tumor model; the tumor size was measured and the number of metastases in lungs was determined. Surface-modified γ-Fe{sub 2}O{sub 3} nanoparticles showed higher antitumor and antimetastatic activities than commercial CuFe{sub 2}O{sub 4} particles and the conventional antitumor agent cisplatin. - Highlights: • Maghemite nanoparticles were prepared and characterized. • Poly(N,N-dimethylacrylamide-co-acrylic acid) coating was synthetized. • Blood lipid, glutathione and protein peroxidation/oxidation was determined. • Antitumor effect of coated particles on Lewis lung carcinoma in mice was observed.

Evaluation of Anti-tumor and Chemoresistance-lowering Effects of ...

African Journals Online (AJOL)

Evaluation of Anti-tumor and Chemoresistance-lowering Effects of Pectolinarigenin from Cirsium japonicum Fisch ex DC in Breast Cancer. Mingqian Lu, Xinhua Xu, Hongda Lu, Zhongxin Lu, Bingqing Xu, Chao Tan, Kezhi Shi, Rong Guo, Qingzhi Kong ...

Host-mediated antitumor effect of DMG, a degraded D-manno-D-glucan from Microellobosporia grisea culture fluid.

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Nakajima, H; Hashimoto, S; Nagao, S; Kita, Y; Khono, M; Ogawa, H; Abe, S; Mizuno, D

1984-03-01

DMG, a new polysaccharide with a well-characterized structure, isolated from the culture filtrate of an actinomycetes and then degraded by acid treatment, was tested for antitumor activity on allogeneic and syngeneic tumors in mice. In the allogeneic Ehrlich solid tumor system, DMG showed antitumor activity over a wide dose range, its optimal dose being 10-100 mg/kg. The optimal time of DMG administration was 1-2 weeks after tumor inoculation, but DMG was also effective when given before tumor inoculation. DMG was effective when given ip, sc, it (intratumorally) or iv. DMG also had antitumor effects on syngeneic tumors. It rapidly inhibited the growth of MM46 mammary carcinoma, MH134 hepatoma, and Meth A fibrosarcoma, and also inhibited spontaneous pulmonary metastases of B16-BL6 melanoma. However, it had no direct cytocidal action on tumor cells in vitro. Its antitumor activity was much less in athymic nude mice and in mice immunosuppressed by whole-body X-irradiation than in normal hosts.Thus, DMG was shown to exert antitumor activity via host-mediated mechanisms. Its antitumor activity is discussed in comparison with those of other antitumor polysaccharides.

Juglans regia Hexane Extract Exerts Antitumor Effect, Apoptosis ...

African Journals Online (AJOL)

Original Research Article. Juglans regia Hexane Extract Exerts Antitumor Effect,. Apoptosis Induction and Cell Circle Arrest in Prostate. Cancer Cells In vitro. Wei Li1, De-Yuan Li2*, ... composition of walnut is juglone (5-hydroxy-1, 4- naphthoquinone), the .... extract was confirmed by studying apoptotic body formation using ...

A novel, polymer-coated oncolytic measles virus overcomes immune suppression and induces robust antitumor activity

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Kaname Nosaki

2016-01-01

Full Text Available Although various therapies are available to treat cancers, including surgery, chemotherapy, and radiotherapy, cancer has been the leading cause of death in Japan for the last 30 years, and new therapeutic modalities are urgently needed. As a new modality, there has recently been great interest in oncolytic virotherapy, with measles virus being a candidate virus expected to show strong antitumor effects. The efficacy of virotherapy, however, was strongly limited by the host immune response in previous clinical trials. To enhance and prolong the antitumor activity of virotherapy, we combined the use of two newly developed tools: the genetically engineered measles virus (MV-NPL and the multilayer virus-coating method of layer-by-layer deposition of ionic polymers. We compared the oncolytic effects of this polymer-coated MV-NPL with the naked MV-NPL, both in vitro and in vivo. In the presence of anti-MV neutralizing antibodies, the polymer-coated virus showed more enhanced oncolytic activity than did the naked MV-NPL in vitro. We also examined antitumor activities in virus-treated mice. Complement-dependent cytotoxicity and antitumor activities were higher in mice treated with polymer-coated MV-NPL than in mice treated with the naked virus. This novel, polymer-coated MV-NPL is promising for clinical cancer therapy in the future.

Cytotoxicity and anti-tumor effects of new ruthenium complexes on triple negative breast cancer cells.

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Cecília P Popolin

Full Text Available Triple-negative breast cancer (TNBC is a highly aggressive breast cancer subtype. The high rate of metastasis associated to the fact that these cells frequently display multidrug resistance, make the treatment of metastatic disease difficult. Development of antitumor metal-based drugs was started with the discovery of cisplatin, however, the severe side effects represent a limitation for its clinical use. Ruthenium (Ru complexes with different ligands have been successfully studied as prospective antitumor drugs. In this work, we demonstrated the activity of a series of biphosphine bipyridine Ru complexes (1 [Ru(SO4(dppb(bipy], (2 [Ru(CO3(dppb(bipy], (3 [Ru(C2O4(dppb(bipy] and (4 [Ru(CH3CO2(dppb(bipy]PF6 [where dppb = 1,4-bis(diphenylphosphinobutane and bipy = 2,2'-bipyridine], on proliferation of TNBC (MDA-MB-231, estrogen-dependent breast tumor cells (MCF-7 and a non-tumor breast cell line (MCF-10A. Complex (4 was most effective among the complexes and was selected to be further investigated on effects on tumor cell adhesion, migration, invasion and in apoptosis. Moreover, DNA and HSA binding properties of this complex were also investigated. Results show that complex (4 was more efficient inhibiting proliferation of MDA-MB-231 cells over non-tumor cells. In addition, complex (4 was able to inhibit MDA-MB231 cells adhesion, migration and invasion and to induce apoptosis and inhibit MMP-9 secretion in TNBC cells. Complex (4 should be further investigated in vivo in order to stablish its potential to improve breast cancer treatment.

Effect of Au-dextran NPs as anti-tumor agent against EAC and solid tumor in mice by biochemical evaluations and histopathological investigations.

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Medhat, Dalia; Hussein, Jihan; El-Naggar, Mehrez E; Attia, Mohamed F; Anwar, Mona; Latif, Yasmine Abdel; Booles, Hoda F; Morsy, Safaa; Farrag, Abdel Razik; Khalil, Wagdy K B; El-Khayat, Zakaria

2017-07-01

Dextran-capped gold nanoparticles (Au-dextran NPs) were prepared exploiting the natural polysaccharide polymer as both reducing and stabilizing agent in the synthesis process, aiming at studying their antitumor effect on solid carcinoma and EAC-bearing mice. To this end, Au-dextran NPs were designed via simple eco-friendly chemical reaction and they were characterized revealing the monodispersed particles with narrow distributed size of around 49nm with high negative charge. In vivo experiments were performed on mice. Biochemical analysis of liver and kidney functions and oxidation stress ratio in addition to histopathological investigations of such tumor tissues were done demonstrating the potentiality of Au-dextran NPs as antitumor agent. The obtained results revealed that EAC and solid tumors caused significant increase in liver and kidney functions, liver oxidant parameters, alpha feto protein levels and diminished liver antioxidant accompanied by positive expression of tumor protein p53 of liver while the treatment with Au-dextran NPs for both types caused improvement in liver and kidney functions, increased liver antioxidant, increased the expression level of B-cell lymphoma 2 gene and subsequently suppressed the apoptotic pathway. As a result, the obtained data provides significant antitumor effects of the Au-dextran NPs in both Ehrlich ascites and solid tumor in mice models. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Antitumor Action of a Novel Histone Deacetylase Inhibitor, YF479, in Breast Cancer

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Tao Zhang

2014-08-01

Full Text Available Accumulating evidence demonstrates important roles for histone deacetylase in tumorigenesis (HDACs, highlighting them as attractive targets for antitumor drug development. Histone deactylase inhibitors (HDACIs, which have shown favorable anti-tumor activity with low toxicity in clinical investigations, are a promising class of anticancer therapeutics. Here, we screened our compound library to explore small molecules that possess anti-HDAC activity and identified a novel HDACI, YF479. Suberoylanilide hydroxamic acid (SAHA, which was the first approved HDAC inhibitor for clinical treatment by the FDA, was as positive control in our experiments. We further demonstrated YF479 abated cell viability, suppressed colony formation and tumor cell motility in vitro. To investigate YF479 with superior pharmacodynamic properties, we developed spontaneous and experimental breast cancer animal models. Our results showed YF479 significantly inhibited breast tumor growth and metastasis in vivo. Further study indicated YF479 suppressed both early and end stages of metastatic progression. Subsequent adjuvant chemotherapy animal experiment revealed the elimination of local-regional recurrence (LRR and distant metastasis by YF479. More important, YF479 remarkably prolonged the survival of tumor-bearing mice. Intriguingly, YF479 displayed more potent anti-tumor activity in vitro and in vivo compared with SAHA. Together, our results suggest that YF479, a novel HDACI, inhibits breast tumor growth, metastasis and recurrence. In light of these results, YF479 may be an effective therapeutic option in clinical trials for patients burdened by breast cancer.

Cellular immunotherapy using irradiated lung cancer cell vaccine co-expressing GM-CSF and IL-18 can induce significant antitumor effects

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Tian, Hongwei; Zhang, Xiaomei; Dai, Lei; Chen, Xiaolei; Zhang, Shuang; Yang, Yang; Yu, Dechao; Wei, Yuquan; Deng, Hongxin; Shi, Gang; Yang, Guoyou; Zhang, Junfeng; Li, Yiming; Du, Tao; Wang, Jianzhou; Xu, Fen; Cheng, Lin

2014-01-01

Although the whole tumor cell vaccine can provide the best source of immunizing antigens, there is still a limitation that most tumors are not naturally immunogenic. Tumor cells genetically modified to secrete immune activating cytokines have been proved to be more immunogenic. IL-18 could augment proliferation of T cells and cytotoxicity of NK cells. GM-CSF could stimulate dendritic cells, macrophages and enhance presentation of tumor antigens. In our study, we used mouse GM-CSF combined with IL-18 to modify Lewis lung cancer LL/2, then investigated whether vaccination could suppress tumor growth and promote survival. The Lewis lung cancer LL/2 was transfected with co-expressing mouse GM-CSF and IL-18 plasmid by cationic liposome, then irradiated with a sublethal dose X ray (100 Gy) to prepare vaccines. Mice were subcutaneously immunized with this inactivated vaccine and then inoculated with autologous LL/2 to estimate the antitumor efficacy. The studies reported here showed that LL/2 tumor cell vaccine modified by a co-expressing mouse GM-CSF and IL-18 plasmid could significantly inhibit tumor growth and increased survival of the mice bearing LL/2 tumor whether prophylactic or adoptive immunotherapy in vivo. A significant reduction of proliferation and increase of apoptosis were also observed in the tumor treated with vaccine of co-expressing GM-CSF and IL-18. The potent antitumor effect correlated with higher secretion levels of pro-inflammatory cytokines such as IL-18, GM-CSF, interferon-γ in serum, the proliferation of CD4 + IFN-γ + , CD8 + IFN-γ + T lymphocytes in spleen and the infiltration of CD4 + , CD8 + T in tumor. Furthermore, the mechanism of tumor-specific immune response was further proved by 51 Cr cytotoxicity assay in vitro and depletion of CD4, CD8, NK immune cell subsets in vivo. The results suggested that the antitumor mechanism was mainly depended on CD4 + , CD8 + T lymphocytes. These results provide a new insight into therapeutic mechanisms

Production of interferon-gamma by in vivo tumor-sensitized T cells: Association with active antitumor immunity

International Nuclear Information System (INIS)

Bursuker, I.; Pearce, M.T.

1990-01-01

The state of active immunity to Meth A fibrosarcoma in mice immunized with an admixture of Meth A cells and Propionibacterium acnes is associated with possession by the host of spleen cells capable of producing interferon-gamma (IFN-gamma) upon in vitro restimulation with irradiated tumor cells. The ability of spleen cells from immunized mice to produce IFN-gamma in response to irradiated Meth A cells decays as active antitumor immunity is replaced by a state of immunological memory. The IFN-producing cells are L3T4+Ly2+, cyclophosphamide-sensitive and radiosensitive T cells, as determined by their sensitivity to corresponding monoclonal antibodies and complement. The induction of IFN-gamma production by in vivo tumor-sensitized T cells is tumor specific, in that spleen cells from mice immunized against Meth A fibrosarcoma can produce IFN in response to irradiated Meth A cells but not in response to another syngeneic tumor M109 lung carcinoma

Anti-tumor efficacy of lymphokine-activated killer cells and recombinant interleukin 2 in vivo: direct correlation between reduction of established metastases and cytolytic activity of lymphokine-activated killer cells

International Nuclear Information System (INIS)

Mule, J.J.; Yang, J.; Shu, S.; Rosenberg, S.A.

1986-01-01

Our previous studies demonstrated that the incubation of human peripheral blood lymphocytes or murine splenocytes in recombinant interleukin 2 (RIL 2) resulted in the generation of lymphokine-activated killer (LAK) cells capable of lysing a broad spectrum of fresh tumors in short-term chromium-release assays. Moreover, injections of LAK cells plus RIL 2 were highly effective in eliminating established 3 day metastases in the lung and liver. We have examined several parameters to define whether or not the cytolytic activity of LAK cells as measured in vitro correlated directly with the in vivo anti-tumor efficacy of adoptively transferred LAK cells. LAK cells plus RIL 2 could mediate marked reductions of established pulmonary metastases in mice rendered T cell deficient by adult thymectomy and lethal, total body irradiation followed by reconstitution with T cell-depleted bone marrow and spleen cells. Thus there was no requirement for additional T lymphocytes of host origin for successful therapy with adoptively transferred LAK cells plus RIL 2. Fresh splenocytes depleted of T cells by anti-Thy-1.2 monoclonal antibody plus complement generated LAK cells that were as highly lytic to fresh tumor in vitro and were as effective in reducing established pulmonary metastases as those generated from untreated or complement-treated splenocytes. Thus, the precursor to LAK cells with anti-tumor activity in vitro and in vivo did not express the Thy-1 antigenic marker. In contrast, treatment of LAK effector cells (those generated from a 3-day incubation of fresh, normal splenocytes in RIL 2) with anti-Thy-1.2 antibody plus complement reduced or abolished their in vitro cytolytic activity

Antibody complementarity-determining regions (CDRs can display differential antimicrobial, antiviral and antitumor activities.

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Luciano Polonelli

Full Text Available BACKGROUND: Complementarity-determining regions (CDRs are immunoglobulin (Ig hypervariable domains that determine specific antibody (Ab binding. We have shown that synthetic CDR-related peptides and many decapeptides spanning the variable region of a recombinant yeast killer toxin-like antiidiotypic Ab are candidacidal in vitro. An alanine-substituted decapeptide from the variable region of this Ab displayed increased cytotoxicity in vitro and/or therapeutic effects in vivo against various bacteria, fungi, protozoa and viruses. The possibility that isolated CDRs, represented by short synthetic peptides, may display antimicrobial, antiviral and antitumor activities irrespective of Ab specificity for a given antigen is addressed here. METHODOLOGY/PRINCIPAL FINDINGS: CDR-based synthetic peptides of murine and human monoclonal Abs directed to: a a protein epitope of Candida albicans cell wall stress mannoprotein; b a synthetic peptide containing well-characterized B-cell and T-cell epitopes; c a carbohydrate blood group A substance, showed differential inhibitory activities in vitro, ex vivo and/or in vivo against C. albicans, HIV-1 and B16F10-Nex2 melanoma cells, conceivably involving different mechanisms of action. Antitumor activities involved peptide-induced caspase-dependent apoptosis. Engineered peptides, obtained by alanine substitution of Ig CDR sequences, and used as surrogates of natural point mutations, showed further differential increased/unaltered/decreased antimicrobial, antiviral and/or antitumor activities. The inhibitory effects observed were largely independent of the specificity of the native Ab and involved chiefly germline encoded CDR1 and CDR2 of light and heavy chains. CONCLUSIONS/SIGNIFICANCE: The high frequency of bioactive peptides based on CDRs suggests that Ig molecules are sources of an unlimited number of sequences potentially active against infectious agents and tumor cells. The easy production and low cost of small

Optimization and anticancer activity in vitro and in vivo of baohuoside I incorporated into mixed micelles based on lecithin and Solutol HS 15.

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Yan, Hong-Mei; Song, Jie; Zhang, Zhen-Hai; Jia, Xiao-Bin

2016-10-01

Baohuoside I, extracted from the Herba epimedii, is an effective but a poorly soluble antitumor drug. To improve its solubility, formulation of baohuoside I-loaded mixed micelles with lecithin and Solutol HS 15 (BLSM) has been performed in this study. We performed a systematic comparative evaluation of the antiproliferative effect, cellular uptake, antitumor efficacy, and in vivo tumor targeting of these micelles using non-small cell lung cancer (NSCLC) A549 cells. Results showed that the obtained micelles have a mean particle size of around 62.54 nm, and the size of micelles was narrowly distributed. With the improved cellular uptake, BLSM displayed a more potent antiproliferative action on A549 cell lines than baohuoside I; half-maximal inhibitory concentration (IC 50 ) was 6.31 versus 18.28 µg/mL, respectively. The antitumor efficacy test in nude mice showed that BLSM exhibited significantly higher antitumor activity against NSCLC with lesser toxic effects on normal tissues. The imaging study for in vivo targeting demonstrated that the mixed micelles formulation achieved effective and targeted drug delivery. Therefore, BLSM might be a potential antitumor formulation.

The vitamin-like dietary supplement para-aminobenzoic acid enhances the antitumor activity of ionizing radiation

International Nuclear Information System (INIS)

Xavier, Sandhya; MacDonald, Shannon; Roth, Jennifer; Caunt, Maresa; Akalu, Abebe; Morais, Danielle; Buckley, Michael T.; Liebes, Leonard; Formenti, Silvia C.; Brooks, Peter C.

2006-01-01

Purpose: To determine whether para-aminobenzoic acid (PABA) alters the sensitivity of tumor cells to ionizing radiation in vitro and in vivo. Methods and Materials: Cellular proliferation was assessed by WST-1 assays. The effects of PABA and radiation on tumor growth were examined with chick embryo and murine models. Real-time reverse transcriptase-polymerase chain reaction and Western blotting were used to quantify p21 CIP1 and CDC25A levels. Results: Para-aminobenzoic acid enhanced (by 50%) the growth inhibitory activity of radiation on B16F10 cells, whereas it had no effect on melanocytes. Para-aminobenzoic acid enhanced (50-80%) the antitumor activity of radiation on B16F10 and 4T1 tumors in vivo. The combination of PABA and radiation therapy increased tumor apoptosis. Treatment of tumor cells with PABA increased expression of CDC25A and decreased levels of p21 CIP1 . Conclusions: Our findings suggest that PABA might represent a compound capable of enhancing the antitumor activity of ionizing radiation by a mechanism involving altered expression of proteins known to regulate cell cycle arrest

Pyruvate induces transient tumor hypoxia by enhancing mitochondrial oxygen consumption and potentiates the anti-tumor effect of a hypoxia-activated prodrug TH-302.

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Yoichi Takakusagi

Full Text Available BACKGROUND: TH-302 is a hypoxia-activated prodrug (HAP of bromo isophosphoramide mustard that is selectively activated within hypoxic regions in solid tumors. Our recent study showed that intravenously administered bolus pyruvate can transiently induce hypoxia in tumors. We investigated the mechanism underlying the induction of transient hypoxia and the combination use of pyruvate to potentiate the anti-tumor effect of TH-302. METHODOLOGY/RESULTS: The hypoxia-dependent cytotoxicity of TH-302 was evaluated by a viability assay in murine SCCVII and human HT29 cells. Modulation in cellular oxygen consumption and in vivo tumor oxygenation by the pyruvate treatment was monitored by extracellular flux analysis and electron paramagnetic resonance (EPR oxygen imaging, respectively. The enhancement of the anti-tumor effect of TH-302 by pyruvate treatment was evaluated by monitoring the growth suppression of the tumor xenografts inoculated subcutaneously in mice. TH-302 preferentially inhibited the growth of both SCCVII and HT29 cells under hypoxic conditions (0.1% O2, with minimal effect under aerobic conditions (21% O2. Basal oxygen consumption rates increased after the pyruvate treatment in SCCVII cells in a concentration-dependent manner, suggesting that pyruvate enhances the mitochondrial respiration to consume excess cellular oxygen. In vivo EPR oxygen imaging showed that the intravenous administration of pyruvate globally induced the transient hypoxia 30 min after the injection in SCCVII and HT29 tumors at the size of 500-1500 mm(3. Pretreatment of SCCVII tumor bearing mice with pyruvate 30 min prior to TH-302 administration, initiated with small tumors (∼ 550 mm(3, significantly delayed tumor growth. CONCLUSIONS/SIGNIFICANCE: Our in vitro and in vivo studies showed that pyruvate induces transient hypoxia by enhancing mitochondrial oxygen consumption in tumor cells. TH-302 therapy can be potentiated by pyruvate pretreatment if started at the

Pyruvate induces transient tumor hypoxia by enhancing mitochondrial oxygen consumption and potentiates the anti-tumor effect of a hypoxia-activated prodrug TH-302.

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Takakusagi, Yoichi; Matsumoto, Shingo; Saito, Keita; Matsuo, Masayuki; Kishimoto, Shun; Wojtkowiak, Jonathan W; DeGraff, William; Kesarwala, Aparna H; Choudhuri, Rajani; Devasahayam, Nallathamby; Subramanian, Sankaran; Munasinghe, Jeeva P; Gillies, Robert J; Mitchell, James B; Hart, Charles P; Krishna, Murali C

2014-01-01

TH-302 is a hypoxia-activated prodrug (HAP) of bromo isophosphoramide mustard that is selectively activated within hypoxic regions in solid tumors. Our recent study showed that intravenously administered bolus pyruvate can transiently induce hypoxia in tumors. We investigated the mechanism underlying the induction of transient hypoxia and the combination use of pyruvate to potentiate the anti-tumor effect of TH-302. The hypoxia-dependent cytotoxicity of TH-302 was evaluated by a viability assay in murine SCCVII and human HT29 cells. Modulation in cellular oxygen consumption and in vivo tumor oxygenation by the pyruvate treatment was monitored by extracellular flux analysis and electron paramagnetic resonance (EPR) oxygen imaging, respectively. The enhancement of the anti-tumor effect of TH-302 by pyruvate treatment was evaluated by monitoring the growth suppression of the tumor xenografts inoculated subcutaneously in mice. TH-302 preferentially inhibited the growth of both SCCVII and HT29 cells under hypoxic conditions (0.1% O2), with minimal effect under aerobic conditions (21% O2). Basal oxygen consumption rates increased after the pyruvate treatment in SCCVII cells in a concentration-dependent manner, suggesting that pyruvate enhances the mitochondrial respiration to consume excess cellular oxygen. In vivo EPR oxygen imaging showed that the intravenous administration of pyruvate globally induced the transient hypoxia 30 min after the injection in SCCVII and HT29 tumors at the size of 500-1500 mm(3). Pretreatment of SCCVII tumor bearing mice with pyruvate 30 min prior to TH-302 administration, initiated with small tumors (∼ 550 mm(3)), significantly delayed tumor growth. Our in vitro and in vivo studies showed that pyruvate induces transient hypoxia by enhancing mitochondrial oxygen consumption in tumor cells. TH-302 therapy can be potentiated by pyruvate pretreatment if started at the appropriate tumor size and oxygen concentration.

Anti-tumor effects of an engineered “killer” transfer RNA

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Zhou, Dong-hui; Lee, Jiyoung; Frankenberger, Casey; Geslain, Renaud; Rosner, Marsha; Pan, Tao

2012-01-01

Highlights: ► tRNA with anti-cancer effects. ► tRNA induced protein misfolding. ► tRNA as anti-tumor agent. -- Abstract: A hallmark of cancer cells is their ability to continuously divide; and rapid proliferation requires increased protein translation. Elevating levels of misfolded proteins can elicit growth arrest due to ER stress and decreased global translation. Failure to correct prolonged ER stress eventually results in cell death via apoptosis. tRNA Ser (AAU) is an engineered human tRNA Ser with an anticodon coding for isoleucine. Here we test the possibility that tRNA Ser (AAU) can be an effective killing agent of breast cancer cells and can effectively inhibit tumor-formation in mice. We found that tRNA Ser (AAU) exert strong effects on breast cancer translation activity, cell viability, and tumor formation. Translation is strongly inhibited by tRNA Ser (AAU) in both tumorigenic and non-tumorigenic cells. tRNA Ser (AAU) significantly decreased the number of viable cells over time. A short time treatment with tRNA Ser (AAU) was sufficient to eliminate breast tumor formation in a xenograft mouse model. Our results indicate that tRNA Ser (AAU) can inhibit breast cancer metabolism, growth and tumor formation. This RNA has strong anti-cancer effects and presents an opportunity for its development into an anti-tumor agent. Because tRNA Ser (AAU) corrupts the protein synthesis mechanism that is an integral component of the cell, it would be extremely difficult for tumor cells to evolve and develop resistance against this anti-tumor agent.

Anti-tumor bioactivities of curcumin on mice loaded with gastric carcinoma.

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Wang, Xiao-Ping; Wang, Qiao-Xia; Lin, Huan-Ping; Chang, Na

2017-09-20

Curcumin, a derivative from the dried rhizome of curcuma longa, has been proven to possess anti-tumor effects. However, the detailed molecular mechanisms have not been fully elucidated. In this study, we aimed to explore the anti-tumor mechanisms of curcumin in treating gastric cancer. BALB/C mice grafted with a mouse gastric adenocarcinoma cell line (MFC) were used as the experimental model. Mice received different doses of curcumin after grafting. Tumor size was measured and tumor weight was determined after tumor inoculation. TUNEL assay and flow cytometric analysis were applied to evaluate the apoptosis of the cancer cells. Serum cytokines IFN-γ, TNF-α, granzyme B and perforin were detected by ELISA assay. The anti-tumor effect was determined using cytotoxic T-lymphocyte (CTL) assays and in vivo tumor prevention tests. The expression of DEC1, HIF-1α, STAT3 and VEGF in tumor tissues was examined by immunostaining and analyzed using an Image J analysis system. Compared with controls, tumor growth (size and weight) was significantly inhibited by curcumin treatment (P curcumin treatment group. Splenocyte cells from mice treated with curcumin exhibited higher cytolytic effects on MFC cancer cells than those from mice treated with saline (P curcumin treatment. Our results indicate that curcumin inhibits the proliferation of gastric carcinoma by inducing the apoptosis of tumor cells, activating immune cells to secrete a large amount of cytokines, and down-regulating the DEC1, HIF-1α, VEGF and STAT3 signal transduction pathways.

Neurofibromin 1 Impairs Natural Killer T-Cell-Dependent Antitumor Immunity against a T-Cell Lymphoma

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Jianyun Liu

2018-01-01

Full Text Available Neurofibromin 1 (NF1 is a tumor suppressor gene encoding a Ras GTPase that negatively regulates Ras signaling pathways. Mutations in NF1 are linked to neurofibromatosis type 1, juvenile myelomonocytic leukemia and Watson syndrome. In terms of antitumor immunity, CD1d-dependent natural killer T (NKT cells play an important role in the innate antitumor immune response. Generally, Type-I NKT cells protect (and Type-II NKT cells impair host antitumor immunity. We have previously shown that CD1d-mediated antigen presentation to NKT cells is regulated by cell signaling pathways. To study whether a haploinsufficiency in NF1 would affect CD1d-dependent activation of NKT cells, we analyzed the NKT-cell population as well as the functional expression of CD1d in Nf1+/− mice. Nf1+/− mice were found to have similar levels of NKT cells as wildtype (WT littermates. Interestingly, however, reduced CD1d expression was observed in Nf1+/− mice compared with their WT littermates. When inoculated with a T-cell lymphoma in vivo, Nf1+/− mice survived longer than their WT littermates. Furthermore, blocking CD1d in vivo significantly enhanced antitumor activity in WT, but not in Nf1+/− mice. In contrast, a deficiency in Type-I NKT cells increased antitumor activity in Nf1+/− mice, but not in WT littermates. Therefore, these data suggest that normal NF1 expression impairs CD1d-mediated NKT-cell activation and antitumor activity against a T-cell lymphoma.

Antitumor activity and inhibitory effects on cancer stem cell-like properties of Adeno-associated virus (AAV) -mediated Bmi-1 interference driven by Bmi-1 promoter for gastric cancer

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Wang, Xiaofeng; Liu, Xinyang; Huang, Mingzhu; Gan, Lu; Cheng, Yufan; Li, Jin

2016-01-01

Bmi-1 is aberrantly activated in various cancers and plays a vital role in maintaining the self-renewal of stem cells. Our previous research revealed that Bmi-1 was overexpressed in gastric cancer (GC) and it's overexpression was an independent negative prognostic factor, suggesting it can be a therapeutic target. The main purpose of this investigation was to explore the antitumor activity of Bmi-1 interference driven by its own promoter (Ad-Bmi-1i) for GC. In this study, we used adenoviral vector to deliver Bmi-1 shRNA driven by its own promoter to treat GC. Our results revealed that Ad-Bmi-1i could selectively silence Bmi-1 in GC cells which overexpress Bmi-1 and suppress the malignant phenotypes and stem-like properties of GC cells in vitro and in vivo. Moreover, direct injection of Ad-Bmi-1i into xenografts suppressed tumor growth and destroyed cancer cells in vivo. Ad-Bmi-1i inhibited the proliferation of GC cells mainly via inducing senescence in vitro, but it suppressed tumor through inducing senescence and apoptosis, and inhibiting angiogenesis in vivo. Bmi-1 knockdown by Ad-Bmi-1i downregulated VEGF via inhibiting AKT activity. These results suggest that Ad-Bmi-1i not only inhibits tumor growth and stem cell-like phenotype by inducing cellular senescence directly, but also has an indirect anti-tumor activity by anti-angiogenesis effects via regulating PTEN/AKT/VEGF pathway. Transfer of gene interference guided by its own promoter by an adeno-associated virus (AAV) vector might be a potent antitumor approach for cancer therapy. PMID:27009837

Anti-tumor effects of (1→3)-β-d-glucan from Saccharomyces cerevisiae in S180 tumor-bearing mice.

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Mo, Li; Chen, Yafei; Li, Wenjian; Guo, Shuai; Wang, Xuzhao; An, Hailong; Zhan, Yong

2017-02-01

(1→3)-β-d-Glucan from Saccharomyces cerevisiae is a typical polysaccharide with various biological effects and is considered a candidate for the prevention and treatment of cancer in vitro. Research into the function of (1→3)-β-d-glucan in tumor-bearing animals in vivo, however, is limited. Here, we investigated the effects of (1→3)-β-d-glucan from S. cerevisiae on S180 tumor-bearing mice and on the immunity of the tumor-bearing host. The molecular mechanisms underlying the observed effects were investigated. (1→3)-β-d-Glucan was shown to exert anti-tumor effects without toxicity in normal mouse cells. The volume and weight of S180 tumors decreased dramatically following treatment with (1→3)-β-d-glucan, and treatment with the polysaccharide was furthermore shown to increase the tumor inhibition rate in a dose-dependent manner. Spleen index, T lymphocyte subsets (CD 4 and CD 8 ), as well as interleukins (IL)-2, (IL-2, IL-6), and tumor necrosis factor-α were assayed to detect the immunoregulatory and anti-tumor effects after (1→3)-β-d-glucan intragastrical administration. (1→3)-β-d-Glucan was shown to significantly potentiate the mouse immune responses by, among other effects, decreasing the ratio of CD 4 to CD 8 . The expression levels of IL-2, IL-6, and TNF-α were also significantly increased by (1→3)-β-d-glucan. These results suggest that (1→3)-β-d-glucan enhances the host's immune function during the tumor inhibition process. S180 tumor cells treated with (1→3)-β-d-glucan also exhibited significant apoptotic characteristics. (1→3)-β-d-glucan increased the ratio of Bax to Bcl-2 at the translation level by up-regulating Bax expression and down-regulating Bcl-2 expression, resulting in the initiation of cell apoptosis in S180 tumor-bearing mice. Taken together, these results indicate that the anti-tumor effects exerted by (1→3)-β-d-glucan may be attributed to the polysaccharide's immunostimulating properties and apoptosis

A color-coded reporter model to study the effect of immunosuppressants on CD8+ T-cell memory in antitumor and alloimmune responses.

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Rovira, Jordi; Sabet-Baktach, Manije; Eggenhofer, Elke; Lantow, Margareta; Koehl, Gudrun E; Schlitt, Hans J; Campistol, Josep M; Geissler, Edward K; Kroemer, Alexander

2013-01-15

Mammalian target of rapamycin (mTOR) inhibitors possess anticancer properties potentially useful in reducing posttransplantation malignancy. Besides controlling tumor-sensitive proliferative and angiogenic effects, mTOR influences transcription factors T-bet and Eomesodermin (Eomes) in CD8 cytotoxic T cells (Tc), which are key in rejecting tumors, and allografts. To study the role of mTOR in tumor and transplant immunity in an antigen-specific way, we used T-cell receptor transgenic B6.OTI recipients, B6.OVA.TG donors, and OVA-B16F10 melanoma cells. For tracking color-coded OTI-Tc cells associated with antitumor and alloimmunity in vivo, CD8-OTI transgenic reporter mice were created by crossbreeding DsRed-expressing B6.Nagy mice with B6.OTI mice. The role of mTOR in regulating the differentiation and function of alloreactive Tc cells in vitro was explored by stimulating OTI-Tc cells with ovalbumin-transgenic antigen-presenting cells in the presence of rapamycin or tacrolimus. Rapamycin, but not tacrolimus, induced a pro-antitumor phenotypic shift from CD62LCD44 effector memory Tc cells to CD62LCD44 central memory Tc cells, which featured up-regulated levels of T-bet and Eomes and preserved levels of interferon-γ and perforin. For future investigations, an in vivo model was established whereby DsRedOTI-Tc cells adoptively transferred into B6 mice bearing either a ovalbumin-transgenic mouse skin transplant or OVA-B16F10 tumor could be traced by fluorescence-activated cell sorting analysis as effector or memory Tc cells in transplant and tumor tissues. mTOR, but not calcineurin, inhibition spares antitumoral memory Tc cells by distinctively regulating T-bet and Eomes. This finding is now testable in a new tumor transplant model, which incorporates DsRedOTI-Tc cell tracing, opening the way to study the differential effects of immunosuppressants in posttransplantation malignancy.

Effect of anhydrosophoradiol-3-acetate of Calotropis gigantea (Linn.) flower as antitumoric agent against Ehrlich's ascites carcinoma in mice.

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Habib, Muhammad R; Karim, Muhammad R

2013-01-01

Over 60% of currently used anti-cancer agents are derived in one-way or another from natural sources, including plants, marine organisms and microorganisms. Calotropis gigantea (Linn.) (Family: Asclepiadaceae) is a perennial shrub and it is used as a traditional folk medicine for the treatment of various health complications. But there is no report on isolation of anticancerous chemicals from the flower of Calotropis gigantea. The objective of the present study is to explore the antitumor effect of anhydrosophoradiol-3-acetate (A3A), isolated from the flower of Calotropis gigantea (Linn.) against Ehrlich's ascites carcinoma (EAC) in Swiss albino mice. Antitumoric effect of A3A was assessed by evaluating viable tumor cell count, survival time, body weight gain due to tumor burden, hematological and biochemical (glucose, cholesterol, triglyceride, blood urea, SALP, SGPT and SGOT) parameters of EAC bearing host at doses of 10 and 20 mg/kg body weight. Treatment with A3A decreased the viable tumor cells and body weight gain thereby increasing the life span of EAC bearing mice. A3A also brought back the altered hematological (Hb, total RBC and total WBC) and biochemical parameters more or less to normal level. Results of this study conclude that in vivo the A3A was effective in inhibiting the growth of EAC with improving in cancer induced complications.

Poly (I:C) enhances the anti-tumor activity of canine parvovirus NS1 protein by inducing a potent anti-tumor immune response.

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Gupta, Shishir Kumar; Yadav, Pavan Kumar; Tiwari, A K; Gandham, Ravi Kumar; Sahoo, A P

2016-09-01

The canine parvovirus NS1 (CPV2.NS1) protein selectively induces apoptosis in the malignant cells. However, for an effective in vivo tumor treatment strategy, an oncolytic agent also needs to induce a potent anti-tumor immune response. In the present study, we used poly (I:C), a TLR3 ligand, as an adjuvant along with CPV2.NS1 to find out if the combination can enhance the oncolytic activity by inducing a potent anti-tumor immune response. The 4T1 mammary carcinoma cells were used to induce mammary tumor in Balb/c mice. The results suggested that poly (I:C), when given along with CPV2.NS1, not only significantly reduced the tumor growth but also augmented the immune response against tumor antigen(s) as indicated by the increase in blood CD4+ and CD8+ counts and infiltration of immune cells in the tumor tissue. Further, blood serum analysis of the cytokines revealed that Th1 cytokines (IFN-γ and IL-2) were significantly upregulated in the treatment group indicating activation of cell-mediated immune response. The present study reports the efficacy of CPV2.NS1 along with poly (I:C) not only in inhibiting the mammary tumor growth but also in generating an active anti-tumor immune response without any visible toxicity. The results of our study may help in developing CPV2.NS1 and poly (I: C) combination as a cancer therapeutic regime to treat various malignancies.

Gene Electrotransfer of Plasmid with Tissue Specific Promoter Encoding shRNA against Endoglin Exerts Antitumor Efficacy against Murine TS/A Tumors by Vascular Targeted Effects.

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Monika Stimac

Full Text Available Vascular targeted therapies, targeting specific endothelial cell markers, are promising approaches for the treatment of cancer. One of the targets is endoglin, transforming growth factor-β (TGF-β co-receptor, which mediates proliferation, differentiation and migration of endothelial cells forming neovasculature. However, its specific, safe and long-lasting targeting remains the challenge. Therefore, in our study we evaluated the transfection efficacy, vascular targeted effects and therapeutic potential of the plasmid silencing endoglin with the tissue specific promoter, specific for endothelial cells marker endothelin-1 (ET (TS plasmid, in comparison to the plasmid with constitutive promoter (CON plasmid, in vitro and in vivo. Tissue specificity of TS plasmid was demonstrated in vitro on several cell lines, and its antiangiogenic efficacy was demonstrated by reducing tube formation of 2H11 endothelial cells. In vivo, on a murine mammary TS/A tumor model, we demonstrated good antitumor effect of gene electrotransfer (GET of either of both plasmids in treatment of smaller tumors still in avascular phase of growth, as well as on bigger tumors, already well vascularized. In support to the observations on predominantly vascular targeted effects of endoglin, histological analysis has demonstrated an increase in necrosis and a decrease in the number of blood vessels in therapeutic groups. A significant antitumor effect was observed in tumors in avascular and vascular phase of growth, possibly due to both, the antiangiogenic and the vascular disrupting effect. Furthermore, the study indicates on the potential use of TS plasmid in cancer gene therapy since the same efficacy as of CON plasmid was determined.

Gene Electrotransfer of Plasmid with Tissue Specific Promoter Encoding shRNA against Endoglin Exerts Antitumor Efficacy against Murine TS/A Tumors by Vascular Targeted Effects.

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Stimac, Monika; Dolinsek, Tanja; Lampreht, Ursa; Cemazar, Maja; Sersa, Gregor

2015-01-01

Vascular targeted therapies, targeting specific endothelial cell markers, are promising approaches for the treatment of cancer. One of the targets is endoglin, transforming growth factor-β (TGF-β) co-receptor, which mediates proliferation, differentiation and migration of endothelial cells forming neovasculature. However, its specific, safe and long-lasting targeting remains the challenge. Therefore, in our study we evaluated the transfection efficacy, vascular targeted effects and therapeutic potential of the plasmid silencing endoglin with the tissue specific promoter, specific for endothelial cells marker endothelin-1 (ET) (TS plasmid), in comparison to the plasmid with constitutive promoter (CON plasmid), in vitro and in vivo. Tissue specificity of TS plasmid was demonstrated in vitro on several cell lines, and its antiangiogenic efficacy was demonstrated by reducing tube formation of 2H11 endothelial cells. In vivo, on a murine mammary TS/A tumor model, we demonstrated good antitumor effect of gene electrotransfer (GET) of either of both plasmids in treatment of smaller tumors still in avascular phase of growth, as well as on bigger tumors, already well vascularized. In support to the observations on predominantly vascular targeted effects of endoglin, histological analysis has demonstrated an increase in necrosis and a decrease in the number of blood vessels in therapeutic groups. A significant antitumor effect was observed in tumors in avascular and vascular phase of growth, possibly due to both, the antiangiogenic and the vascular disrupting effect. Furthermore, the study indicates on the potential use of TS plasmid in cancer gene therapy since the same efficacy as of CON plasmid was determined.

Novel synergistic antitumor effects of rapamycin with bortezomib on hepatocellular carcinoma cells and orthotopic tumor model

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Wang Cun

2012-05-01

Full Text Available Abstract Background Despite recent advances in the treatment of hepatocellular carcinoma (HCC, the chemotherapy efficacy against HCC is still unsatisfactory. The mammalian target of rapamycin (mTOR has been emerged as an important cancer therapeutic target. However, HCC cells often resistant to rapamycin because of the paradoxical activation of Akt by rapamycin. In this study, we investigated whether bortezomib could enhance the antitumor effects of rapamycin. Methods The effects of rapamycin and bortezomib on HCC proliferation, apoptosis, migration, and invasiveness in vitro were assessed by CCK-8 analysis, flow cytometry, Hoechst 33342 staining and transwell assays, respectively. Total and phosphorylated protein levels of Akt were detected by Western blotting. The effects of rapamycin and/or bortezomib on the mRNA expression levels of p53, p27, p21 and Bcl-2 family in HCCLM3 cells were evaluated by RT-PCR. The roles of rapamycin and bortezomib on HCC growth and metastasis in xenograft models were evaluated by tumor volumes and fluorescent signals. The effects of rapamycin and bortezomib on cell proliferation and apoptosis in vivo were test by PCNA and TUNEL staining. Results Bortezomib synergized with rapamycin to reduce cell growth, induce apoptosis, and inhibit cell mobility in vitro. Further mechanistic studies showed that bortezomib inhibited rapamycin-induced phosphorylated Akt, which in turn enhanced apoptosis of HCC cell lines. The alteration of the mRNA expression of cell cycle inhibitors p53, p27, p21 and apoptosis associated genes Bcl-2, Bax were also involved in the synergistic antitumor effects of rapamycin and bortezomib. P53 inhibitor PFT-α significantly attenuate the effect of rapamycin and bortezomib on cell apoptosis, which indicated that the pro-apoptotic effect of rapamycin and bortezomib may be p53-dependent. Treatment of HCCLM3-R bearing nude mice with rapamycin and bortezomib significantly enhanced tumor growth

Improved Antitumor Efficacy and Pharmacokinetics of Bufalin via PEGylated Liposomes

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Yuan, Jiani; Zhou, Xuanxuan; Cao, Wei; Bi, Linlin; Zhang, Yifang; Yang, Qian; Wang, Siwang

2017-11-01

Bufalin was reported to show strong pharmacological effects including cardiotonic, antiviral, immune-regulation, and especially antitumor effects. The objective of this study was to determine the characterization, antitumor efficacy, and pharmacokinetics of bufalin-loaded PEGylated liposomes compared with bufalin entity, which were prepared by FDA-approved pharmaceutical excipients. Bufalin-loaded PEGylated liposomes and bufalin-loaded liposomes were prepared reproducibly with homogeneous particle size by the combination of thin film evaporation method and high-pressure homogenization method. Their mean particle sizes were 127.6 and 155.0 nm, mean zeta potentials were 2.24 and - 18.5 mV, and entrapment efficiencies were 76.31 and 78.40%, respectively. In vitro release profile revealed that the release of bufalin in bufalin-loaded PEGylated liposomes was slower than that in bufalin-loaded liposomes. The cytotoxicity of blank liposomes has been found within acceptable range, whereas bufalin-loaded PEGylated liposomes showed enhanced cytotoxicity to U251 cells compared with bufalin entity. In vivo pharmacokinetics indicated that bufalin-loaded PEGylated liposomes could extend or eliminate the half-life time of bufalin in plasma in rats. The results suggested that bufalin-loaded PEGylated liposomes improved the solubility and increased the drug concentration in plasma.

Dual PI3K/mTOR inhibitor BEZ235 exerts extensive antitumor activity in HER2-positive gastric cancer

International Nuclear Information System (INIS)

Zhu, Yan; Tian, Tiantian; Zou, Jianling; Wang, Qiwei; Li, Zhongwu; Li, Yanyan; Liu, Xijuan; Dong, Bin; Li, Na; Gao, Jing; Shen, Lin

2015-01-01

To investigate the in vitro and in vivo antitumor activity of dual PI3K/mTOR inhibitor BEZ235 (NVP-BEZ235) in HER2-positive gastric cancer. HER2-positive breast cancer cell line (BT474), HER2-positive (NCI-N87 and SNU216), and HER2-negative (MKN45) gastric cancer cell lines were used in this study. Cell viability, cell cycle, and HER2 downstream signaling pathways were analyzed using the MTS assay, flow cytometry, and western blotting, respectively. For the in vivo experiments, HER2-positive gastric cancer patient-derived xenografts were treated with BEZ235 to assess its antitumor activity. The sensitivity of trastuzumab in BT474 cells was higher than that for NCI-N87 and SNU216 cells, which may be partially attributed to continuously active HER2 downstream signaling pathway. BEZ235 inhibited the proliferation of NCI-N87 and SNU216 cells in vitro in a dose-dependent manner by inducing the cell cycle arrest at the G1 phase. BEZ235 demonstrated greater inhibitory effects than trastuzumab, a unique targeted drug, in both the in vitro and in vivo set of experiments. Additionally, our results indicate that BEZ235 displayed some synergism with trastuzumab. BEZ235 exhibited its antitumor activity in gastric cancer by inhibiting important HER2 downstream signaling pathways, as indicated by the inhibition of phosphorylated AKT and S6. The present study has demonstrated, for the first time, the antitumor activity of BEZ235 against HER2-positive gastric cancer in patient-derived xenografts, as well its synergistic interaction with trastuzumab. These important findings can be utilized to facilitate the design of future clinical trials. The online version of this article (doi:10.1186/s12885-015-1900-y) contains supplementary material, which is available to authorized users

Anti-tumor effects of Egr-IFN gamma gene therapy combined with {sup 125}I-UdR radionuclide therapy

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Jingguo, Zhao [No.403 Hospital of PLA, Dalian (China); Yanjun, Ni; Xiangfu, Song; Yanyi, Li; Wei, Yang; Ting, Sun; Qingjie, Ma; Fengtong, Gao

2008-12-15

Objective: To explore the anti-tumor effects of Egr-IFNgamma gene therapy combined with {sup 125}I-UdR radionuclide therapy in mice bearing H22 hepatocarcinoma and its mechanism. Methods: The recombinant plasmid pcDNAEgr-IFNgamma mixed with liposome was injected into tumor. 48 h later, 370 kBq {sup 125}I-UdR was injected into tumor. The tumor growth rates at different times were observed. After 3 d gene-radionuclide therapy, the concentration of IFNgamma in cytoplasm of H22 cells and cytotoxic activities of splenic CTL of the mice in different groups were examined. Results: The tumor growth rates of pcDNAEgr-IFNgamma + {sup 125}I-UdR group were obviously lower than those of control group, {sup 125}I-UdR group and pcDNAEgr-1 + {sup 125}I-UdR group 6-15 d after gene-radionuclide therapy. IFNgamma protein was found in cytoplasm of H22 cells in pcDNAEgr-IFNgamma + {sup 125}I-UdR group after 3 d gene-radionuclide therapy. Cytotoxic activity of splenic CTL in pcDNAEgr-IFNgamma + {sup 125}I-UdR group was significantly higher than that in the other groups (P<0.01). Conclusions: The anti-tumor effects in vivo of pcDNAEgr-IFNgamma gene therapy combined with {sup 125}I-UdR radionuclide therapy are better than those of {sup 125}I-UdR therapy. (authors)

Synthesis and antitumor evaluation of arctigenin derivatives based on antiausterity strategy.

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Kudou, Naoki; Taniguchi, Akira; Sugimoto, Kenji; Matsuya, Yuji; Kawasaki, Masashi; Toyooka, Naoki; Miyoshi, Chika; Awale, Suresh; Dibwe, Dya Fita; Esumi, Hiroyasu; Kadota, Shigetoshi; Tezuka, Yasuhiro

2013-02-01

A series of new (-)-arctigenin derivatives with variably modified O-alkyl groups were synthesized and their preferential cytotoxicity was evaluated against human pancreatic cancer cell line PANC-1 under nutrient-deprived conditions. The results showed that monoethoxy derivative 4i (PC(50), 0.49 μM), diethoxy derivative 4h (PC(50), 0.66 μM), and triethoxy derivative 4m (PC(50), 0.78 μM) showed the preferential cytotoxicities under nutrient-deprived conditions, which were identical to or more potent than (-)-arctigenin (1) (PC(50), 0.80 μM). Among them, we selected the triethoxy derivative 4m and examined its in vivo antitumor activity using a mouse xenograft model. Triethoxy derivative 4m exhibited also in vivo antitumor activity with the potency identical to or slightly more than (-)-arctigenin (1). These results would suggest that a modification of (-)-arctigenin structure could lead to a new drug based on the antiausterity strategy. Copyright © 2012 Elsevier Masson SAS. All rights reserved.

Antitumor-promoting activity of scopadulcic acid B, isolated from the medicinal plant Scoparia dulcis L.

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Nishino, H; Hayashi, T; Arisawa, M; Satomi, Y; Iwashima, A

1993-01-01

Scopadulcic acid B (SDB), a tetracyclic diterpenoid isolated from a medicinal plant, Scoparia dulcis L., inhibited the effects of tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) in vitro and in vivo; SDB inhibited TPA-enhanced phospholipid synthesis in cultured cells, and also suppressed the promoting effect of TPA on skin tumor formation in mice initiated with 7,12-dimethylbenz[a]anthracene. The potency of SDB proved to be stronger than that of other natural antitumor-promoting terpenoids, such as glycyrrhetinic acid.

Evaluation of cytotoxic and antitumoral properties of Tessaria absinthioides (Hook & Arn DC, "pájaro bobo", aqueous extract

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Fabio A. Persia

2017-08-01

Full Text Available Higher plants have provided various natural derived drugs used currently in western medicine. Tessaria absinthioides (Hook. & Arn. DC, Asteraceae, is a native plant from South-America with reported ethnopharmacological and culinary uses. Despite recent scientific reports about plants properties, there is not a well conducted research about its anticancer and potential toxic effects. The current work demonstrates the plant aqueous extract composition; the in vitro induced cytotoxicity, and explores, in vivo, its oral toxicity and antitumoral effects. Composition of aqueous extract was determined by phytochemical reactions. Cytotoxicity was tested in tumoral (Hela, Gli-37, HCT-116 and MCF-7 and non-tumoral (HBL-100 cells, using MTT assay. Oral toxicity and the antitumor activity against colorectal carcinoma were studied in rodents. The chemical analysis revealed the presence of flavonoids, carbohydrates, sterols, terpenes and tannins. Cytotoxicity towards tumoral cells was observed (CV50: 3.0 to 14.8 ug/ml; while in non-tumoral cells, extracts evidenced a selective reduced toxicity (CV50: 29.5 ug/ml. Oral administration of the extract does not induce acute nor dose-repeated toxicity at doses up to 2000 mg/kg and 1000 mg/kg/day, respectively. The antitumoral effect was confirmed by a significant increase in a median survival from 24 weeks (non-treated to 30 weeks (T. absinthioides treated. The present data indicate that T. absinthioides extract exhibits cytotoxicity against cancer cell lines, with no-toxic effects and significant antitumoral effects in colorectal cancer when is orally administrated. In conclusion, T. absinthioides possesses selective cytotoxicity and antitumoral activities, making its plant derivatives products promising for cancer research and treatment.

Role of a bacillus Calmette-Guérin fibronectin attachment protein in BCG-induced antitumor activity.

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Zhao, W; Schorey, J S; Bong-Mastek, M; Ritchey, J; Brown, E J; Ratliff, T L

2000-04-01

Intravesical Mycobacterium bovis bacillus Calmette-Gu*erin (BCG) is the treatment of choice for superficial bladder cancer. Previous studies showed that attachment of BCG to fibronectin within the bladder was necessary for mediation of the antitumor response. Further studies identified a bacterial receptor, fibronectin attachment protein (FAP), as an important mediator of BCG attachment to fibronectin. In vitro studies showed that a stable BCG/fibronectin interaction was dependent on FAP binding to fibronectin; however, no role for FAP in the attachment of BCG in vivo has been characterized. We now report the cloning of the M. bovis BCG FAP (FAP-B) and demonstrate an important role for FAP in the in vivo attachment of BCG to the bladder wall and in the induction of BCG-mediated antitumor activity. The predicted amino acid sequence for FAP-B shows 61% and 71% homology, respectively, with Mycobacterium avium FAP (FAP-A) and Mycobacterium leprae FAP (FAP-L). Rabbit polyclonal antibodies against Mycobacterium vaccae FAP (FAP-V) reacted with all 3 recombinant FAP proteins on Western blots. Functional studies show FAP-B to bind fibronectin via the highly conserved attachment regions previously identified for FAP-A and FAP-L and also to competitively inhibit attachment of BCG to matrix fibronectin. In vivo studies show FAP to be a necessary protein for the stable attachment of BCG to the bladder wall. Moreover, stable binding of BCG via FAP was shown to be necessary for the expression of BCG-induced antitumor activity. Our results demonstrate a biological role for FAP in the mediation of BCG-induced antitumor activity.

Amplexicaule A exerts anti-tumor effects by inducing apoptosis in human breast cancer

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Xiang, Meixian; Su, Hanwen; Shu, Guangwen; Wan, Dingrong; He, Feng; Loaec, Morgann; Ding, Yali; Li, Jun; Dovat, Sinisa; Yang, Gaungzhong; Song, Chunhua

2016-01-01

Chemotherapy is the main treatment for patients with breast cancer metastases, but natural alternatives have been receiving attention for their potential as novel anti-tumor reagents. Amplexicaule A (APA) is a flavonoid glucoside isolated from rhizomes of Polygonum amplexicaule D. Don var. sinense Forb (PADF). We found that APA has anti-tumor effects in a breast cancer xenograft mouse model and induces apoptosis in breast cancer cell lines. APA increased levels of cleaved caspase-3,-8,-9 and ...

TCR-Engineered, Customized, Antitumor T Cells for Cancer Immunotherapy: Advantages and Limitations

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Arvind Chhabra

2011-01-01

Full Text Available The clinical outcome of the traditional adoptive cancer immunotherapy approaches involving the administration of donor-derived immune effectors, expanded ex vivo, has not met expectations. This could be attributed, in part, to the lack of sufficient high-avidity antitumor T-cell precursors in most cancer patients, poor immunogenicity of cancer cells, and the technological limitations to generate a sufficiently large number of tumor antigen-specific T cells. In addition, the host immune regulatory mechanisms and immune homeostasis mechanisms, such as activation-induced cell death (AICD, could further limit the clinical efficacy of the adoptively administered antitumor T cells. Since generation of a sufficiently large number of potent antitumor immune effectors for adoptive administration is critical for the clinical success of this approach, recent advances towards generating customized donor-specific antitumor-effector T cells by engrafting human peripheral blood-derived T cells with a tumor-associated antigen-specific transgenic T-cell receptor (TCR are quite interesting. This manuscript provides a brief overview of the TCR engineering-based cancer immunotherapy approach, its advantages, and the current limitations.

TCR-engineered, customized, antitumor T cells for cancer immunotherapy: advantages and limitations.

Science.gov (United States)

Chhabra, Arvind

2011-01-05

The clinical outcome of the traditional adoptive cancer immunotherapy approaches involving the administration of donor-derived immune effectors, expanded ex vivo, has not met expectations. This could be attributed, in part, to the lack of sufficient high-avidity antitumor T-cell precursors in most cancer patients, poor immunogenicity of cancer cells, and the technological limitations to generate a sufficiently large number of tumor antigen-specific T cells. In addition, the host immune regulatory mechanisms and immune homeostasis mechanisms, such as activation-induced cell death (AICD), could further limit the clinical efficacy of the adoptively administered antitumor T cells. Since generation of a sufficiently large number of potent antitumor immune effectors for adoptive administration is critical for the clinical success of this approach, recent advances towards generating customized donor-specific antitumor-effector T cells by engrafting human peripheral blood-derived T cells with a tumor-associated antigen-specific transgenic T-cell receptor (TCR) are quite interesting. This manuscript provides a brief overview of the TCR engineering-based cancer immunotherapy approach, its advantages, and the current limitations.

Differential Antitumoral Properties and Renal-Associated Tissue Damage Induced by Tacrolimus and Mammalian Target of Rapamycin Inhibitors in Hepatocarcinoma: In Vitro and In Vivo Studies.

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Elena Navarro-Villarán

Full Text Available Orthotopic liver transplantation (OLT is the recommended treatment for patients at early stages of hepatocarcinoma (HCC with potential portal hypertension and/or bilirubinemia, but without vascular-associated diseases. The patients are receiving immunosuppressive therapy to reduce graft rejection, but differential side effects have been related to calcineurin and mTOR inhibitor administration regarding tumor recurrence and nephrotoxicity. The in vitro studies showed that Tacrolimus exerted a more potent pro-apoptotic effect than Everolimus (Huh 7>Hep 3B>HepG2, being sirolimus only active in Hep3B cell line. Tacrolimus and Everolimus exerted potent antiproliferative properties in Huh 7 and Hep3B in which cells Sirolimus was inactive. Interestingly, Tacrolimus- and Everolimus-dependent G0/G1 cell accumulation occurred as a consequence of drastic reduction in S, as well as in S and G2+M phases, respectively. The in vivo studies support data on the more effective antitumoral properties of Everolimus, eventual risk of pro-angiogenic tumoral properties and nephrotoxicity of Tacrolimus, and pro-proliferative properties of Sirolimus in tumors developed in nude mice.

A novel polysaccharide from Ganoderma atrum exerts antitumor activity by activating mitochondria-mediated apoptotic pathway and boosting the immune system.

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Zhang, Shenshen; Nie, Shaoping; Huang, Danfei; Feng, Yanling; Xie, Mingyong

2014-02-19

Ganoderma is a precious health-care edible medicinal fungus in China. A novel Ganoderma atrum polysaccharide (PSG-1) is the main bioactive component. We investigated the antitumor effect and molecular mechanisms of PSG-1. It exhibited no significant effect on cell proliferation directly. In contrast, administration of PSG-1 markedly suppressed tumor growth in CT26 tumor-bearing mice. It was observed that PSG-1 caused apoptosis in CT26 cells. Apoptosis was associated with loss of mitochondrial membrane potential, enhancement of mitochondrial cytochrome c release and intracellular ROS production, elevation of p53 and Bax expression, downregulation of Bcl-2, and the activation of caspase-9 and -3. Moreover, PSG-1 enhanced immune organ index and promoted lymphocyte proliferation as well as cytokine levels in serum. Taken together, our data indicate that PSG-1 has potential antitumor activity in vivo by inducing apoptosis via mitochondria-mediated apoptotic pathway and enhances host immune system function. Therefore, PSG-1 could be a safe and effective antitumor, bioactive agent or functional food.

Experimental study on anti-tumor effect of pcEgr-IFNγ gene-radiotherapy

International Nuclear Information System (INIS)

Wu Congmei; Li Xiuyi; Liu Shuzheng

2001-01-01

Objective: To study the anti-tumor effect of IFN γ gene-radiotherapy to murine melanoma and its immunologic mechanism. Methods: pcEgr-IFNγ plasmids were injected locally into tumor, and 36 hours later, the tumors were given 20 Gy X-ray irradiation. Tumor growth at different time, IFN γ expression 3 days later and immunologic indexes 15 days later were detected. Results: At 3-15 days after pcEgr-IFNγ gene-radiotherapy, the tumor growth rate was lower than that of irradiation alone group. It was also lower than that of gene therapy alone group and control plasmid combined with X-ray irradiation group significantly. Day 3 tumor IFN γ expression was higher than that of plasmid treatment alone group. NK activity, IL-2 and IFN γ secretion activities were higher than those of gene therapy alone and irradiation alone groups significantly. Conclusion: The antitumor effect of IFN γ gene-radiotherapy is better than that of either of them applied solely. Its mechanism might be concerned with the higher expression of IFN γ induced by irradiation in tumors and activation of anti-tumor immunologic functions

A novel lipid-based nanomicelle of docetaxel: evaluation of antitumor activity and biodistribution

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Ma M

2012-07-01

Full Text Available Mingshu Ma,1 Yanli Hao,1 Nan Liu,1 Zhe Yin,1 Lan Wang,1 Xingjie Liang,2 Xiaoning Zhang11Department of Pharmacology and Pharmaceutical Sciences, School of Medicine, Tsinghua University, Beijing, China; 2National Center for Nanoscience and Technology, Beijing, ChinaPurpose: A lipid-based, nanomicelle-loaded docetaxel (M-DOC was designed and characterized. Optical imaging was employed to evaluate the pharmacokinetics and antitumor efficacy of docetaxel in vivo.Materials and methods: The M-DOC was prepared using the emulsion-diffusion method. Transmission electron microscopy and dynamic light scattering were used to assess the morphology and particle size of the M-DOC. Critical micelle concentrations, their stability under physiological conditions, and their encapsulation efficiency – as measured by high-performance liquid chromatography – were assessed. Pharmacological features were evaluated in two different animal models by comparing M-DOC treatments with docetaxel injections (I-DOC. Bioluminescence imaging was used to assess antitumor activity and docetaxel distribution in vivo, using nude mice injected with luciferase-expressing MDA-MB-231 human breast tumor cells. In addition, animals injected with B16 melanoma cells were used to measure survival time and docetaxel distribution.Results: The M-DOC was prepared as round, uniform spheres with an effective diameter of 20.8 nm. The critical micelle concentration of the original emulsion was 0.06%. Satisfactory encapsulation efficiency (87.6% ± 3.0% and 12-hour stability were achieved. Xenograft results demonstrated that the M-DOC was more effective in inhibiting tumor growth, without significantly changing body weight. Survival was prolonged by 12.6% in the M-DOC group. Tumor growth inhibitory rates in the M-DOC and I-DOC groups were 91.2% and 57.8% in volume and 71.8% and 44.9% in weight, respectively. Optical bioluminescence imaging of tumor growths yielded similar results. Area under the

Activation of antitumor immune responses by Ganoderma formosanum polysaccharides in tumor-bearing mice.

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Wang, Cheng-Li; Lu, Chiu-Ying; Hsueh, Ying-Chao; Liu, Wen-Hsiung; Chen, Chun-Jen

2014-11-01

Fungi of the genus Ganoderma are basidiomycetes that have been used as traditional medicine in Asia and have been shown to exhibit various pharmacological activities. We recently found that PS-F2, a polysaccharide fraction purified from the submerged culture broth of Ganoderma formosanum, stimulates the maturation of dendritic cells and primes a T helper 1 (Th1)-polarized adaptive immune response in vivo. In this study, we investigated whether the immune adjuvant function of PS-F2 can stimulate antitumor immune responses in tumor-bearing mice. Continuous intraperitoneal or oral administration of PS-F2 effectively suppressed the growth of colon 26 (C26) adenocarcinoma, B16 melanoma, and sarcoma 180 (S180) tumor cells in mice without adverse effects on the animals' health. PS-F2 did not cause direct cytotoxicity on tumor cells, and it lost the antitumor effect in mice with severe combined immunodeficiency (SCID). CD4(+) T cells, CD8(+) T cells, and serum from PS-F2-treated tumor-bearing mice all exhibited antitumor activities when adoptively transferred to naïve animals, indicating that PS-F2 treatment stimulates tumor-specific cellular and humoral immune responses. These data demonstrate that continuous administration of G. formosanum polysaccharide PS-F2 can activate host immune responses against ongoing tumor growth, suggesting that PS-F2 can potentially be developed into a preventive/therapeutic agent for cancer immunotherapy.

Antioxidants Impair Anti-Tumoral Effects of Vorinostat, but Not Anti-Neoplastic Effects of Vorinostat and Caspase-8 Downregulation

OpenAIRE

Bergadà, Laura; Yeramian, Andree; Sorolla, Annabel; Matias-Guiu, Xavier; Dolcet, Xavier

2014-01-01

We have recently demonstrated that histone deacetylase inhibitor, Vorinostat, applied as a single therapy or in combination with caspase-8 downregulation exhibits high anti-tumoral activity on endometrial carcinoma cell lines. In the present study, we have assessed the signalling processes underlying anti-tumoral effects of Vorinostat. Increasing evidence suggests that reactive oxygen species are responsible for histone deacetylase inhibitor-induced cell killing. We have found that Vorinostat...

d-α-Tocopheryl polyethylene glycol succinate/Solutol HS 15 mixed micelles for the delivery of baohuoside I against non-small-cell lung cancer: optimization and in vitro, in vivo evaluation.

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Yan, Hongmei; Zhang, Zhenhai; Jia, Xiaobin; Song, Jie

Baohuoside I, extracted from the Herba epimedii, is an effective but a poorly soluble antitumor drug. To improve its solubility, formulation of baohuoside I-loaded mixed micelles with d-α-tocopheryl polyethylene glycol succinate and Solutol HS 15 (BTSM) has been developed in this study. We performed a systematic comparative evaluation of the antiproliferative effect, cellular uptake, antitumor efficacy, and in vivo tumor targeting of these micelles using non-small-cell lung cancer (NSCLC) A549 cells. Results showed that the obtained micelles have a mean particle size of ~62.54 nm, and the size of micelles was narrowly distributed. With the improved cellular uptake, BTSM displayed a more potent anti-proliferative action on A549 cell lines than baohuoside I; half-maximal inhibitory concentration was 7.83 vs 20.37 µg/mL, respectively. The antitumor efficacy test in nude mice showed that BTSM exhibited significantly higher antitumor activity against NSCLC with lesser toxic effects on normal tissues. The imaging study for in vivo targeting demonstrated that the mixed micelles formulation achieved effective and targeted drug delivery. Therefore, BTSM might be a potential antitumor formulation.

Antitumor and biological effects of black pine (Pinus nigra) pollen nuclease

Czech Academy of Sciences Publication Activity Database

Lipovová, P.; Podzimek, T.; Orctová, Lidmila; Matoušek, Jaroslav; Poučková, P.; Souček, J.; Matoušek, Josef

2008-01-01

Roč. 55, - (2008), s. 158-164 ISSN 0028-2685 Institutional research plan: CEZ:AV0Z50510513; CEZ:AV0Z50450515 Keywords : pollen nuclease * Antitumor effect Subject RIV: FD - Oncology ; Hematology Impact factor: 1.179, year: 2008

Anti-tumor effects of an engineered 'killer' transfer RNA

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Zhou, Dong-hui [Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL 60637 (United States); Lee, Jiyoung; Frankenberger, Casey [Ben May Department for Cancer Research, University of Chicago, Chicago, IL 60637 (United States); Geslain, Renaud, E-mail: rgeslain@depaul.edu [Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL 60637 (United States); Department of Biology, DePaul University, Chicago, IL 60614 (United States); Rosner, Marsha, E-mail: m-rosner@uchicago.edu [Ben May Department for Cancer Research, University of Chicago, Chicago, IL 60637 (United States); Pan, Tao, E-mail: taopan@uchicago.edu [Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL 60637 (United States)

2012-10-12

Highlights: Black-Right-Pointing-Pointer tRNA with anti-cancer effects. Black-Right-Pointing-Pointer tRNA induced protein misfolding. Black-Right-Pointing-Pointer tRNA as anti-tumor agent. -- Abstract: A hallmark of cancer cells is their ability to continuously divide; and rapid proliferation requires increased protein translation. Elevating levels of misfolded proteins can elicit growth arrest due to ER stress and decreased global translation. Failure to correct prolonged ER stress eventually results in cell death via apoptosis. tRNA{sup Ser}(AAU) is an engineered human tRNA{sup Ser} with an anticodon coding for isoleucine. Here we test the possibility that tRNA{sup Ser}(AAU) can be an effective killing agent of breast cancer cells and can effectively inhibit tumor-formation in mice. We found that tRNA{sup Ser}(AAU) exert strong effects on breast cancer translation activity, cell viability, and tumor formation. Translation is strongly inhibited by tRNA{sup Ser}(AAU) in both tumorigenic and non-tumorigenic cells. tRNA{sup Ser}(AAU) significantly decreased the number of viable cells over time. A short time treatment with tRNA{sup Ser}(AAU) was sufficient to eliminate breast tumor formation in a xenograft mouse model. Our results indicate that tRNA{sup Ser}(AAU) can inhibit breast cancer metabolism, growth and tumor formation. This RNA has strong anti-cancer effects and presents an opportunity for its development into an anti-tumor agent. Because tRNA{sup Ser}(AAU) corrupts the protein synthesis mechanism that is an integral component of the cell, it would be extremely difficult for tumor cells to evolve and develop resistance against this anti-tumor agent.

Synergistic antitumor effect of 3-bromopyruvate and 5-fluorouracil against human colorectal cancer through cell cycle arrest and induction of apoptosis.

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Chong, Dianlong; Ma, Linyan; Liu, Fang; Zhang, Zhirui; Zhao, Surong; Huo, Qiang; Zhang, Pei; Zheng, Hailun; Liu, Hao

2017-09-01

3-Bromopyruvic acid (3-BP) is a well-known inhibitor of energy metabolism. It has been proposed as an anticancer agent as well as a chemosensitizer for use in combination with anticancer drugs. 5-Fluorouracil (5-FU) is the first-line chemotherapeutic agent for colorectal cancer; however, most patients develop resistance to 5-FU through various mechanisms. The aim of this study was to investigate whether 3-BP has a synergistic antitumor effect with 5-FU on human colorectal cancer cells. In our study, combined 3-BP and 5-FU treatment upregulated p53 and p21, whereas cyclin-dependent kinase CDK4 and CDK2 were downregulated, which led to G0/G1 phase arrest. Furthermore, there was an increase in reactive oxygen species levels and a decrease in adenosine triphosphate levels. It was also observed that Bax expression increased, whereas Bcl-2 expression reduced, which were indicative of mitochondria-dependent apoptosis. In addition, the combination of 3-BP and 5-FU significantly suppressed tumor growth in the BALB/c mice in vivo. Therefore, 3-BP inhibits tumor proliferation and induces S and G2/M phase arrest. It also exerts a synergistic antitumor effect with 5-FU on SW480 cells.

Combining antiangiogenic therapy with adoptive cell immunotherapy exerts better antitumor effects in non-small cell lung cancer models.

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Shujing Shi

Full Text Available INTRODUCTION: Cytokine-induced killer cells (CIK cells are a heterogeneous subset of ex-vivo expanded T lymphocytes which are characterized with a MHC-unrestricted tumor-killing activity and a mixed T-NK phenotype. Adoptive CIK cells transfer, one of the adoptive immunotherapy represents a promising nontoxic anticancer therapy. However, in clinical studies, the therapeutic activity of adoptive CIK cells transfer is not as efficient as anticipated. Possible explanations are that abnormal tumor vasculature and hypoxic tumor microenvironment could impede the infiltration and efficacy of lymphocytes. We hypothesized that antiangiogenesis therapy could improve the antitumor activity of CIK cells by normalizing tumor vasculature and modulating hypoxic tumor microenvironment. METHODS: We combined recombinant human endostatin (rh-endostatin and CIK cells in the treatment of lung carcinoma murine models. Intravital microscopy, dynamic contrast enhanced magnetic resonance imaging, immunohistochemistry, and flow cytometry were used to investigate the tumor vasculature and hypoxic microenvironment as well as the infiltration of immune cells. RESULTS: Our results indicated that rh-endostatin synergized with adoptive CIK cells transfer to inhibit the growth of lung carcinoma. We found that rh-endostatin normalized tumor vasculature and reduced hypoxic area in the tumor microenvironment. Hypoxia significantly inhibited the proliferation, cytotoxicity and migration of CIK cells in vitro and impeded the homing of CIK cells into tumor parenchyma ex vivo. Furthermore, we found that treatment with rh-endostatin significantly increased the homing of CIK cells and decreased the accumulation of suppressive immune cells in the tumor tissue. In addition, combination therapy produced higher level of tumor-infiltration lymphocytes compared with other treatments. CONCLUSIONS: Our results demonstrate that rh-endostatin improves the therapeutic effect of adoptive CIK cells

Hydrogels based on polysaccharide-calcium phosphate with antibacterial / antitumor activity for 3D printing

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Teterina, A. Yu; Fedotov, A. Yu; Zobkov, Yu V.; Sergeeva, N. S.; Sviridova, I. K.; Kirsanova, V. A.; Karalkin, P. A.; Komlev, V. S.

2018-04-01

The purpose of this study was to develop hydrogels for 3D printing of sodium alginate/gelatin/octacalcium phosphate-based constructs with antibacterial and antitumor activity intended for bone defects replacement in patients with malignant diseases. In this work, we evaluated the drug release kinetic and physico-chemical characteristics of constructs, as well as their specific activity, biocompatibility and osteoplastic properties by means of in vitro and in vivo tests. The principal possibility of creating the biocompatible bone substitutes with antibacterial/antitumor activity and osteoconductive-retaining properties of 3D printing method was demonstrated.

Establishment of a novel clear cell sarcoma cell line (Hewga-CCS), and investigation of the antitumor effects of pazopanib on Hewga-CCS.

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Outani, Hidetatsu; Tanaka, Takaaki; Wakamatsu, Toru; Imura, Yoshinori; Hamada, Kenichiro; Araki, Nobuhito; Itoh, Kazuyuki; Yoshikawa, Hideki; Naka, Norifumi

2014-06-19

Clear cell sarcoma (CCS) is a therapeutically unresolved, aggressive, soft tissue sarcoma (STS) that predominantly affects young adults. This sarcoma is defined by t(12;22)(q13;q12) translocation, which leads to the fusion of Ewing sarcoma gene (EWS) to activating transcription factor 1 (ATF1) gene, producing a chimeric EWS-ATF1 fusion gene. We established a novel CCS cell line called Hewga-CCS and developed an orthotopic tumor xenograft model to enable comprehensive bench-side investigation for intensive basic and preclinical research in CCS with a paucity of experimental cell lines. Hewga-CCS was derived from skin metastatic lesions of a CCS developed in a 34-year-old female. The karyotype and chimeric transcript were analyzed. Xenografts were established and characterized by morphology and immunohistochemical reactivity. Subsequently, the antitumor effects of pazopanib, a recently approved, novel, multitargeted, tyrosine kinase inhibitor (TKI) used for the treatment of advanced soft tissue sarcoma, on Hewga-CCS were assessed in vitro and in vivo. Hewga-CCS harbored the type 2 EWS-ATF1 transcript. Xenografts morphologically mimicked the primary tumor and expressed S-100 protein and antigens associated with melanin synthesis (Melan-A, HMB45). Pazopanib suppressed the growth of Hewga-CCS both in vivo and in vitro. A phospho-receptor tyrosine kinase array revealed phosphorylation of c-MET, but not of VEGFR, in Hewga-CCS. Subsequent experiments showed that pazopanib exerted antitumor effects through the inhibition of HGF/c-MET signaling. CCS is a rare, devastating disease, and our established CCS cell line and xenograft model may be a useful tool for further in-depth investigation and understanding of the drug-sensitivity mechanism.

Antitumor activity of biflorin, an o-naphthoquinone isolated from Capraria biflora.

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Vasconcellos, Marne Carvalho de; Bezerra, Daniel Pereira; Fonseca, Aluísio Marques; Pereira, Márcio Roberto Pinho; Lemos, Telma Leda Gomes; Pessoa, Otília Deusdênia Loiola; Pessoa, Cláudia; Moraes, Manoel Odorico de; Alves, Ana Paula Negreiros Nunes; Costa-Lotufo, Letícia Veras

2007-08-01

Pharmacological studies with an aqueous extract obtained from leaves of Capraria biflora showed potent cytotoxic, analgesic, antimicrobial and anti-inflammatory activities. It has been demonstrated that biflorin possesses an in vitro cytotoxic activity against tumor cells. The in vivo antitumor activity of biflorin was evaluated on two mouse models, sarcoma 180 and Ehrlich carcinoma. Biflorin was active against both tumors with a very similar profile. In addition, biflorin was also able to increase the response elicited by 5-FU in mice inoculated with both tumors. The results showed a decrease in Ki67 staining in tumor cells from treated-animals when compared with non-treated groups, which suggests an inhibition of tumor proliferation rate. Histopathological analysis from kidneys and liver showed that biflorin possessed weak and reversible toxic effects. It was also demonstrated that biflorin acts as an immunoadjuvant agent, rising the production of ovalbumin-specific antibodies and inducing a discreet increase of the white pulp and nest of megakaryocytic in spleen of treated mice, which can be related to its antitumor properties.

Selective anti-tumor activity of the novel fluoropyrimidine polymer F10 towards G48a orthotopic GBM tumors.

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Gmeiner, William H; Lema-Tome, Carla; Gibo, Denise; Jennings-Gee, Jamie; Milligan, Carol; Debinski, Waldemar

2014-02-01

F10 is a novel anti-tumor agent with minimal systemic toxicity in vivo and which displays strong cytotoxicity towards glioblastoma (GBM) cells in vitro. Here we investigate the cytotoxicity of F10 towards GBM cells and evaluate the anti-tumor activity of locally-administered F10 towards an orthotopic xenograft model of GBM. The effects of F10 on thymidylate synthase (TS) inhibition and Topoisomerase 1 (Top1) cleavage complex formation were evaluated using TS activity assays and in vivo complex of enzyme bioassays. Cytotoxicity of F10 towards normal brain was evaluated using cortices from embryonic (day 18) mice. F10 displays minimal penetrance of the blood-brain barrier and was delivered by intra-cerebral (i.c.) administration and prospective anti-tumor response towards luciferase-expressing G48a human GBM tumors in nude mice was evaluated using IVIS imaging. Histological examination of tumor and normal brain tissue was used to assess the selectivity of anti-tumor activity. F10 is cytotoxic towards G48a, SNB-19, and U-251 MG GBM cells through dual targeting of TS and Top1. F10 is not toxic to murine primary neuronal cultures. F10 is well-tolerated upon i.c. administration and induces significant regression of G48a tumors that is dose-dependent. Histological analysis from F10-treated mice revealed tumors were essentially completely eradicated in F10-treated mice while vehicle-treated mice displayed substantial infiltration into normal tissue. F10 displays strong efficacy for GBM treatment with minimal toxicity upon i.c. administration establishing F10 as a promising drug-candidate for treating GBM in human patients.

Antitumor effects of radioiodinated antisense oligonucleotide mediated by VIP receptor

International Nuclear Information System (INIS)

Ou Xiaohong; Tan Tianzhi; Li Yunchun; Kuang Anren

2004-01-01

Purpose: we had constructed a targeting delivery system based on intestinal peptide (VIP) for antisense oligonucleotide (ASON) transfer into VIP receptor-positive cells in previous study. The aims of present studies are to observe the antitumor effect of VIP-131I-ASON in HT29 human colon adenocarcinoma xenografts. Methods: A 15-met phosphorothioate ASON, which was complementary to the translation start region of the C-myc oncogene mRNA, was labeled with 131I and the labelled compound was linked to the VIP bound covalently 'to a polylysine chain so as to deliver oligonucleotide into tumor cells. Distribution experiments for evaluating the radiolabeled antisense complexe uptake in tumor tissue were performed in BALB/c nude mice bearing with HT29 tumor xenografts. Nude mice beating HT29 tumor xenografts were adminstered VIP-131I-ASON (3.7,7.4 MBq) or 131I-ASON (3.7 MBq), 131I labeled control sense and nosense DNA (3.7 MBq), or saline. Antitumor effects were assessed using endpoints of tumor growth delay. C-myc-encoded protein expression of tumor was measured by immunocytohistochemical staining. Results: Distribution experiment performed with athymic mice bearing human colon tumor xenografts revealed maximal accumulation of conjugated ASON in the tumor tissue 2 h after administration and significantly higher than that in nude mice injected unconjngated ASON [(5.89±1.03)%ID/g and(1.56±0.31)%ID/g, respectively; t=7.7954 P<0.001]. The radioratio of tumor to muscle was peaked 4h after administration. VIP-131I-ASON exhibited strong antitumor effects against HT29 xenografts, decreasing their growth rate 7-fold compare with that in saline-treated mice(tumor growth delay, 25.4±0.89 day). The antitumor effects of unconjugated 131I-ASON were much less profound than VIP-131I-ASON (tumor growth delay, 3.2±1.3 and 25.4±0.89 day, respectively; q=51.4126 P<0.01). Sense, nosense control ON with VIP carder caused no therapeutic effect. There was no progressive weight loss or

T lymphocytes derived from human cord blood provide effective antitumor immunotherapy against a human tumor

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Kim Tae-Sik

2011-06-01

Full Text Available Abstract Background Although the graft-versus-tumor (GVT effect of donor-derived T cells after allogeneic hematopoietic stem cell transplantation has been used as an effective adoptive immunotherapy, the antitumor effects of cord blood (CB transplantation have not been well studied. Methods We established the animal model by transplantation of CB mononuclear cells and/or tumor cells into NOD/SCID mice. The presence of CB derived T cells in NOD/SCID mice or tumor tissues were determined by flow cytometric and immunohistochemical analysis. The anti-tumor effects of CB derived T cells against tumor was determined by tumor size and weight, and by the cytotoxicity assay and ELISPOT assay of T cells. Results We found dramatic tumor remission following transfer of CB mononuclear cells into NOD/SCID mice with human cervical tumors with a high infiltration of CD3+ T cells in tumors. NOD/SCID mice that receive neonatal CB transplants have reconstituted T cells with significant antitumor effects against human cervical and lung tumors, with a high infiltration of CD3+ T cells showing dramatic induction of apoptotic cell death. We also confirmed that T cells showed tumor specific antigen cytotoxicity in vitro. In adoptive transfer of CD3+ T cells into mice with pre-established tumors, we observed much higher antitumor effects of HPV-specific T cells by ELISPOT assays. Conclusions Our results show that CB derived T lymphocytes will be useful for novel immunotherapeutic candidate cells for therapy of several tumors in clinic.

Poly(γ-glutamic acid)-coated lipoplexes loaded with Doxorubicin for enhancing the antitumor activity against liver tumors

Science.gov (United States)

Qi, Na; Tang, Bo; Liu, Guang; Liang, Xingsi

2017-05-01

The study was to develop poly-γ-glutamic acid (γ-PGA)-coated Doxorubicin (Dox) lipoplexes that enhance the antitumor activity against liver tumors. γ-PGA-coated lipoplexes were performed by electrostatistically attracting to the surface of cationic charge liposomes with anionic γ-PGA. With the increasing of γ-PGA concentration, the particle size of γ-PGA-coated Dox lipoplexes slightly increased, the zeta potential from positive shifted to negative, and the entrapment efficiency (EE) were no significant change. The release rate of γ-PGA-coated Dox lipoplexes slightly increased at acidic pH, the accelerated Dox release might be attributed to greater drug delivery to tumor cells, resulting in a higher antitumor activity. Especially, γ-PGA-coated Dox lipoplexes exhibited higher cellular uptake, significant in vitro cytotoxicity in HepG2 cells, and improved in vivo antitumor efficacy toward HepG2 hepatoma-xenografted nude models in comparison with Dox liposomes and free Dox solution. In addition, the analysis results via flow cytometry showed that γ-PGA-coated Dox lipoplexes induce S phase cell cycle arrest and significantly increased apoptosis rate of HepG2 cells. In conclusion, the presence of γ-PGA on the surface of Dox lipoplexes enhanced antitumor effects of liver tumors.

Delivery of vincristine sulfate-conjugated gold nanoparticles using liposomes: a light-responsive nanocarrier with enhanced antitumor efficiency

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Liu Y

2015-04-01

Full Text Available Ying Liu,1,* Man He,1,* Mengmeng Niu,1 Yiqing Zhao,1 Yuanzhang Zhu,1 Zhenhua Li,2 Nianping Feng1 1Department of Pharmaceutical Sciences, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China; 2Cedars-Sinai Medical Center, Los Angeles, CA, USA *These authors contributed equally to this work Abstract: Rapid drug release at the specific site of action is still a challenge for antitumor therapy. Development of stimuli-responsive hybrid nanocarriers provides a promising strategy to enhance therapeutic effects by combining the unique features of each component. The present study explored the use of drug–gold nanoparticle conjugates incorporated into liposomes to enhance antitumor efficiency. A model drug, vincristine sulfate, was physically conjugated with gold nanoparticles and verified by UV-visible and fourier transform infrared spectroscopy, and differential scanning calorimetry. The conjugates were incorporated into liposomes by film dispersion to yield nanoparticles (113.4 nm with light-responsive release properties, as shown by in vitro release studies. Intracellular uptake and distribution was studied in HeLa cells using transmission electron microscopy and confocal laser scanning microscopy. This demonstrated liposome internalization and localization in endosomal–lysosomal vesicles. Fluorescence intensity increased in cells exposed to UV light, indicating that this stimulated intracellular drug release; this finding was confirmed by quantitative analyses using flow cytometry. Antitumor efficacy was evaluated in HeLa cells, both in culture and in implants in vivo in nude mice. HeLa cell viability assays showed that light exposure enhanced liposome cytotoxicity and induction of apoptosis. Furthermore, treatment with the prepared liposomes coupled with UV light exposure produced greater antitumor effects in nude mice and reduced side effects, as compared with free vincristine sulfate

A study on the thermochemotherapy effect of nanosized As2O3/MZF thermosensitive magnetoliposomes on experimental hepatoma in vitro and in vivo

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Wang, Li; Zhang, Jia; An, Yanli; Wang, Ziyu; Liu, Jing; Li, Yutao; Zhang, Dongsheng

2011-08-01

In this paper, we describe the synthesis and characterization of a nanosized, thermosensitive magnetoliposome encapsulating magnetic nanoparticles (MZFs) and antitumor drugs (As2O3). The nanoliposomes were spherical and mostly single volume, with an average diameter of 128.2 nm. Differential scanning calorimetry (DSC) showed a liposome phase transition temperature of 42.71 °C. After that, we studied the liposomes' anti-hepatoma effect in vitro and in vivo. The antitumor effect of the nanoliposomes on human hepatoma cells, SMMC-7721, and changes in expression of apoptosis-related proteins were examined in vitro. The results show that As2O3/MZF thermosensitive magnetoliposomes combined with hyperthermia had a great impact on the Bax/Bcl-2 ratio, which increased to 1.914 and exhibited a rapid response to induce apoptosis of tumor cells. An in situ rabbit liver tumor model was established and used to evaluate the antitumor effect of combined hyperthermia and chemotherapy following transcatheter arterial embolization with As2O3/MZF thermosensitive magnetoliposomes. The results demonstrated a strong anti-hepatoma effect, with a tumor volume inhibition rate of up to 85.22%. Thus, As2O3/MZF thermosensitive magnetoliposomes may play a great role in the treatment of hepatocarcinoma.

Comparison of two self-assembled macromolecular prodrug micelles with different conjugate positions of SN38 for enhancing antitumor activity

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Liu Y

2015-03-01

Full Text Available Yi Liu,1 Hongyu Piao,1 Ying Gao,1 Caihong Xu,2 Ye Tian,1 Lihong Wang,1 Jinwen Liu,1 Bo Tang,1 Meijuan Zou,1 Gang Cheng1 1Department of Pharmaceutics, Shenyang Pharmaceutical University, Shenyang, Liaoning Province, People’s Republic of China; 2Department of Food Science, Shenyang Normal University, Shenyang, Liaoning Province, People’s Republic of China Abstract: 7-Ethyl-10-hydroxycamptothecin (SN38, an active metabolite of irinotecan (CPT-11, is a remarkably potent antitumor agent. The clinical application of SN38 has been extremely restricted by its insolubility in water. In this study, we successfully synthesized two macromolecular prodrugs of SN38 with different conjugate positions (chitosan-(C10-OHSN38 and chitosan-(C20-OHSN38 to improve the water solubility and antitumor activity of SN38. These prodrugs can self-assemble into micelles in aqueous medium. The particle size, morphology, zeta potential, and in vitro drug release of SN38 and its derivatives, as well as their cytotoxicity, pharmacokinetics, and in vivo antitumor activity in a xenograft BALB/c mouse model were studied. In vitro, chitosan-(C10-OHSN38 (CS-(10sSN38 and chitosan-(C20-OHSN38 (CS-(20sSN38 were 13.3- and 25.9-fold more potent than CPT-11 in the murine colon adenocarcinoma cell line CT26, respectively. The area under the curve (AUC0–24 of SN38 after intravenously administering CS-(10sSN38 and CS-(20sSN38 to Sprague Dawley rats was greatly improved when compared with CPT-11 (both P<0.01. A larger AUC0–24 of CS-(20sSN38 was observed when compared to CS-(10sSN38 (P<0.05. Both of the novel self-assembled chitosan-SN38 prodrugs demonstrated superior anticancer activity to CPT-11 in the CT26 xenograft BALB/c mouse model. We have also investigated the differences between these macromolecular prodrug micelles with regards to enhancing the antitumor activity of SN38. CS-(20sSN38 exhibited better in vivo antitumor activity than CS-(10sSN38 at a dose of 2.5 mg/kg (P<0

Artemisinic acid exhibits antitumor activity in MCF-7 breast cancer cells through the inhibition of angiogenesis, VEGF, m-TOR and AKT signalling pathways

Directory of Open Access Journals (Sweden)

Yan Cui

2016-09-01

Full Text Available The aim of the present study was to evaluate the antitumor and anti-angiogenic effects of artemisinic acid in MCF-7 human breast cancer cells. Various cell signalling pathways (VEGF, m-TOR and AKT signalling pathways and MTT assay were used. The in vivo antitumor activity of artemisinic acid was evaluated by means of tumor xenograft mouse model. Transwell cell migration assay was used to examine the chemotactic motility of the human umbilical vascular endothelial cells (HUVECs, while as endothelial cell capillary-like tube formation assay was used to evaluate the effect of artemisinic acid on the tube formation in HUVECs. We found that artemisinic acid considerably reduced both the volume and weight of concrete tumors and reduced angiogenesis in a xenograft mouse tumor model in vivo. Further, artemisinic acid suppressed the VEGF-induced cell migration and capillary-like tube formation of HUVECs in a dose-dependent manner. Artemisinic acid was found to suppress the VEGF-induced phosphorylation of VEGFR2 and also the activity of AKT and m-TOR.

Liposomal n-butylidenephthalide protects the drug from oxidation and enhances its antitumor effects in glioblastoma multiforme

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Lin YL

2015-09-01

Full Text Available Yu-Ling Lin,1,2,* Kai-Fu Chang,3,* Xiao-Fan Huang,3 Che-Lun Hung,4 Shyh-Chang Chen,5 Wan-Ru Chao,6,7 Kuang-Wen Liao,1,8 Nu-Man Tsai3,9 1College of Biological Science and Technology, 2Center for Bioinformatics Research, National Chiao Tung University, Hsinchu, 3School of Medical Laboratory and Biotechnology, Chung Shan Medical University, 4Department of Computer Science and Communication Engineering, Providence University, 5Department of Pathology and Laboratory Medicine, Taichung Veterans General Hospital, 6Institute of Medicine, Chung Shan Medical University, 7Department of Pathology, Chung Shan Medical University and Chung Shan Medical University Hospital, Taichung, 8Institute of Molecular Medicine and Bioengineering, National Chiao Tung University, Hsinchu, 9Clinical Laboratory, Chung Shan Medical University Hospital, Taichung, Taiwan *These authors contributed equally to this work Background: The natural compound n-butylidenephthalide (BP can pass through the blood–brain barrier to inhibit the growth of glioblastoma multiforme tumors. However, BP has an unstable structure that reduces its antitumor activity and half-life in vivo.Objective: The aim of this study is to design a drug delivery system to encapsulate BP to enhance its efficacy by improving its protection and delivery.Methods: To protect its structural stability against protein-rich and peroxide solutions, BP was encapsulated into a lipo-PEG-PEI complex (LPPC. Then, the cytotoxicity of BP/LPPC following preincubation in protein-rich, acid/alkaline, and peroxide solutions was analyzed by MTT. Cell uptake of BP/LPPC was also measured by confocal microscopy. The therapeutic effects of BP/LPPC were analyzed in xenograft mice following intratumoral and intravenous injections.Results: When BP was encapsulated in LPPC, its cytotoxicity was maintained following preincubation in protein-rich, acid/alkaline, and peroxide solutions. The cytotoxic activity of encapsulated BP was higher than

Identification, characterization and potent antitumor activity of ECO-4601, a novel peripheral benzodiazepine receptor ligand.

Science.gov (United States)

Gourdeau, Henriette; McAlpine, James B; Ranger, Maxime; Simard, Bryan; Berger, Francois; Beaudry, Francis; Farnet, Chris M; Falardeau, Pierre

2008-05-01

ECO-4601 is a structurally novel farnesylated dibenzodiazepinone discovered through DECIPHER technology, Thallion's proprietary drug discovery platform. The compound was shown to have a broad cytotoxic activity in the low micromolar range when tested in the NCI 60 cell line panel. In the work presented here, ECO-4601 was further evaluated against brain tumor cell lines. Preliminary mechanistic studies as well as in vivo antitumor evaluation were performed. Since ECO-4601 has a benzodiazepinone moiety, we first investigated if it binds the central and/or peripheral benzodiazepine receptors. ECO-4601 was tested in radioligand binding assays on benzodiazepine receptors obtained from rat hearts. The ability of ECO-4601 to inhibit the growth of CNS cancers was evaluated on a panel of mouse, rat and human glioma cell lines using a standard MTT assay. Antitumor efficacy studies were performed on gliomas (rat and human), human breast and human prostate mouse tumor xenografts. Antitumor activity and pharmacokinetic analysis of ECO-4601 was evaluated following intravenous (i.v.), subcutaneous (s.c.), and intraperitoneal (i.p.) bolus administrations. ECO-4601 was shown to bind the peripheral but not the central benzodiazepine receptor and inhibited the growth of CNS tumor cell lines. Bolus s.c. and i.p. administration gave rise to low but sustained drug exposure, and resulted in moderate to significant antitumor activity at doses that were well tolerated. In a rat glioma (C6) xenograft model, ECO-4601 produced up to 70% tumor growth inhibition (TGI) while in a human glioma (U-87MG) xenograft, TGI was 34%. Antitumor activity was highly significant in both human hormone-independent breast (MDA-MB-231) and prostate (PC-3) xenografts, resulting in TGI of 72 and 100%, respectively. On the other hand, i.v. dosing was followed by rapid elimination of the drug and was ineffective. Antitumor efficacy of ECO-4601 appears to be associated with the exposure parameter AUC and/or sustained

Andrographolide enhanced 5-fluorouracil-induced antitumor effect in colorectal cancer via inhibition of c-MET pathway

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Su M

2017-11-01

Full Text Available Meng Su,1 Baoli Qin,1 Fang Liu,2 Yuze Chen,2 Rui Zhang2 1Department of Internal Medicine, 2Department of Colorectal Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Liaoning, China Abstract: Colorectal cancer (CRC is the third most common malignant neoplasm worldwide. 5-Fluorouracil (5-Fu is the most important chemotherapeutic drug used for the treatment of CRC. However, resistance to 5-Fu therapies is a growing concern in CRC clinical practice recently. Andrographolide (Andro is a main bioactive constituent of the herb Andrographis paniculata, which has various biological effects including anti-inflammation and antitumor activities. In the present study, we investigated the effects of combined Andro with 5-Fu against CRC HCT-116 cells. In vitro studies showed that Andro synergistically enhanced the anti-proliferation effect of 5-Fu on HCT-116 cells due to increased apoptotic cells. Meanwhile, results of the enzyme linked immunosorbent assay indicated that the level of phosphorylated cellular-mesenchymal to epithelial transition factor (p-MET was decreased by the combination treatment. Further study suggested that Andro promoted the antitumor effect of 5-Fu by downregulating the level of p-MET. In conclusion, these results confirmed the synergistic antitumor activity of Andro on CRC and provide evidence for possible clinical application of Andro for enhancing the antitumor effect of 5-Fu in CRC treatment. Keywords: Andro, 5-Fu, HCT-116 cells, apoptosis, p-MET

A novel selective small-molecule PI3K inhibitor is effective against human multiple myeloma in vitro and in vivo

International Nuclear Information System (INIS)

Glauer, J; Pletz, N; Schön, M; Schneider, P; Liu, N; Ziegelbauer, K; Emmert, S; Wulf, G G; Schön, M P

2013-01-01

Developing effective therapies against multiple myeloma (MM) is an unresolved challenge. Phosphatidylinositol-3-kinase (PI3K) activation may be associated with tumor progression and drug resistance, and inhibiting PI3K can induce apoptosis in MM cells. Thus, targeting of PI3K is predicted to increase the susceptibility of MM to anticancer therapy. The lead compound of a novel class of PI3K inhibitors, BAY80-6946 (IC 50 =0.5 nM against PI3K-α), was highly efficacious in four different MM cell lines, where it induced significant antitumoral effects in a dose-dependent manner. The compound inhibited cell cycle progression and increased apoptosis (P<0.001 compared with controls). Moreover, it abrogated the stimulation conferred by insulin-like growth-factor-1, a mechanism relevant for MM progression. These cellular effects were paralleled by decreased Akt phosphorylation, the main downstream target of PI3K. Likewise, profound antitumoral activity was observed ex vivo, as BAY80-6946 significantly inhibited proliferation of freshly isolated myeloma cells from three patients (P<0.001 compared with vehicle). In addition, BAY80-6946 showed convincing in vivo activity against the human AMO-1 and MOLP-8 myeloma cell lines in a preclinical murine xenograft model, where treatment with 6 mg/kg every other day for 2 weeks reduced the cell numbers by 87.0% and 69.3%, respectively (P<0.001 compared with vehicle), without overt toxicity in treated animals

Antitumor Effect of Selenium and Modified Pectin Nano Particles and Gamma Radiation on Ehrilch Solid Tumor in Female Mice

International Nuclear Information System (INIS)

Mansour, S. Z.; Anis, L.M.; EI- Batal, A.I.

2010-01-01

Selenium nano particle (Nano- Se) is a novel Se species with novel biological activities with low toxicity. The aim of the present work was to evaluate the antitumor activity of a novel Nano- Se compound with or without gamma irradiation of female mice. Selenium size- controlled Nano-Se was prepared by a simple method by adding modified pectin to the selenious acid and ascorbic acid. The antitumor activity of Selenium and Modified Pectin Nano Particles (Se-Mp- NPs) were evaluated against Ehrilch ascites carcinoma (In vitro) and Ehrilch solid tumor model (In vivo). The antioxidant states of the novel compound were assessed measuring parameters in blood and tumor tissue of female mice. Malonaldehydoyl (MDA) end product of lipid peroxidation was evaluated in plasma and tumor tissue. Glutathione -S- transferase (GST) and cytochrome P450 (Cyto P450) were determined in tumor tissue homogenate. Tumor necrosis factor alpha (TNF- a) concentration and interleukin 10 (IL- 10) concentrations was evaluated in plasma of female mice. The effect of tumor inoculation and different treatments on liver enzymes (ALT and AST) and kidney Function (urea and creatinine) were detected in the plasma of animals. Apoptosis was shown and estimated in tumor tissue of animals histopathological of tumor in different groups of mice were examined. Ehrilch solid tumor induced a significant increase in MDA content, GSH-Px and GST activities level and in the amount of metabolites of CYP 450. Moreover, a significant decrease was observed in GSH content, SOD activity level in the tumor tissue, INF- a concentration, IL- 10 concentration in the plasma. Also, a significant alteration in kidney and liver functions was occurred as compared to control group. The results showed a significant antitumor activity of selenium and Modified Pectin Nano Particles (Se-Mp- NPs) at the concentration 2.25 μg / ml was 70%

Antitumor effect of free rhodium (II) citrate and rhodium (II) citrate-loaded maghemite nanoparticles on mice bearing breast cancer: a systemic toxicity assay.

Science.gov (United States)

Peixoto, Raphael Cândido Apolinário; Miranda-Vilela, Ana Luisa; de Souza Filho, José; Carneiro, Marcella Lemos' Brettas; Oliveira, Ricardo G S; da Silva, Matheus Oliveira; de Souza, Aparecido R; Báo, Sônia Nair

2015-05-01

Breast cancer is one of the most prevalent cancer types among women. The use of magnetic fluids for specific delivery of drugs represents an attractive platform for chemotherapy. In our previous studies, it was demonstrated that maghemite nanoparticles coated with rhodium (II) citrate (Magh-Rh2Cit) induced in vitro cytotoxicity and in vivo antitumor activity, followed by intratumoral administration in breast carcinoma cells. In this study, our aim was to follow intravenous treatment to evaluate the systemic antitumor activity and toxicity induced by these formulations in Balb/c mice bearing orthotopic 4T1 breast carcinoma. Female Balb/c mice were evaluated with regard to toxicity of intravenous treatments through analyses of hemogram, serum levels of alanine aminotransferase, iron, and creatinine and liver, kidney, and lung histology. The antitumor activity of rhodium (II) citrate (Rh2Cit), Magh-Rh2Cit, and maghemite nanoparticles coated with citrate (Magh-Cit), used as control, was evaluated by tumor volume reduction, histology, and morphometric analysis. Magh-Rh2Cit and Magh-Cit promoted a significant decrease in tumor area, and no experimental groups presented hematotoxic effects or increased levels of serum ALT and creatinine. This observation was corroborated by the histopathological examination of the liver and kidney of mice. Furthermore, the presence of nanoparticles was verified in lung tissue with no morphological changes, supporting the idea that our nanoformulations did not induce toxicity effects. No studies about the systemic action of rhodium (II) citrate-loaded maghemite nanoparticles have been carried out, making this report a suitable starting point for exploring the therapeutic potential of these compounds in treating breast cancer.

A review of electroporation-based antitumor skin therapies and investigation of betulinic acid-loaded ointment.

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Bakonyi, Monika; Berko, Szilvia; Eros, Gabor; Varju, Gabor; Dehelean, Cristina; Szucs, Maria Budai; Csanyi, Erzsebet

2017-11-13

Electrochemotherapy is a novel treatment for cutaneous and subcutaneous tumors utilizing the combination of electroporation and chemotherapeutic agents. Since tumors have an increasing incidence nowadays as a result of environmental and genetic factors, electrochemotherapy could be a promising treatment for cancer patients. The aim of this article is to summarize the novel knowledge about the use of electroporation for antitumor treatments and to present a new application of electrochemotherapy with a well-known plant derived antitumor drug betulinic acid. For the review we have searched the databases of scientific and medical research to collect the available publications about the use of electrochemotherapy in the treatment of various types of cancer. By the utilization of the available knowledge, we investigated the effect of electroporation on the penetration of a topically applied betulinic acid formulation into the skin by ex vivo Raman spectroscopy on hairless mouse skin Results: Raman measurements have demonstrated that the penetration depth of betulinic acid can be remarkably ameliorated by the use of electroporation, so this protocol can be a possibility for the treatment of deeper localized cancer nodules. Furthermore, it proved the influence of various treatment times, since they caused different spatial distributions of the drug in the skin. The review demonstrates that electrochemotherapy is a promising tool to treat different kinds of tumors with high efficiency and with only a few moderate adverse effects. Moreover, it presents a non-invasive method to enhance the penetration of antitumor agents, which can offer novel prospects for antitumor therapies. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Inecalcitol, an analog of 1,25D₃, displays enhanced antitumor activity through the induction of apoptosis in a squamous cell carcinoma model system

Science.gov (United States)

Ma, Yingyu; Yu, Wei-Dong; Hidalgo, Alejandro A.; Luo, Wei; Delansorne, Remi; Johnson, Candace S.; Trump, Donald L.

2013-01-01

Epidemiological data suggest an important role of vitamin D signaling in cancer development and progression, and experimental studies demonstrate that the active vitamin D metabolite 1α, 25-dihydroxyvitamin D₃ (1,25D₃) has broad spectrum antitumor activity. Hypercalcemia has often been suggested to limit the clinical application of these data. The 14-epi-analog of 1,25D₃, inecalcitol [19-nor-14-epi-23-yne-1,25-(OH)₂D₃; TX522], was developed to have superagonistic antitumor activities but low hypercalcemia potential. We examined the antitumor activity of inecalcitol and the underlying mechanisms in a murine squamous cell carcinoma (SCC) model system. In vitro, compared with 1,25D₃, inecalcitol showed enhanced vitamin D receptor (VDR)-mediated transcriptional activity. Inecalcitol suppressed SCC cell proliferation in a dose-dependent manner with an IC₅₀ value 30 times lower than that of 1,25D₃. Both inecalcitol and 1,25D₃ induced a comparable level of G₀/G₁ cell cycle arrest in SCC cells. The level of apoptosis induced by inecalcitol was markedly higher than that of 1,25D₃. Apoptosis was mediated through the activation of the caspase 8/10- caspase 3 pathway. Further, inecalcitol markedly inhibited the mRNA and protein expression of c-IAP1 and XIAP compared with 1,25D₃. In vivo, inecalcitol inhibits SCC tumor growth in a dose-dependent fashion. Notably, inecalcitol induced a significantly higher level of apoptosis in the SCC xenograft model. While in vitro inecalcitol demonstrates apparent enhanced VDR binding and antiproliferative effects compared to 1,25D₃, in vivo these advantages disappear; at doses of inecalcitol that have equivalent antitumor effects, similar hypercalcemia is seen. This may be explained by the pharmacokinetics of 1,25D₃ vs. inecalcitol and attributed to the much shorter serum half-life of inecalcitol.We show that inecalcitol has potent antitumor activity in the SCC model system, and this is associated with a

Antitumor and apoptotic effects of cucurbitacin a in A-549 lung ...

African Journals Online (AJOL)

Background: The main aim of this study was to demonstrate the antitumor potential of cucurbitacin A on A-549 NSCLC (non-small cell lung cancer cells). The effects of Cucurbitacin A on apoptotic induction, cell physic, cell cycle failure and m-TOR/PI3K/Akt signalling pathway were also investigated in the present study.

A study on the thermochemotherapy effect of nanosized As{sub 2}O{sub 3}/MZF thermosensitive magnetoliposomes on experimental hepatoma in vitro and in vivo

Energy Technology Data Exchange (ETDEWEB)

Wang Li; Zhang Jia; Wang Ziyu; Liu Jing; Li Yutao; Zhang Dongsheng [School of Medicine, Southeast University, NO. 87 Ding jia qiao, Nanjing 210009 (China); An Yanli, E-mail: wangli040418@163.com, E-mail: zdszds1222@163.com [Affiliated Zhong-Da Hospital of Southeast University, Nanjing 210009 (China)

2011-08-05

In this paper, we describe the synthesis and characterization of a nanosized, thermosensitive magnetoliposome encapsulating magnetic nanoparticles (MZFs) and antitumor drugs (As{sub 2}O{sub 3}). The nanoliposomes were spherical and mostly single volume, with an average diameter of 128.2 nm. Differential scanning calorimetry (DSC) showed a liposome phase transition temperature of 42.71 deg. C. After that, we studied the liposomes' anti-hepatoma effect in vitro and in vivo. The antitumor effect of the nanoliposomes on human hepatoma cells, SMMC-7721, and changes in expression of apoptosis-related proteins were examined in vitro. The results show that As{sub 2}O{sub 3}/MZF thermosensitive magnetoliposomes combined with hyperthermia had a great impact on the Bax/Bcl-2 ratio, which increased to 1.914 and exhibited a rapid response to induce apoptosis of tumor cells. An in situ rabbit liver tumor model was established and used to evaluate the antitumor effect of combined hyperthermia and chemotherapy following transcatheter arterial embolization with As{sub 2}O{sub 3}/MZF thermosensitive magnetoliposomes. The results demonstrated a strong anti-hepatoma effect, with a tumor volume inhibition rate of up to 85.22%. Thus, As{sub 2}O{sub 3}/MZF thermosensitive magnetoliposomes may play a great role in the treatment of hepatocarcinoma.

Clostridium butyricum MIYAIRI 588 shows antitumor effects by enhancing the release of TRAIL from neutrophils through MMP-8.

Science.gov (United States)

Shinnoh, Masahide; Horinaka, Mano; Yasuda, Takashi; Yoshikawa, Sae; Morita, Mie; Yamada, Takeshi; Miki, Tsuneharu; Sakai, Toshiyuki

2013-03-01

Bacillus Calmette-Guérin (BCG) intravesical therapy against superficial bladder cancer is one of the most successful immunotherapies in cancer, though the precise mechanism has not been clarified. Recent studies have demonstrated urinary tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) levels to be higher in BCG-responsive patients than non-responders and shown that polymorphonuclear neutrophils (PMNs) migrating to the bladder after BCG instillation release large amounts of TRAIL. To establish a safer and more effective intravesical therapy than BCG, we examined whether other bacteria induced similar effects. We stimulated PMNs or peripheral blood mononuclear cells (PBMCs) with BCG or other bacteria, and then aliquots of the culture supernatants or cell lysates were assayed for TRAIL. We examined the signaling pathway regulating the release of TRAIL from PMNs and evaluated the antitumor effects of BCG or other bacteria in vitro and in vivo. We have found that Clostridium butyricum MIYAIRI 588 (CBM588) induces the release of endogenous TRAIL from PMNs as well as BCG. In addition, we have shown that matrix metalloproteinase 8 (MMP-8) is one of the key factors responsible for the release. Interestingly, TLR2/4 signaling pathway has been suggested to be important for the release of TRAIL by MMP-8. CBM588 has been proven to be as effective as BCG against cancer cells by inducing apoptosis in vivo as well as in vitro. Taken together, these results strongly suggest that CBM588 is promising for a safer and more effective therapy against bladder cancer.

Anti-tumor immunotherapy by blockade of the PD-1/PD-L1 pathway with recombinant human PD-1-IgV.

Science.gov (United States)

Zhang, C; Wu, S; Xue, X; Li, M; Qin, X; Li, W; Han, W; Zhang, Y

2008-01-01

Blockade of the programmed death-1 (PD-1)/PD-ligand 1 (PD-L1) pathway can delay tumor growth and prolong the survival of tumor-bearing mice. The extracellular immunoglobulin (Ig) V domain of PD-1 is important for the interaction between PD-1 and PD-L1, suggesting that PD-1-IgV may be a potential target for anti-tumor immunotherapy. The extracellular sequence of human PD-1-IgV (hPD-1-IgV) was expressed in Escherichia coli and purified. The anti-tumor effect of hPD-1-IgV on tumor-bearing mice was tested. hPD-1-IgV recombinant protein could bind PD-L1 at molecular and cellular levels and enhance Cytotoxic T Lymphocyte (CTL) activity and anti-tumor effect on tumor-bearing mice in vivo. The percentage of CD4(+)CD25(+) T cells in tumor-bearing mice was decreased compared with control mice after administration of the recombinant protein. Our results suggest that inhibition of the interaction between PD-1 and PD-L1 by hPD-1-IgV may be a promising strategy for specific tumor immunotherapy.

Doxil Synergizes with Cancer Immunotherapies to Enhance Antitumor Responses in Syngeneic Mouse Models

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Jonathan Rios-Doria

2015-08-01

Full Text Available Based on the previously described roles of doxorubicin in immunogenic cell death, both doxorubicin and liposomal doxorubicin (Doxil were evaluated for their ability to boost the antitumor response of different cancer immunotherapies including checkpoint blockers (anti–PD-L1, PD-1, and CTLA-4 mAbs and TNF receptor agonists (OX40 and GITR ligand fusion proteins in syngeneic mouse models. In a preventative CT26 mouse tumor model, both doxorubicin and Doxil synergized with anti–PD-1 and CTLA-4 mAbs. Doxil was active when CT26 tumors were grown in immunocompetent mice but not immunocompromised mice, demonstrating that Doxil activity is increased in the presence of a functional immune system. Using established tumors and maximally efficacious doses of Doxil and cancer immunotherapies in either CT26 or MCA205 tumor models, combination groups produced strong synergistic antitumor effects, a larger percentage of complete responders, and increased survival. In vivo pharmacodynamic studies showed that Doxil treatment decreased the percentage of tumor-infiltrating regulatory T cells and, in combination with anti–PD-L1, increased the percentage of tumor-infiltrating CD8+ T cells. In the tumor, Doxil administration increased CD80 expression on mature dendritic cells. CD80 expression was also increased on both monocytic and granulocytic myeloid cells, suggesting that Doxil may induce these tumor-infiltrating cells to elicit a costimulatory phenotype capable of activating an antitumor T-cell response. These results uncover a novel role for Doxil in immunomodulation and support the use of Doxil in combination with checkpoint blockade or TNFR agonists to increase response rates and antitumor activity.

Immunological and antitumor effects of IL-23 as a cancer vaccine adjuvant

NARCIS (Netherlands)

Overwijk, Willem W.; de Visser, Karin E.; Tirion, Felicia H.; de Jong, Laurina A.; Pols, Thijs W. H.; van der Velden, Yme U.; van den Boorn, Jasper G.; Keller, Anna M.; Buurman, Wim A.; Theoret, Marc R.; Blom, Bianca; Restifo, Nicholas P.; Kruisbeek, Ada M.; Kastelein, Robert A.; Haanen, John B. A. G.

2006-01-01

The promising, but modest, clinical results of many human cancer vaccines indicate a need for vaccine adjuvants that can increase both the quantity and the quality of vaccine-induced, tumor-specific T cells. In this study we tested the immunological and antitumor effects of the proinflammatory

Antitumor effect of degalactosylated gc-globulin on orthotopic grafted lung cancer in mice.

Science.gov (United States)

Hirota, Keiji; Nakagawa, Yoshinori; Takeuchi, Ryota; Uto, Yoshihiro; Hori, Hitoshi; Onizuka, Shinya; Terada, Hiroshi

2013-07-01

Group-specific component (Gc)-globulin-derived macrophage-activating factor (GcMAF) generated by a cascade of catalytic reactions with deglycosidase enzymes exerts antitumor activity. We hypothesized that degalactosyl Gc-globulin (DG3), a precursor of GcMAF, also plays a role in recovery from cancer as well as GcMAF due to progression of deglycosylation by generally resident sialidases and mannosidases. We prepared the subtypes of DG3, such as 1f1f and 1s1s and its 22 homodimers, by using vitamin D3-binding Sepharose CL-6B and examined their antitumor activity in mice bearing Lewis lung carcinoma cells, by counting the number of nodules formed in their lungs. Antitumor activity of DG3 was observed regardless of its subtype, being equivalent to that of GcMAF. The injection route of DG3 affected its antitumor activity, with subcutaneous and intramuscular administration being more favorable than the intraperitoneal or intravenous route. In order to obtain significant antitumor activity, more than 160 ng/kg of DG3 were required. DG3 proved to be promising as an antitumor agent, similarly to GcMAF.

Antitumor function and mechanism of phycoerythrin from Porphyra haitanensis

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Qunwen Pan

2013-01-01

Full Text Available The anti-tumor effect of R-Phycoerythrin (R-PE from Porphyra haitanensis was studied using cell line HeLa as an in vitro model and Sarcoma-180 (S180 tumor-bearing mice as an in vivo model. The results showed that the combination treatment of R-PE and photodynamic therapy PDT significantly inhibited the growth of HeLa cells up to 81.5%, with a fair dose-effect relationship, but did not inhibit endothelial cells. The annexin v-fitc/PI fluorescence staining experiments demonstrated that at doses between 0~60µg/mL, apoptosis cells and later stage apoptosis cells or necrosis cells increased significantly as the R-PE dosage increased. DNA electrophoresis showed that after R-PE+PDT treatment of HeLa cells for 24 hours, a light "smear" band between 100~400bp appeared to indicate the degradation of genomic DNA. The QRT-PCR results showed that R-PE+PDT treatment increased caspase-3 and caspase-10 gene expression and decreased the Bcl-2 gene expression level significantly as the R-PE dose increased, implying that R-PE promoted HeLa cell apoptosis. Compared with untreated S180 tumor-bearing mice, R-PE injection significantly inhibited the growth of S180 in tumor-bearing mice up to 41.3% at a dose of 300mg-kg-1. Simultaneously, the significant increase of superoxide dismutase (SOD activity in serum (p < 0.01 and the decrease of the malondialdehyde (MDA level in liver suggests that R-PE improved the anti-oxidant ability of the S180 tumor-bearing mice, which may related to its antitumor effect. In addition, the R-PE caused a significant increase (p < 0.05 in the spleen index and thymus index, and a significant increase (p < 0.01 in lymphocyte proliferation, NK cell kill activity and the TNF-α level in the serum of S180 tumor-bearing mice. These results strongly suggest that the antitumor effect of R-PE from Porphyra haitanensis functioned by increasing the immunity and antioxidant ability of S180 tumor-bearing mice, promoting apoptosis by increasing protease

The in vitro sustained release profile and antitumor effect of etoposide-layered double hydroxide nanohybrids

Directory of Open Access Journals (Sweden)

Qin LL

2013-05-01

Full Text Available Lili Qin,1 Mei Wang,2 Rongrong Zhu,3 Songhui You,1 Ping Zhou,1 Shilong Wang31Department of Physical Education, Tongji University, Shanghai, People's Republic of China; 2Department of Chemistry, Tongji University, Shanghai, People's Republic of China; 3School of Life Science and Technology, Tongji University, Shanghai, People's Republic of ChinaAbstract: Magnesium-aluminum layered double hydroxides intercalated with antitumor drug etoposide (VP16 were prepared for the first time using a two-step procedure. The X-ray powder diffraction data suggested the intercalation of VP16 into layers with the increased basal spacing from 0.84–1.18 nm was successful. Then, it was characterized by X-ray powder diffraction, Fourier transform infrared spectroscopy, thermogravimetry and differential thermal analysis, and transmission electron microscopy. The prepared nanoparticles, VP16-LDH, showed an average diameter of 62.5 nm with a zeta potential of 20.5 mV. Evaluation of the buffering effect of VP16-LDH indicated that the nanohybrids were ideal for administration of the drugs that treat human stomach irritation. The loading amount of intercalated VP16 was 21.94% and possessed a profile of sustained release. The mechanism of VP16-LDH release in the phosphate buffered saline solution at pH 7.4 is likely controlled by the diffusion of VP16 anions from inside to the surface of LDH particles. The in vitro cytotoxicity and antitumor assays indicated that VP16-LDH hybrids were less toxic to GES-1 cells while exhibiting better antitumor efficacy on MKN45 and SGC-7901 cells. These results imply that VP16-LDH is a potential antitumor drug for a broad range of gastric cancer therapeutic applications.Keywords: layered double hydroxides, etoposide, drug delivery, antitumor effect, sustained release

Assessment of antitumoral and antimicrobial effects of a maslinic acid derivative

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Ioana Z. Pavel

2016-12-01

Full Text Available INTRODUCTION Maslinic acid, a naturally occurring triterpene, has been reported to possess several therapeutic effects including antioxidant, anti-inflammatory and antiparasitic properties. Structural changes of the compound led to the development of new derivatives in order to expand the spectrum of activities. OBJECTIVES AND BACKGROUND The present study was purposed to assess the in vitro antitumoral and antibacterial effects of a maslinic acid derivative, namely benzyl (2α, 3β 2,3-diacetoxy-olean-12- en-28-amide (EM2. MATERIALS AND METHODS Four compound concentrations (12.5, 25, 50 and 100 µM were evaluated for their cytotoxic effect on A375 human melanoma and B164A5 murine melanoma cell lines using the MTT assay. Furthermore, EM2 was tested on ten bacterial strains by means of agar disk diffusion method with the assessment of the inhibition zone diameters at 24h period of time. RESULTS EM2 elicited a dose-dependent cytotoxic effect on both melanoma cell lines. Regarding the antibacterial activity, EM2 determined a significant growth inhibition on Streptococcus pyogenes (20 ± 0.26 mm and Staphylococcus aureus (13 ± 0.19 mm. CONCLUSIONS The tested maslinic acid derivative is a promising antitumoral agent against skin cancer and antimicrobial agent against cocci bacteria. Graphical abstract: EM2 in vitro effects

Constructing TC-1-GLUC-LMP2 Model Tumor Cells to Evaluate the Anti-Tumor Effects of LMP2-Related Vaccines

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Sun, Liying; Hao, Yanzhe; Wang, Zhan; Zeng, Yi

2018-01-01

Epstein-Barr virus (EBV) is related to a variety of malignant tumors, and its encoded protein, latent membrane protein 2 (LMP2), is an effective target antigen that is widely used to construct vector vaccines. However, the model cells carrying LMP2 have still not been established to assess the oncolytic effect of LMP2-related vaccines at present. In this study, TC-1-GLUC-LMP2 tumor cells were constructed as target cells to evaluate the anti-tumor effects of LMP2-assosiated vaccines. The results showed that both LMP2 and Gaussia luciferase (GLuc) genes could be detected by polymerase chain reaction (PCR) and reverse transcription-polymerase chain reaction (RT-PCR) in TC-1-GLUC-LMP2 cells. Western blot results showed that the LMP2 and Gaussia luciferase proteins were stably expressed in tumor cells for at least 30 generations. We mixed 5 × 104 LMP2-specific mouse splenic lymphocytes with 5 × 103 TC-1-GLUC-LMP2 target cells and found that the target cells were killed as the specific killing effect was obviously enhanced by the increased quantities of LMP2-peptide stimulated spleens. Furthermore, the tumor cells could not be observed in the mice inoculated TC-1-GLUC-LMP2 cells after being immunized with vaccine-LMP2, while the vaccine-NULL immunized mice showed that tumor volume gradually grew with increased inoculation time. These results indicated that the TC-1-GLUC-LMP2 cells stably expressing LMP2 and GLuc produced tumors in mice, and that the LMP2-specific cytotoxic T lymphocyte (CTL) effectively killed the cells in vitro and in vivo, suggesting that TC-1-GLUC-LMP2 cells can be used as model cells to assess the immune and antitumor effects of LMP2-related vaccines. PMID:29570629

明党参根皮中异欧前胡素的体内抗肿瘤活性研究%Study on Anti-tumor Activity of Isoimperatorin in the Root Bark of Changium Smyrnioides Wolff in Vivo

Institute of Scientific and Technical Information of China (English)

王萌

2016-01-01

Objective: To study anti-tumor activity of isoimperatorin in the root bark of Changium smyrnioides Wolff in vivo. Methods:There are three dose groups of isoimperatorin, low dose group (0.2mg·kg-1), middle dose group (0.4mg·kg-1), high dose group (0.8mg·kg-1);Positive drug group (cyclophosphamide 30mg·kg-1). This research uses the method of transplanted tumor model, to observe the growth of solid tumor, and calculate the anti-tumor rate of each group. Results:The anti-tumor rates of isoimperatorin in low, middle, high dose group are 28.67%, 59.29%, 66.38%; anti-tumor rate of the positive drug group is 66.93%, but the immune organs of mice are damaged. Conclusion:Isoimperatorin has obvious anti-tumor effect on liver cancer transplanted tumor in mice, and has a protective effect on immune organs.%目的:研究明党参根皮中异欧前胡素的体内抗肿瘤作用.方法:异欧前胡素设三个剂量组,低剂量组(0.2mg·kg-1)、中剂量组(0.4mg·kg-1)、高剂量组(0.8mg·kg-1),阳性药物组(环磷酰胺30mg·kg-1),采用移植性肿瘤模型的方法,观察实体瘤生长情况,并计算各组抑瘤率.结果:异欧前胡素低、中、高剂量组的抑瘤率分别为28.67%、59.29%、66.38%,阳性药物组的抑瘤率为66.93%,但对小鼠免疫器官有损伤.结论:异欧前胡素对小鼠肝癌移植瘤有明显的抗肿瘤作用,并对机体免疫器官有保护作用.

Transcutaneous carbon dioxide enhances the antitumor effect of radiotherapy on oral squamous cell carcinoma.

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Iwata, Eiji; Hasegawa, Takumi; Ueha, Takeshi; Takeda, Daisuke; Saito, Izumi; Kawamoto, Teruya; Akisue, Toshihiro; Sakai, Yoshitada; Sasaki, Ryohei; Kuroda, Ryosuke; Komori, Takahide

2018-05-16

Radiotherapy (RT) is one of the main treatment modalities for oral squamous cell carcinoma (OSCC), however, radioresistance is a major impediment to its clinical success and poses as a concern that needs to be addressed. Tumor hypoxia is known to be significantly associated with radioresistance in various malignancies, hence, resolving the hypoxic state of a tumor may improve the antitumor effect of RT on OSCC. We have previously revealed that transcutaneous CO2 induced mitochondrial apoptosis and suppressed tumor growth in OSCC by resolving hypoxia. Considering the previous study, we hypothesized that transcutaneous CO2 may enhance the antitumor effect of RT on OSCC by improving intratumoral hypoxia, thereby overcoming radioresistance. In the present study, the combination of transcutaneous CO2 and RT significantly inhibited tumor growth compared with other treatments. This combination therapy also led to decreased expression of HIF-1α in parallel with increased expression of the cleaved forms of caspase-3-8-9 and PARP, which play essential roles in mitochondrial apoptosis. Additionally, the combination therapy increased the expression of ROS modulator 1 and subsequent mitochondrial ROS production, compared to RT alone. These results indicated that transcutaneous CO2 could potentially improve the antitumor effect of RT by decreasing the intratumoral hypoxia and increasing the mitochondrial apoptosis. Our findings indicated that CO2 therapy may be a novel adjuvant therapy in combination with RT for OSCC.

[Antitumor effects of matrix protein of vesicular stomatic virus on EL4 lymphoma mice].

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Lin, Shi-jia; Yu, Qin-mei; Meng, Wen-tong; Wen, Yan-jun; Chen, Li-juan; Niu, Ting

2011-03-01

To explore antitumor effects of plasmid pcDNA3. 1-MP encoding matrix protein of vesicular stomatitis virus (VSV) complexed with cationic liposome (DOTAP:CHOL) in mice with EL4 lymphoma. C57BL/6 mouse model with EL4 lymphoma was established. Sixty mice bearing EL4 lymphoma were divided randomly into five groups including Lip-MP, Lip-pVAX, Lip, ADM and NS groups, which were intravenously injected with liposome-pcDNA 3. 1-MP complex, liposome-pVAX complex, empty liposome, Adriamycin and normal saline respectively every three days. Tumor volumes and survival time were monitored. Microvessel density and tumor proliferative index in tumor tissues were determined by CD31, Ki-67 immunohistochemistry staining, meanwhile the tumor apoptosis index was measured by TUNEL method. From 6 days after treatments on, the tumor volume in Lip-MP group was much smaller than that in Lip-pVAX, Lip and NS group (P EL4 tumor cells in vivo (P EL4 lymphoma, which may be related to the induction of tumor cell apoptosis, inhibition of tumor angiogenesis, and suppression of tumor cell proliferation.

Effects of Androgen Ablation on Anti-Tumor Immunity

National Research Council Canada - National Science Library

Kast, Martin

2004-01-01

.... This AA induced autoimmune-like response exerts limited anti-tumor activity in a murine prostate cancer model, but could be synergistic with CTLA-4 blockade that promotes the development of autoreactive T cell...

D-α-Tocopheryl polyethylene glycol succinate/Solutol HS 15 mixed micelles for the delivery of baohuoside I against non-small-cell lung cancer: optimization and in vitro, in vivo evaluation

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Yan H

2016-09-01

Full Text Available Hongmei Yan,1,2 Zhenhai Zhang,2 Xiaobin Jia,1,2 Jie Song1,2 1College of Pharmacy, Nanjing University of Chinese Medicine, 2Key Laboratory of New Drug Delivery System of Chinese Materia Medica, Third School of Clinical Medical of Nanjing University of Chinese Medicine, Nanjing, People’s Republic of China Abstract: Baohuoside I, extracted from the Herba epimedii, is an effective but a poorly soluble antitumor drug. To improve its solubility, formulation of baohuoside I-loaded mixed micelles with d-α-tocopheryl polyethylene glycol succinate and Solutol HS 15 (BTSM has been developed in this study. We performed a systematic comparative evaluation of the antiproliferative effect, cellular uptake, antitumor efficacy, and in vivo tumor targeting of these micelles using non-small-cell lung cancer (NSCLC A549 cells. Results showed that the obtained micelles have a mean particle size of ~62.54 nm, and the size of micelles was narrowly distributed. With the improved cellular uptake, BTSM displayed a more potent antiproliferative action on A549 cell lines than baohuoside I; half-maximal inhibitory concentration was 7.83 vs 20.37 µg/mL, respectively. The antitumor efficacy test in nude mice showed that BTSM exhibited significantly higher antitumor activity against NSCLC with lesser toxic effects on normal tissues. The imaging study for in vivo targeting demonstrated that the mixed micelles formulation achieved effective and targeted drug delivery. Therefore, BTSM might be a potential antitumor formulation. Keywords: baohuoside I-loaded mixed micelles, TPGS, Solutol HS 15, antitumor

OSI-930: a novel selective inhibitor of Kit and kinase insert domain receptor tyrosine kinases with antitumor activity in mouse xenograft models.

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Garton, Andrew J; Crew, Andrew P A; Franklin, Maryland; Cooke, Andrew R; Wynne, Graham M; Castaldo, Linda; Kahler, Jennifer; Winski, Shannon L; Franks, April; Brown, Eric N; Bittner, Mark A; Keily, John F; Briner, Paul; Hidden, Chris; Srebernak, Mary C; Pirrit, Carrie; O'Connor, Matthew; Chan, Anna; Vulevic, Bojana; Henninger, Dwight; Hart, Karen; Sennello, Regina; Li, An-Hu; Zhang, Tao; Richardson, Frank; Emerson, David L; Castelhano, Arlindo L; Arnold, Lee D; Gibson, Neil W

2006-01-15

OSI-930 is a novel inhibitor of the receptor tyrosine kinases Kit and kinase insert domain receptor (KDR), which is currently being evaluated in clinical studies. OSI-930 selectively inhibits Kit and KDR with similar potency in intact cells and also inhibits these targets in vivo following oral dosing. We have investigated the relationships between the potency observed in cell-based assays in vitro, the plasma exposure levels achieved following oral dosing, the time course of target inhibition in vivo, and antitumor activity of OSI-930 in tumor xenograft models. In the mutant Kit-expressing HMC-1 xenograft model, prolonged inhibition of Kit was achieved at oral doses between 10 and 50 mg/kg and this dose range was associated with antitumor activity. Similarly, prolonged inhibition of wild-type Kit in the NCI-H526 xenograft model was observed at oral doses of 100 to 200 mg/kg, which was the dose level associated with significant antitumor activity in this model as well as in the majority of other xenograft models tested. The data suggest that antitumor activity of OSI-930 in mouse xenograft models is observed at dose levels that maintain a significant level of inhibition of the molecular targets of OSI-930 for a prolonged period. Furthermore, pharmacokinetic evaluation of the plasma exposure levels of OSI-930 at these effective dose levels provides an estimate of the target plasma concentrations that may be required to achieve prolonged inhibition of Kit and KDR in humans and which would therefore be expected to yield a therapeutic benefit in future clinical evaluations of OSI-930.

Interference with PSMB4 Expression Exerts an Anti-Tumor Effect by Decreasing the Invasion and Proliferation of Human Glioblastoma Cells

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Yu-Chen Cheng

2018-01-01

Full Text Available Background/Aims: Glioblastoma (GBM is a malignant brain tumor with a poor prognosis. Proteasome subunit beta type-4 (PSMB4 is an essential subunit that contributes to the assembly of the 20S proteasome complex. However, the role of PSMB4 in glioblastomas remains to be clarified. The aim of this study was to investigate the role of PSMB4 in GBM tumor progression. Methods: We first analyzed the PSMB4 protein and mRNA expression in 80 clinical brain specimens and 77 datasets from the National Center for Biotechnology Information (NCBI Gene Expression Omnibus (GEO database. Next, we inhibited the PSMB4 expression by siRNA in cellular and animal models to explore PSMB4’s underlying mechanisms. The cell survival after siPSMB4 transfection was assayed by MTT assay. Annexin V and propidium iodide staining was used to monitor the apoptosis by flow cytometric analysis. Moreover, the migration and invasion were evaluated by wound healing and Transwell assays. The expression of migration-related and invasion-related proteins after PSMB4 inhibition was detected by Western blotting. In addition, an orthotropic xenograft mouse model was used to assay the effect of PSMB4 knockdown in the in vivo study. Results: Basis on the results of bioinformatics study, glioma patients with higher PSMB4 expression had a shorter survival time than those with lower PSMB4 expression. The staining of clinical brain tissues showed elevated PSMB4 expression in GBM tissues compared with normal brain tissues. The PSMB4 inhibition decreased proliferation, migration and invasion abilities in human GBM cells. Downregulated PSMB4 resulted in cell cycle arrest and apoptosis in vitro. In an orthotropic xenograft mouse model, the glioma tumors progression was reduced when PSMB4 was down-regulated. The decreased PSMB4 enhanced the anti-tumor effect of temozolomide (TMZ on tumor growth. In addition, the absence of PSMB4 decreased the expression of phosphorylated focal adhesion kinase and

Antitumor and angiostatic activities of the antimicrobial peptide dermaseptin B2.

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van Zoggel, Hanneke; Carpentier, Gilles; Dos Santos, Célia; Hamma-Kourbali, Yamina; Courty, José; Amiche, Mohamed; Delbé, Jean

2012-01-01

Recently, we have found that the skin secretions of the Amazonian tree frog Phyllomedusa bicolor contains molecules with antitumor and angiostatic activities and identified one of them as the antimicrobial peptide dermaseptin (Drs) B2. In the present study we further explored the in vitro and in vivo antitumor activity of this molecule and investigated its mechanism of action. We showed that Drs B2 inhibits the proliferation and colony formation of various human tumor cell types, and the proliferation and capillary formation of endothelial cells in vitro. Furthermore, Drs B2 inhibited tumor growth of the human prostate adenocarcinoma cell line PC3 in a xenograft model in vivo. Research on the mechanism of action of Drs B2 on tumor PC3 cells demonstrated a rapid increasing amount of cytosolic lactate dehydrogenase, no activation of caspase-3, and no changes in mitochondrial membrane potential. Confocal microscopy analysis revealed that Drs B2 can interact with the tumor cell surface, aggregate and penetrate the cells. These data together indicate that Drs B2 does not act by apoptosis but possibly by necrosis. In conclusion, Drs B2 could be considered as an interesting and promising pharmacological and therapeutic leader molecule for the treatment of cancer.

Antitumor and angiostatic activities of the antimicrobial peptide dermaseptin B2.

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Hanneke van Zoggel

Full Text Available Recently, we have found that the skin secretions of the Amazonian tree frog Phyllomedusa bicolor contains molecules with antitumor and angiostatic activities and identified one of them as the antimicrobial peptide dermaseptin (Drs B2. In the present study we further explored the in vitro and in vivo antitumor activity of this molecule and investigated its mechanism of action. We showed that Drs B2 inhibits the proliferation and colony formation of various human tumor cell types, and the proliferation and capillary formation of endothelial cells in vitro. Furthermore, Drs B2 inhibited tumor growth of the human prostate adenocarcinoma cell line PC3 in a xenograft model in vivo. Research on the mechanism of action of Drs B2 on tumor PC3 cells demonstrated a rapid increasing amount of cytosolic lactate dehydrogenase, no activation of caspase-3, and no changes in mitochondrial membrane potential. Confocal microscopy analysis revealed that Drs B2 can interact with the tumor cell surface, aggregate and penetrate the cells. These data together indicate that Drs B2 does not act by apoptosis but possibly by necrosis. In conclusion, Drs B2 could be considered as an interesting and promising pharmacological and therapeutic leader molecule for the treatment of cancer.

Antitumor effect of malaria parasite infection in a murine Lewis lung cancer model through induction of innate and adaptive immunity.

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Chen, Lili; He, Zhengxiang; Qin, Li; Li, Qinyan; Shi, Xibao; Zhao, Siting; Chen, Ling; Zhong, Nanshan; Chen, Xiaoping

2011-01-01

Lung cancer is the most common malignancy in humans and its high fatality means that no effective treatment is available. Developing new therapeutic strategies for lung cancer is urgently needed. Malaria has been reported to stimulate host immune responses, which are believed to be efficacious for combating some clinical cancers. This study is aimed to provide evidence that malaria parasite infection is therapeutic for lung cancer. Antitumor effect of malaria infection was examined in both subcutaneously and intravenously implanted murine Lewis lung cancer (LLC) model. The results showed that malaria infection inhibited LLC growth and metastasis and prolonged the survival of tumor-bearing mice. Histological analysis of tumors from mice infected with malaria revealed that angiogenesis was inhibited, which correlated with increased terminal deoxynucleotidyl transferase-mediated (TUNEL) staining and decreased Ki-67 expression in tumors. Through natural killer (NK) cell cytotoxicity activity, cytokine assays, enzyme-linked immunospot assay, lymphocyte proliferation, and flow cytometry, we demonstrated that malaria infection provided anti-tumor effects by inducing both a potent anti-tumor innate immune response, including the secretion of IFN-γ and TNF-α and the activation of NK cells as well as adaptive anti-tumor immunity with increasing tumor-specific T-cell proliferation and cytolytic activity of CD8(+) T cells. Notably, tumor-bearing mice infected with the parasite developed long-lasting and effective tumor-specific immunity. Consequently, we found that malaria parasite infection could enhance the immune response of lung cancer DNA vaccine pcDNA3.1-hMUC1 and the combination produced a synergistic antitumor effect. Malaria infection significantly suppresses LLC growth via induction of innate and adaptive antitumor responses in a mouse model. These data suggest that the malaria parasite may provide a novel strategy or therapeutic vaccine vector for anti-lung cancer

Antitumor effect of malaria parasite infection in a murine Lewis lung cancer model through induction of innate and adaptive immunity.

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Lili Chen

Full Text Available BACKGROUND: Lung cancer is the most common malignancy in humans and its high fatality means that no effective treatment is available. Developing new therapeutic strategies for lung cancer is urgently needed. Malaria has been reported to stimulate host immune responses, which are believed to be efficacious for combating some clinical cancers. This study is aimed to provide evidence that malaria parasite infection is therapeutic for lung cancer. METHODOLOGY/PRINCIPAL FINDINGS: Antitumor effect of malaria infection was examined in both subcutaneously and intravenously implanted murine Lewis lung cancer (LLC model. The results showed that malaria infection inhibited LLC growth and metastasis and prolonged the survival of tumor-bearing mice. Histological analysis of tumors from mice infected with malaria revealed that angiogenesis was inhibited, which correlated with increased terminal deoxynucleotidyl transferase-mediated (TUNEL staining and decreased Ki-67 expression in tumors. Through natural killer (NK cell cytotoxicity activity, cytokine assays, enzyme-linked immunospot assay, lymphocyte proliferation, and flow cytometry, we demonstrated that malaria infection provided anti-tumor effects by inducing both a potent anti-tumor innate immune response, including the secretion of IFN-γ and TNF-α and the activation of NK cells as well as adaptive anti-tumor immunity with increasing tumor-specific T-cell proliferation and cytolytic activity of CD8(+ T cells. Notably, tumor-bearing mice infected with the parasite developed long-lasting and effective tumor-specific immunity. Consequently, we found that malaria parasite infection could enhance the immune response of lung cancer DNA vaccine pcDNA3.1-hMUC1 and the combination produced a synergistic antitumor effect. CONCLUSIONS/SIGNIFICANCE: Malaria infection significantly suppresses LLC growth via induction of innate and adaptive antitumor responses in a mouse model. These data suggest that the malaria

Antitumor activity of vorinostat-incorporated nanoparticles against human cholangiocarcinoma cells.

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Kwak, Tae Won; Kim, Do Hyung; Jeong, Young-Il; Kang, Dae Hwan

2015-09-26

The aim of this study is to evaluate the anticancer activity of vorinostat-incorporated nanoparticles (vorinostat-NPs) against HuCC-T1 human cholangiocarcinoma cells. Vorinostat-NPs were fabricated by a nanoprecipitation method using poly(DL-lactide-co-glycolide)/poly(ethylene glycol) copolymer. Vorinostat-NPs exhibited spherical shapes with sizes Vorinostat-NPs have anticancer activity similar to that of vorinostat in vitro. Vorinostat-NPs as well as vorinostat itself increased acetylation of histone-H3. Furthermore, vorinostat-NPs have similar effectiveness in the suppression or expression of histone deacetylase, mutant type p53, p21, and PARP/cleaved caspase-3. However, vorinostat-NPs showed improved antitumor activity against HuCC-T1 cancer cell-bearing mice compared to vorinostat, whereas empty nanoparticles had no effect on tumor growth. Furthermore, vorinostat-NPs increased the expression of acetylated histone H3 in tumor tissue and suppressed histone deacetylase (HDAC) expression in vivo. The improved antitumor activity of vorinostat-NPs can be explained by molecular imaging studies using near-infrared (NIR) dye-incorporated nanoparticles, i.e. NIR-dye-incorporated nanoparticles were intensively accumulated in the tumor region rather than normal one. Our results demonstrate that vorinostat and vorinostat-NPs exert anticancer activity against HuCC-T1 cholangiocarcinoma cells by specific inhibition of HDAC expression. Thus, we suggest that vorinostat-NPs are a promising candidate for anticancer chemotherapy in cholangiocarcinoma. Graphical abstract Local delivery strategy of vorinostat-NPs against cholangiocarcinomas.

1,25D3 enhances antitumor activity of gemcitabine and cisplatin in human bladder cancer models

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Ma, Yingyu; Yu, Wei-Dong; Trump, Donald L.; Johnson, Candace S.

2010-01-01

Background 1,25 dihydroxyvitamin D3 (1,25D3) potentiates the cytotoxic effects of several common chemotherapeutic agents. The combination of gemcitabine and cisplatin (GC) is a current standard chemotherapy regimen for bladder cancer. We investigated whether 1,25D3 could enhance the antitumor activity of GC in bladder cancer model systems. Methods Human bladder cancer T24 and UMUC3 cells were pretreated with 1,25D3 followed by GC. Apoptosis were assessed by annexin V staining. Caspase activation was examined by immunoblot analysis and substrate-based caspase activity assay. The cytotoxic effects were examined using MTT and in vitro clonogenic assay. p73 protein levels were assessed by immunoblot analysis. Knockdown of p73 was achieved by siRNA. The in vivo antitumor activity was assessed by in vivo excision clonogenic assay and tumor regrowth delay in the T24 xenograft model. Results 1,25D3 pretreatment enhanced GC-induced apoptosis and the activities of caspases- 8, 9 and 3 in T24 and UMUC3 cells. 1,25D3 synergistically reduced GC-suppressed surviving fraction in T24 cells. 1,25D3, gemcitabine, or cisplatin induced p73 accumulation, which was enhanced by GC or 1,25D3 and GC. p73 expression was lower in human primary bladder tumor tissue compared with adjacent normal tissue. Knockdown of p73 increased clonogenic capacity of T24 cells treated with 1,25D3, GC or 1,25D3 and GC. 1,25D3 and GC combination enhanced tumor regression compared with 1,25D3 or GC alone. Conclusions 1,25D3 potentiates GC-mediated growth inhibition in human bladder cancer models in vitro and in vivo, which involves p73 induction and apoptosis. PMID:20564622

Optimizing the dosing schedule of l-asparaginase improves its anti-tumor activity in breast tumor-bearing mice

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Shoya Shiromizu

2018-04-01

Full Text Available Proliferation of acute lymphoblastic leukemic cells is nutritionally dependent on the external supply of asparagine. l-asparaginase, an enzyme hydrolyzing l-asparagine in blood, is used for treatment of acute lymphoblastic leukemic and other related blood cancers. Although previous studies demonstrated that l-asparaginase suppresses the proliferation of cultured solid tumor cells, it remains unclear whether this enzyme prevents the growth of solid tumors in vivo. In this study, we demonstrated the importance of optimizing dosing schedules for the anti-tumor activity of l-asparaginase in 4T1 breast tumor-bearing mice. Cultures of several types of murine solid tumor cells were dependent on the external supply of asparagine. Among them, we selected murine 4T1 breast cancer cells and implanted them into BALB/c female mice kept under standardized light/dark cycle conditions. The growth of 4T1 tumor cells implanted in mice was significantly suppressed by intravenous administration of l-asparaginase during the light phase, whereas its administration during the dark phase failed to show significant anti-tumor activity. Decreases in plasma asparagine levels due to the administration of l-asparaginase were closely related to the dosing time-dependency of its anti-tumor effects. These results suggest that the anti-tumor efficacy of l-asparaginase in breast tumor-bearing mice is improved by optimizing the dosing schedule. Keywords: l-asparaginase, Asparagine, Solid tumor, Chrono-pharmacotherapy

Optimizing the dosing schedule of l-asparaginase improves its anti-tumor activity in breast tumor-bearing mice.

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Shiromizu, Shoya; Kusunose, Naoki; Matsunaga, Naoya; Koyanagi, Satoru; Ohdo, Shigehiro

2018-04-01

Proliferation of acute lymphoblastic leukemic cells is nutritionally dependent on the external supply of asparagine. l-asparaginase, an enzyme hydrolyzing l-asparagine in blood, is used for treatment of acute lymphoblastic leukemic and other related blood cancers. Although previous studies demonstrated that l-asparaginase suppresses the proliferation of cultured solid tumor cells, it remains unclear whether this enzyme prevents the growth of solid tumors in vivo. In this study, we demonstrated the importance of optimizing dosing schedules for the anti-tumor activity of l-asparaginase in 4T1 breast tumor-bearing mice. Cultures of several types of murine solid tumor cells were dependent on the external supply of asparagine. Among them, we selected murine 4T1 breast cancer cells and implanted them into BALB/c female mice kept under standardized light/dark cycle conditions. The growth of 4T1 tumor cells implanted in mice was significantly suppressed by intravenous administration of l-asparaginase during the light phase, whereas its administration during the dark phase failed to show significant anti-tumor activity. Decreases in plasma asparagine levels due to the administration of l-asparaginase were closely related to the dosing time-dependency of its anti-tumor effects. These results suggest that the anti-tumor efficacy of l-asparaginase in breast tumor-bearing mice is improved by optimizing the dosing schedule. Copyright © 2018 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

Selenium-substituted hydroxyapatite nanoparticles and their in vivo antitumor effect on hepatocellular carcinoma.

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Yanhua, Wang; Hao, Hang; Li, Yan; Zhang, Shengmin

2016-04-01

Absence of curative treatment creates urgent need for new strategies for unresectable hepatoma. Novel selenium-substituted hydroxyapatite nanoparticles (SeHAN) were designed to serve as anticancer agent. The authors examined the nanoparticles by physicochemical techniques. The in vivo efficacy and toxicity of these nanoparticles were also investigated on a nude mice model of human hepatocellular carcinoma. The results showed that the selenite ions can be incorporated into the hydroxyapatite lattice facilely. They exhibited bundles of needles shape with a size of 160-200 nm. In the in vivo study, they showed better survival advantage. The overall survival rate of nude mice in the control, pure hydroxyapatite and SeHAN group were 50.00%, 76.92%, and 100.00% respectively. Blood biochemical studies showed that SeHAN group had significantly lower toxicities on the liver and kidney functions. Histopathological studies confirmed that massive tumor necrosis and calcium deposition were evident after SeHAN treatment. Moreover, immunohistochemistry and Western blot assay showed significantly reduced expression of the Ki-67, VEGF and MMP-9 protein in the SeHAN group. Taken together, these results suggest that the selenium-substituted hydroxyapatite nanoparticles could be a new type of promising anticancer agent to provide both survival advantage and lower toxicity. Copyright © 2016 Elsevier B.V. All rights reserved.

Antitumor Effects In Vitro and In Vivo and Mechanisms of Protection against Melanoma B16F10-Nex2 Cells By Fastuosain, a Cysteine Proteinase from Bromelia fastuosa

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Carla A. Guimarães-Ferreira

2007-09-01

Full Text Available In the present work, the antitumor effect of fastuosain, a cysteine proteinase from Bromelia fastuosa, was investigated. In the intravenous model of lung colonization in C57BI/6 mice, fastuosain and bromelain injected intraperitoneally were protective, very few nodules of B16F10-Nex2 melanoma cells were detected. Tumor cells treated with fastuosain showed reduced expression of CD44 and decreased invasion through Matrigel, lost their cytoplasmic extensions and substrate adherence, became round and detached, forming strongly bound cell clusters in suspension. Peritoneal cells recruited and activated by fastuosain treatment (mainly monocytic cells and lymphocytes migrated to the lung, where pulmonary melanoma metastases grew. Adoptive transference of peritoneal cells recruited by fastuosain had no protective effect against lung metastases in recipient mice. Treatment of green fluorescent protein -chimeric animals with fastuosain did not change the number of cells that migrated to the lung, compared to PBSinjected control mice, but the number of positive major histocompatibility complex class II cells increased with fastuosain treatment. Murine antibodies against fastuosain, bromelain, cathepsins B and L crossreacted in ELISA and recognized surface and cytoplasmic components expressed on B16F10-Nex2 cells. Anti-fastuosain antibodies were cytotoxic/lytic to B16F10-Nex2 cells. Antitumor effects of fastuosain involve mainly the direct effect of the enzyme and elicitation of protective antibodies.

Antitumor effect of triptolide in T-cell lymphoblastic lymphoma by inhibiting cell viability, invasion, and epithelial–mesenchymal transition via regulating the PI3K/AKT/mTOR pathway

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Huang Y

2018-02-01

Full Text Available Yan Huang, Sun Wu, Yuan Zhang, Lihua Wang, Yan Guo Department of Hematology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, People’s Republic of China Introduction: T-cell lymphoblastic lymphoma (T-LBL is a widely disseminated disease worldwide. Triptolide (TPL is purified from Chinese herb and displays anti-inflammatory, anti-fertility, anti-tumor and immunosuppressive effects. Materials and methods: Here, in vitro and in vivo experiments were conducted to investigate the anti-tumor effect of TPL treatment in T-LBL and the potential mechanism in T-LBL progression. Results: TPL inhibited cell proliferation of T-LBL cells (Jurkat cells and Molt-3 cells in a dose-dependent manner. Flow cytometry analysis showed that cell apoptosis rate was increased by TPL treatment. TPL also up-regulated the expression of Caspase-3, Bax and down-regulated the expression of Bcl-2, indicating that TPL promoted apoptosis in Jurkat cells. Moreover, TPL inhibited invasion ability of Jurkat cells and down-regulated the expression of MMP-3 and MMP-9 in a dose-dependent manner. The expression of Snail, Slug, Twist and Integrin αVβ6 was decreased and the expression of E-cadherin was increased by TPL treatment, indicating that TPL inhibited EMT of Jurkat cells. Apart from that, TPL treatment attenuated the phoslevels of PI3K, Akt and mTOR and suppressed AKT activation compared with control group, suggesting that TPL inhibited PI3K/Akt/mTOR signal pathway in T-LBL. In vivo experiments showed that TPL inhibited tumor growth of T-LBL and promoted apoptosis of tumor cells. The expression of PCNA, Bcl-2, Snail, p-PI3K, p-Akt and mTOR was suppressed by TPL in a dose-dependent manner, suggesting that TPL suppressed tumor growth and promoted apoptosis of tumor cells by inhibiting PI3K/Akt/mTOR signal pathway in T-LBL. Conclusion: In conclusion, TPL exerted anti-tumor effect in T-LBL by inhibiting cell viability, invasion and EMT via regulating the PI3K

Immunotherapeutic effect of Concholepas hemocyanin in the murine bladder cancer model: evidence for conserved antitumor properties among hemocyanins.

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Moltedo, Bruno; Faunes, Fernando; Haussmann, Denise; De Ioannes, Pablo; De Ioannes, Alfredo E; Puente, Javier; Becker, María Inés

2006-12-01

We determined the antitumor properties of a newly available hemocyanin obtained from the Chilean gastropod Concholepas concholepas (Biosonda Corp., Santiago, Chile) in a syngeneic heterotopic mouse bladder carcinoma model. Since keyhole limpet hemocyanin (Pierce, Rockford, Illinois) is used increasingly in biomedicine as a carrier for vaccines and an immunotherapeutic agent for bladder transitional cell carcinoma, there is a growing interest in finding new substances that share its potent immunomodulatory properties. Considering that keyhole limpet hemocyanin and Concholepas concholepas hemocyanin differ significantly, it was not possible to predict a priori the antitumor properties of Concholepas concholepas hemocyanin. C3H/He mice were primed with Concholepas concholepas hemocyanin before subcutaneous implantation of mouse bladder tumor-2 cells. Treatment consisted of a subcutaneous dose of Concholepas concholepas hemocyanin (1 mg or 100 mug) at different intervals after implantation. Keyhole limpet hemocyanin and phosphate buffered saline served as positive and negative controls, respectively. In addition, experiments were designed to determine which elements of the immune response were involved in its adjuvant immunostimulatory effect. Mice treated with Concholepas concholepas hemocyanin showed a significant antitumor effect, as demonstrated by decreased tumor growth and incidence, prolonged survival and lack of toxic effects. These effects were similar to those achieved with keyhole limpet hemocyanin. We found that each hemocyanin increased natural killer cell activity but the effect of Concholepas concholepas hemocyanin was stronger. Analysis of serum from treated mice showed an increased interferon-gamma and low interleukin-4, which correlated with antibody isotypes, confirming that hemocyanins induce a T helper type 1 cytokine profile. To our knowledge our results are the first demonstration of the antitumor effect of a hemocyanin other than keyhole limpet

Carcinogenic and antitumor effects of aminotriazole on acatalasemic and normal catalase mice

International Nuclear Information System (INIS)

Feinstein, R.N.; Fry, R.J.M.; Staffeidt, E.F.

1978-01-01

Dietary 3-amino-1H-1,2,4-triazole (AT), although carcinogenic when administered alone, was an antitumor agent when combined with certain other carcinogenic stimuli. The carcinogenic effect was prominent in the livers of C3H mice; thyroid tumors were less common because they required a longer period of development, and the life-span of the animal was shortened by the AT diet. The antitumor effects of AT included: delay in appearance of mammary tumors, striking reduction in γ-radiation-induced lymphomas, and sharp reduction in neutron radiation-induced harderian gland and ovarian tumors. On an AT diet, the inbred C3H acatalasemic mouse substrain developed more liver tumors, starting earlier, than did the C3H normal catalase substrain. We suggest that our findings pointed to a possible relevance of catalase and H 2 O 2 in carcinogenesis. The most probable mechanism for the increased incidence of liver tumors in AT-treated acatalasemic mice was the diminished rate of degradation of endogenous H 2 O 2

N-ω-chloroacetyl-L-ornithine has in-vitro activity against cancer cell lines and in-vivo activity against ascitic and solid tumors.

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Vargas-Ramírez, Alba L; Medina-Enríquez, Miriam M; Cordero-Rodríguez, Neira I; Ruiz-Cuello, Tatiana; Aguilar-Faisal, Leopoldo; Trujillo-Ferrara, José G; Alcántara-Farfán, Verónica; Rodríguez-Páez, Lorena

2016-07-01

N-ω-chloroacetyl-L-ornithine (NCAO) is an ornithine decarboxylase (ODC) inhibitor that is known to exert cytotoxic and antiproliferative effects on three neoplastic human cancer cell lines (HeLa, MCF-7, and HepG2). Here, we show that NCAO has antiproliferative activity in 13 cancer cell lines, of diverse tissue origin from human and mice, and in a mouse cancer model in vivo. All cell lines were sensitive to NCAO after 72 h of treatment (the EC50 ranged from 1 to 50.6 µmol/l). The Ca Ski cell line was the most sensitive (EC50=1.18±0.07 µmol/l) and MDA-MB-231 was the least sensitive (EC50=50.6±0.3 µmol/l). This ODC inhibitor showed selectivity for cancer cells, exerting almost no cytotoxic effect on the normal Vero cell line (EC50>1000 µmol/l). NCAO induced apoptosis and inhibited tumor cell migration in vitro. Furthermore, in vivo, this compound (at 50 and 100 mg/kg, daily intraperitoneal injection for 7 days) exerted potent antitumor activity against both solid and ascitic tumors in a mouse model using the myeloma (Ag8) cell line. At these same two doses, the toxicological evaluation showed that NCAO has no obvious systemic toxicity. The current results suggest that the antitumor activity is exerted by apoptosis related not only to a local but also a systemic cytotoxic effect exerted by NCAO on tumor cells. The applications for NCAO as an antitumor agent may be extensive; however, further studies are needed to ascertain the antitumor activity on other types of tumor in vivo and to determine the precise molecular mechanism of its activity.

[Effective productions of plant secondary metabolites having antitumor activity by plant cell and tissue cultures].

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Taniguchi, Shoko

2005-06-01

Methods for the effective production of plant secondary metabolites with antitumor activity using plant cell and tissue cultures were developed. The factors in tannin productivity were investigated using culture strains producing different types of hydrolyzable tannins, i.e., gallotannins (mixture of galloylglucoses), ellagi-, and dehydroellagitannins. Production of ellagi- and dehydroellagitannins was affected by the concentrations and ratio of nitrogen sources in the medium. The formation of oligomeric ellagitannins in shoots of Oenothera tetraptera was correlated with the differentiation of tissues. Cultured cells of Eriobotrya japonica producing ursane- and oleanane-type triterpenes with antitumor activities were also established.

Ibrutinib, a Bruton's tyrosine kinase inhibitor, exhibits antitumoral activity and induces autophagy in glioblastoma.

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Wang, Jin; Liu, Xiaoyang; Hong, Yongzhi; Wang, Songtao; Chen, Pin; Gu, Aihua; Guo, Xiaoyuan; Zhao, Peng

2017-07-17

Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults. Ibrutinib, a Bruton's tyrosine kinase (BTK) inhibitor, is a novel anticancer drug used for treating several types of cancers. In this study, we aimed to determine the role of ibrutinib on GBM. Cell proliferation was determined by using cell viability, colony formation, and 5-ethynyl-2'-deoxyuridine (EdU) assays. Cell cycle and cell apoptosis were analyzed by flow cytometry. Cell migratory ability was evaluated by wound healing assays and trans-well migration assays. ATG7 expression was knocked-down by transfection with Atg7-specific small interfering RNA. Overexpression of active Akt protein was achieved by transfecting the cells with a plasmid expressing constitutively active Akt (CA-Akt). Transmission electron microscopy was performed to examine the formation of autophagosomes in cells. Immunofluorescence and western blot analyses were used to analyze protein expression. Tumor xenografts in nude mice and immunohistochemistry were performed to evaluate the effect of ibrutinib on tumor growth in vivo. Ibrutinib inhibited cellular proliferation and migration, and induced apoptosis and autophagy in LN229 and U87 cells. Overexpression of the active Akt protein decreased ibrutinib-induced autophagy, while inhibiting Akt by LY294002 treatment enhanced ibrutinib-induced autophagy. Specific inhibition of autophagy by 3-methyladenine (3MA) or Atg7 targeting with small interfering RNA (si-Atg7) enhanced the anti-GBM effect of ibrutinib in vitro and in vivo. Our results indicate that ibrutinib exerts a profound antitumor effect and induces autophagy through Akt/mTOR signaling pathway in GBM cells. Autophagy inhibition promotes the antitumor activity of ibrutinib in GBM. Our findings provide important insights into the action of an anticancer agent combining with autophagy inhibitor for malignant glioma.

Macrophage PPARγ inhibits Gpr132 to mediate the anti-tumor effects of rosiglitazone

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Cheng, Wing Yin; Huynh, HoangDinh; Chen, Peiwen; Peña-Llopis, Samuel; Wan, Yihong

2016-01-01

Tumor-associated macrophage (TAM) significantly contributes to cancer progression. Human cancer is enhanced by PPARγ loss-of-function mutations, but inhibited by PPARγ agonists such as TZD diabetes drugs including rosiglitazone. However, it remains enigmatic whether and how macrophage contributes to PPARγ tumor-suppressive functions. Here we report that macrophage PPARγ deletion in mice not only exacerbates mammary tumor development but also impairs the anti-tumor effects of rosiglitazone. Mechanistically, we identify Gpr132 as a novel direct PPARγ target in macrophage whose expression is enhanced by PPARγ loss but repressed by PPARγ activation. Functionally, macrophage Gpr132 is pro-inflammatory and pro-tumor. Genetic Gpr132 deletion not only retards inflammation and cancer growth but also abrogates the anti-tumor effects of PPARγ and rosiglitazone. Pharmacological Gpr132 inhibition significantly impedes mammary tumor malignancy. These findings uncover macrophage PPARγ and Gpr132 as critical TAM modulators, new cancer therapeutic targets, and essential mediators of TZD anti-cancer effects. DOI: http://dx.doi.org/10.7554/eLife.18501.001 PMID:27692066

Properties of realgar bioleaching using an extremely acidophilic bacterium and its antitumor mechanism as an anticancer agent.

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Chen, Peng; Xu, Ruixiang; Yan, Lei; Wu, Zhengrong; Wei, Yan; Zhao, Wenbin; Wang, Xin; Xie, Qinjian; Li, Hongyu

2017-05-22

Realgar is a naturally occurring arsenic sulfide (or Xionghuang, in Chinese). It contains over 90% tetra-arsenic tetra-sulfide (As 4 S 4 ). Currently, realgar has been confirmed the antitumor activities, both in vitro and in vivo, of realgar extracted using Acidithiobacillus ferrooxidans (A. ferrooxidans). Bioleaching, a new technology to greatly improve the use rate of arsenic extraction from realgar using bacteria, is a novel methodology that addressed a limitation of the traditional method for realgar preparation. The present systematic review reports on the research progress in realgar bioleaching and its antitumor mechanism as an anticancer agent. A total of 93 research articles that report on the biological activity of extracts from realgar using bacteria and its preparation were presented in this review. The realgar bioleaching solution (RBS) works by inducing apoptosis when it is used to treat tumor cells in vitro and in vivo. When it is used to treat animal model organisms in vivo, such as mice and Caenorhabditis elegans, tumor tissues grew more slowly, with mass necrosis. Meanwhile, the agent also showed obvious inhibition of tumor cell growth. Bioleaching technology greatly improves the utilization of realgar and is a novel methodology to improve the traditional method.

Ascorbyl palmitate/d-α-tocopheryl polyethylene glycol 1000 succinate monoester mixed micelles for prolonged circulation and targeted delivery of compound K for antilung cancer therapy in vitro and in vivo

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Zhang Y

2017-01-01

Full Text Available Youwen Zhang, Deyin Tong, Daobiao Che, Bing Pei, Xiaodong Xia, Gaofeng Yuan, Xin Jin Department of Hospital Pharmacy, The First Hospital of Suqian, Suqian, People’s Republic of China Abstract: The roles of ginsenoside compound K (CK in inhibiting tumor have been widely recognized in recent years. However, low water solubility and significant P-gp efflux have restricted its application. In this study, CK ascorbyl palmitate (AP/d-α-tocopheryl polyethylene glycol 1000 succinate monoester (TPGS mixed micelles were prepared as a delivery system to increase the absorption and targeted antitumor effect of CK. Consequently, the solubility of CK increased from 35.2±4.3 to 1,463.2±153.3 µg/mL. Furthermore, in an in vitro A549 cell model, CK AP/TPGS mixed micelles significantly inhibited cell growth, induced G0/G1 phase cell cycle arrest, induced cell apoptosis, and inhibited cell migration compared to free CK, all indicating that the developed micellar delivery system could increase the antitumor effect of CK in vitro. Both in vitro cellular fluorescence uptake and in vivo near-infrared imaging studies indicated that AP/TPGS mixed micelles can promote cellular uptake and enhance tumor targeting. Moreover, studies in the A549 lung cancer xenograft mouse model showed that CK AP/TPGS mixed micelles are an efficient tumor-targeted drug delivery system with an effective antitumor effect. Western blot analysis further confirmed that the marked antitumor effect in vivo could likely be due to apoptosis promotion and P-gp efflux inhibition. Therefore, these findings suggest that the AP/TPGS mixed micellar delivery system could be an efficient delivery strategy for enhanced tumor targeting and antitumor effects. Keywords: ginsenoside CK, ascorbyl palmitate, TPGS, mixed micelles, anti-tumor therapy

Dual actions of albumin packaging and tumor targeting enhance the antitumor efficacy and reduce the cardiotoxicity of doxorubicin in vivo

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Zheng K

2015-08-01

Full Text Available Ke Zheng,1 Rui Li,2 Xiaolei Zhou,2 Ping Hu,2 Yaxin Zhang,2 Yunmei Huang,3 Zhuo Chen,2 Mingdong Huang2 1College of Chemistry, Fuzhou University, Fuzhou, People’s Republic of China; 2State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, People’s Republic of China; 3Fujian Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, People’s Republic of China Abstract: Doxorubicin (DOX is an effective chemotherapy drug used to treat different types of cancers. However, DOX has severe side effects, especially life-threatening cardiotoxicity. We herein report a new approach to reduce the toxicity of DOX by embedding DOX inside human serum albumin (HSA. HSA is further fused by a molecular biology technique with a tumor-targeting agent, amino-terminal fragment of urokinase (ATF. ATF binds with a high affinity to urokinase receptor, which is a cell-surface receptor overexpressed in many types of tumors. The as-prepared macromolecule complex (ATF–HSA:DOX was not as cytotoxic as free DOX to cells in vitro, and was mainly localized in cell cytosol in contrast to DOX that was localized in cell nuclei. However, in tumor-bearing mice, ATF–HSA:DOX was demonstrated to have an enhanced tumor-targeting and antitumor efficacy compared with free DOX. More importantly, histopathological examinations of the hearts from the mice treated with ATF–HSA:DOX showed a significantly reduced cardiotoxicity compared with hearts from mice treated with free DOX. These results demonstrate the feasibility of this approach in reducing the cardiotoxicity of DOX while strengthening its antitumor efficacy. Such a tumor-targeted albumin packaging strategy can also be applied to other antitumor drugs. Keywords: amino-terminal fragment of urokinase, urokinase receptor, drug carrier, human serum albumin, doxorubicin, cytotoxicity

In vitro and in vivo studies of the combination of IGF1R inhibitor figitumumab (CP-751,871) with HER2 inhibitors trastuzumab and neratinib.

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Chakraborty, Ashok K; Zerillo, Cynthia; DiGiovanna, Michael P

2015-08-01

The insulin-like growth factor I receptor (IGF1R) has been linked to resistance to HER2-directed therapy with trastuzumab (Herceptin). We examined the anti-tumor activity of figitumumab (CP-751,871), a human monoclonal antibody that blocks IGF1R ligand binding, alone and in combination with the therapeutic anti-HER2 antibody trastuzumab and the pan-HER family tyrosine kinase inhibitor neratinib, using in vitro and in vivo breast cancer model systems. In vitro assays of proliferation, apoptosis, and signaling, and in vivo anti-tumor experiments were conducted in HER2-overexpressing (BT474) and HER2-normal (MCF7) models. We find single-agent activity of the HER2-targeting drugs but not figitumumab in the BT474 model, while the reverse is true in the MCF7 model. However, in both models, combining figitumumab with HER2-targeting drugs shows synergistic anti-proliferative and apoptosis-inducing effects, and optimum inhibition of downstream signaling. In murine xenograft models, synergistic anti-tumor effects were observed in the HER2-normal MCF7 model for the combination of figitumumab with trastuzumab, and, in the HER2-overexpressing BT474 model, enhanced anti-tumor effects were observed for the combination of figitumumab with either trastuzumab or neratinib. Analysis of tumor extracts from the in vivo experiments showed evidence of the most optimal inhibition of downstream signaling for the drug combinations over the single-agent therapies. These results suggest promise for such combinations in treating patients with breast cancer, and that, unlike the case for single-agent therapy, the therapeutic effects of such combinations may be independent of expression levels of the individual receptors or the single-agent activity profile.

Radiation protection and antitumor effects in Hatakeshimeji (Lyophyllum decastes sing)

International Nuclear Information System (INIS)

Ukawa, Yuuichi; Gu, Yeunhwa; Suzuki, Ikukatsu; Park, Sangrae; Hasegawa, Takeo; Tsukada, Sekihito; Terai, Kaoru; Tawaraya, Hitoshi

2002-01-01

The effect on an anti-tumor is admitted in the lyophyllum decastes sing extraction thing, and it has the action mechanism cleared to depend on the immunity action. The existence of the synergistic effect in effect on an anti-tumor radiation irradiation, an individual with the medication of lyophyllum decastes sing and effect on combination and the effect on protection of the leukocyte decrease by the radiation was examined by this research. After about 2x10 6 inoculated sarcoma 180 on the ICR mice, a lyophyllum decastes sing extraction thing gave 100mg/kg for 2 weeks in endoceliac at the every other day. After that, the radiation irradiation of 2 Gy was done three times, and it went to the sutra time target the number of the leukocytes, the lymph node ball some prizes of measurement. And, weight and tumor size were measured after the cancer cell inoculation two weeks. The decrease of the clear tumor size was recognized by the group that only a cancer cell was inoculated by the radiation independent irradiation group, lyophyllum decastes sing and the radiation combination group though tumor size increased as it passed. It faced by the group that only a cancer cell was inoculated after the irradiation 15 days though it died the precedent, and a half existed by lyophyllum decastes sing and the radiation combination group. And, the numbers of the leukocytes, the number of the lymphocyte were on the increase regardless of the existence of the radiation irradiation by the medication of lyophyllum decastes sing. It thinks with the thing that the effect is shown for the effect on immunity recovery in the radiotherapy and the prevention of a side effect of the radiation from this result. Showing the effect for not only effect on prevention of the cancer and effect on healing but also the effect on immunity recovery in the radiotherapy, the prevention of a side effect by taking lyophyllum decastes sing is considered

Antitumor activity of Chlorella sorokiniana and Scenedesmus sp. microalgae native of Nuevo León State, México

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Beltrán-Rocha, Julio Cesar

2018-01-01

Cancer cases result in 13% of all deaths worldwide. Unwanted side effects in patients under conventional treatments have led to the search for beneficial alternative therapies. Microalgae synthesize compounds with known in vitro and in vivo biological activity against different tumor cell lines. Therefore, native microalgae from the State of Nuevo Leon, Mexico may become a potential source of antitumor agents. The aim of the present study was to evaluate the in vitro cytotoxic effect of Nuevo Leon regional Chlorella sorokiniana (Chlorellales: Chlorellaceae) and Scenedesmus sp. (Chlorococcales: Scenedesmaceae). Native microalgae crude organic extracts cytotoxicity against murine L5178Y-R lymphoma cell line and normal lymphocyte proliferation were evaluated using the MTT reduction colorimetric assay. Cell death pathway was analyzed by acridine orange and ethidium bromide staining, DNA degradation in 2% agarose gel electrophoresis and caspases activity. Results indicated significant (p Scenedesmus sp. methanol extracts, respectively, at 500 µg/mL, by the mechanism of apoptosis. This study contributes to Mexican microalgae biodiversity knowledge and their potential as antitumor agent sources. PMID:29441241

Degalactosylated/desialylated human serum containing GcMAF induces macrophage phagocytic activity and in vivo antitumor activity.

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Kuchiike, Daisuke; Uto, Yoshihiro; Mukai, Hirotaka; Ishiyama, Noriko; Abe, Chiaki; Tanaka, Daichi; Kawai, Tomohito; Kubo, Kentaro; Mette, Martin; Inui, Toshio; Endo, Yoshio; Hori, Hitoshi

2013-07-01

The group-specific component protein-derived macrophage-activating factor (GcMAF) has various biological activities, such as macrophage activation and antitumor activity. Clinical trials of GcMAF have been carried out for metastatic breast cancer, prostate cancer, and metastatic colorectal cancer. In this study, despite the complicated purification process of GcMAF, we used enzymatically-treated human serum containing GcMAF with a considerable macrophage-stimulating activity and antitumor activity. We detected GcMAF in degalactosylated/desialylated human serum by western blotting using an anti-human Gc globulin antibody, and Helix pomatia agglutinin lectin. We also found that GcMAF-containing human serum significantly enhanced the phagocytic activity of mouse peritoneal macrophages and extended the survival time of mice bearing Ehrlich ascites tumors. We demonstrated that GcMAF-containing human serum can be used as a potential macrophage activator for cancer immunotherapy.

The anti-tumor effect of the quinoline-3-carboxamide tasquinimod: blockade of recruitment of CD11b+ Ly6Chi cells to tumor tissue reduces tumor growth

International Nuclear Information System (INIS)

Deronic, Adnan; Leanderson, Tomas; Ivars, Fredrik

2016-01-01

Previous work has demonstrated immunomodulatory, anti-tumor, anti-metastatic and anti-angiogenic effects of the small molecule quinoline-3-carboxamide tasquinimod in pre-clinical cancer models. To better understand the anti-tumor effects of tasquinimod in transplantable tumor models, we have evaluated the impact of the compound both on recruitment of myeloid cells to tumor tissue and on tumor-induced myeloid cell expansion as these cells are known to promote tumor development. Mice bearing subcutaneous 4 T1 mammary carcinoma tumors were treated with tasquinimod in the drinking water. A BrdU-based flow cytometry assay was utilized to assess the impact of short-term tasquinimod treatment on myeloid cell recruitment to tumors. Additionally, long-term treatment was performed to study the anti-tumor effect of tasquinimod as well as its effects on splenic myeloid cells and their progenitors. Myeloid cell populations were also immune-depleted by in vivo antibody treatment. Short-term tasquinimod treatment did not influence the proliferation of splenic Ly6C hi and Ly6G hi cells, but instead reduced the influx of Ly6C hi cells to the tumor. Treatment with tasquinimod for various periods of time after tumor inoculation revealed that the anti-tumor effect of this compound mainly operated during the first few days of tumor growth. Similar to tasquinimod treatment, antibody-mediated depletion of Ly6C hi cells within that same time frame, caused reduced tumor growth, thereby confirming a significant role for these cells in tumor development. Additionally, long-term tasquinimod treatment reduced the splenomegaly and expansion of splenic myeloid cells during a later phase of tumor development. In this phase, tasquinimod normalized the tumor-induced alterations in myeloerythroid progenitor cells in the spleen but had only limited impact on the same populations in the bone marrow. Our results indicate that tasquinimod treatment reduces tumor growth by operating early after tumor

Novel Antitumor Strategy Utilizing a Plasmid Expressing a Mycobacterium tuberculosis Antigen as a “Danger Signal” to Block Immune Escape of Tumor Cells

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Yoshiyuki Koyama

2015-07-01

Full Text Available Immune escape of tumor cells is one of the main obstacles hindering the effectiveness of cancer immunotherapy. We developed a novel strategy to block immune escape by transfecting tumor cells in vivo with genes of pathogenic antigens from Mycobacterium tuberculosis (TB. This induces presentation of the TB antigen on tumor cell surfaces, which can be recognized by antigen presenting cells (APCs as a “danger signal” to stimulate antitumor immune response. This strategy is also expected to amplify the immune response against tumor-associated antigens, and block immune escape of the tumor. DNA/PEI/chondroitin sulfate ternary complex is a highly effective non-viral gene vector system for in vivo transfection. A therapeutic complex was prepared using a plasmid encoding the TB antigen, early secretory antigenic target-6 (ESAT-6. This was injected intratumorally into syngeneic tumor-bearing mice, and induced significant tumor growth suppression comparable to or higher than similar complexes expressing cytokines such as interleukin-2 (IL-2 and interleukin-12 (IL-12. Co-transfection of the cytokine-genes and the ESAT-6-gene enhanced the antitumor efficacy of either treatment alone. In addition, complete tumor regression was achieved with the combination of ESAT-6 and IL-2 genes.

Effects of Different Temperatures on the Chemical Structure and Antitumor Activities of Polysaccharides from Cordyceps militaris

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Eliyas Nurmamat

2018-04-01

Full Text Available The effects of different extraction temperatures (4 and 80 °C on the physicochemical properties and antitumor activity of water soluble polysaccharides (CMPs-4 and CMPs-80 from Cordyceps militaris (C. militaris were evaluated in this study. The results of gas chromatography (GC and high-performance gel permeation chromatography (HPGPC showed that a higher extraction temperature could degrade the polysaccharides with 188 kDa, mainly composed of glucose, and increase the dissolution rate of polysaccharides about 308 kDa, mainly consisting of rhamnose and galactose. In addition, the CMPs displayed the same sugar ring and category of glycosidic linkage based on Fourier-transform infrared spectroscopy (FTIR analysis, however, their invisible structural difference occurred in the specific rotation and conformational characteristics according to the results of specific optical rotation measurement and Congo red test. In vitro antitumor experiments indicated that CMPs-4 possessed stronger inhibitory effects on human esophagus cancer Eca-109 cells by inducing cell apoptosis more than CMPs-80 did. These findings demonstrated that the polysaccharides extracted with cold water (4 °C could be applied as a novel alternative chemotherapeutic agent or dietary supplement with its underlying antitumor property.

Potent antitumor bifunctional DNA alkylating agents, synthesis and biological activities of 3a-aza-cyclopenta[a]indenes.

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Kakadiya, Rajesh; Dong, Huajin; Lee, Pei-Chih; Kapuriya, Naval; Zhang, Xiuguo; Chou, Ting-Chao; Lee, Te-Chang; Kapuriya, Kalpana; Shah, Anamik; Su, Tsann-Long

2009-08-01

A series of bifunctional DNA interstrand cross-linking agents, bis(hydroxymethyl)- and bis(carbamates)-8H-3a-azacyclopenta[a]indene-1-yl derivatives were synthesized for antitumor evaluation. The preliminary antitumor studies revealed that these agents exhibited potent cytotoxicity in vitro and antitumor therapeutic efficacy against human tumor xenografts in vivo. Furthermore, these derivatives have little or no cross-resistance to either Taxol or Vinblastine. Remarkably, complete tumor remission in nude mice bearing human breast carcinoma MX-1 xenograft by 13a,b and 14g,h and significant suppression against prostate adenocarcinoma PC3 xenograft by 13b were achieved at the maximum tolerable dose with relatively low toxicity. In addition, these agents induce DNA interstrand cross-linking and substantial G2/M phase arrest in human non-small lung carcinoma H1299 cells. The current studies suggested that these agents are promising candidates for preclinical studies.

Polysaccharides Extracted from Rhizoma Pleionis Have Antitumor Properties In Vitro and in an H22 Mouse Hepatoma Ascites Model In Vivo

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Yukun Fang

2018-05-01

Full Text Available Malignant ascites is a highly severe and intractable complication of advanced or recurrent malignant tumors that is often immunotherapy-resistant. Rhizoma Pleionis is widely used in traditional medicine as an antimicrobial and anticancer agent, but its effectiveness in treating malignant ascites is unclear. In the current study, we investigated the effect of polysaccharides isolated from Rhizoma Pleionis (PRP on murine hepatocarcinoma H22 cells in an ascites model. We have found that the main components of PRP, that presented a relative molecular weight of 383.57 kDa, were mannose and glucose. We also found that PRP reduced the occurrence of abdominal ascites and increased survival in our mouse model. An immune response in the ascites tumor model was observed by performing a lymphocytes proliferation experiment and an E-rosette test. The ratios of CD8+ cytotoxic T cells and NK cells in the spleen were examined by flow cytometry, and the mRNA expression of Foxp3+in CD4+CD25+ (T regulatory Tregs was measured by RT-PCR (reverse transcription-polymerase chain reaction. The levels of the cytokines TNF-α (tumor necrosis factor, VEGF (vascular endothelial growth factor, IL-2 (interleukin, and IFN-γ (interferon in the serum and ascites supernatants were measured by ELISA. The expression of Foxp3 and Stat3 in peritoneal cells in the mouse model was measured by immunocytochemistry. The results indicated that PRP increased H22 tumor cell apoptosis in vivo by activating and enhancing the immune response. Furthermore, the effects of PRP on the proliferation of H22 cells were assessed by the CCK8 assay, Hoechest 33258, and TUNEL staining in vitro. We found that PRP suppressed the proliferation of H22 tumor cells but had no effect on BRL (Big rat liver -3A rat hepatoma normal cells in vitro. Next, we investigated the underlying immunological mechanism by which PRP inhibits malignant ascites. PRP induced tumor cell apoptosis by inhibiting the Jak1–Stat3

Multilineage hematopoietic recovery with concomitant antitumor effects using low dose Interleukin-12 in myelosuppressed tumor-bearing mice

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Miller Joseph D

2008-05-01

Full Text Available Abstract Background Interleukin-12 (IL-12 is a cytokine well known for its role in immunity. A lesser known function of IL-12 is its role in hematopoiesis. The promising data obtained in the preclinical models of antitumor immunotherapy raised hope that IL-12 could be a powerful therapeutic agent against cancer. However, excessive clinical toxicity, largely due to repeat dose regimens, and modest clinical response observed in the clinical trials have pointed to the necessity to design protocols that minimize toxicity without affecting the anti-tumor effect of IL-12. We have focused on the lesser known role of IL-12 in hematopoiesis and hypothesized that an important clinical role for IL-12 in cancer may be as an adjuvant hematological cancer therapy. In this putative clinical function, IL-12 is utilized for the prevention of cancer therapy-related cytopenias, while providing concomitant anti-tumor responses over and above responses observed with the primary therapy alone. This putative clinical function of IL-12 focuses on the dual role of IL-12 in hematopoiesis and immunity. Methods We assessed the ability of IL-12 to facilitate hematopoietic recovery from radiation (625 rad and chemotherapy (cyclophosphamide in two tumor-bearing murine models, namely the EL4 lymphoma and the Lewis lung cancer models. Antitumor effects and changes in bone marrow cellularity were also assessed. Results We show herein that carefully designed protocols, in mice, utilizing IL-12 as an adjuvant to radiation or chemotherapy yield facile and consistent, multilineage hematopoietic recovery from cancer therapy-induced cytopenias, as compared to vehicle and the clinically-utilized cytokine granulocyte colony-stimulating factor (G-CSF (positive control, while still providing concomitant antitumor responses over and above the effects of the primary therapy alone. Moreover, our protocol design utilizes single, low doses of IL-12 that did not yield any apparent toxicity

The enhanced inhibitory effect of different antitumor agents in self-microemulsifying drug delivery systems on human cervical cancer HeLa cells.

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Ujhelyi, Zoltán; Kalantari, Azin; Vecsernyés, Miklós; Róka, Eszter; Fenyvesi, Ferenc; Póka, Róbert; Kozma, Bence; Bácskay, Ildikó

2015-07-21

The aim of this study was to develop topical self-microemulsifying drug delivery systems (SMEDDS) containing antitumor agents (bleomycin, cisplatin and ifosfamide) and to investigate their inhibitory potential in SMEDDS on human cervical cancer HeLa cells. The physicochemical properties of cytostatic drug loaded SMEDDS were characterized. The cytotoxicity of main components of SMEDDS was also investigated. Their IC50 values were determined. HeLa cells were treated by different concentrations of cisplatin, bleomycin and ifosfamide alone and in various SMEDDS. The inhibitory effect on cell growth was analyzed by MTT cell viability assay. Inflammation is a driving force that accelerates cancer development. The inhibitory effect of these antitumor agents has also been tested on HeLa cells in the presence of inflammatory mediators (IL-1-β, TNF-α) as an in vitro model of inflamed human cervix. Significant differences in the cytotoxicity of cytostatic drugs alone and in SMEDDS have been found in a concentration-dependent manner. The self-micro emulsifying system may potentiate the effectiveness of bleomycin, cisplatin and ifosfamide topically. The effect of SMEDDS containing antitumor agents was decreased significantly in the presence of inflammatory mediators. According to our experiments, the optimal SMEDDS formulation is 1:1:2:6:2 ratios of Isopropyl myristate, Capryol 90, Kolliphor RH 40, Cremophor RH40, Transcutol HP and Labrasol. It can be concluded that SMEDDS may increase the inhibitory effect of bleomycin, ifosfamide and cisplatin on human cervical cancer HeLa cells. Inflammation on HeLa cells hinders the effectiveness of SMEDDS containing antitumor agents. Our results might ensure useful data for development of optimal antitumor formulations.

In vivo evaluation of neutron capture therapy effectivity using calcium phosphate-based nanoparticles as Gd-DTPA delivery agent.

Science.gov (United States)

Dewi, Novriana; Mi, Peng; Yanagie, Hironobu; Sakurai, Yuriko; Morishita, Yasuyuki; Yanagawa, Masashi; Nakagawa, Takayuki; Shinohara, Atsuko; Matsukawa, Takehisa; Yokoyama, Kazuhito; Cabral, Horacio; Suzuki, Minoru; Sakurai, Yoshinori; Tanaka, Hiroki; Ono, Koji; Nishiyama, Nobuhiro; Kataoka, Kazunori; Takahashi, Hiroyuki

2016-04-01

A more immediate impact for therapeutic approaches of current clinical research efforts is of major interest, which might be obtained by developing a noninvasive radiation dose-escalation strategy, and neutron capture therapy represents one such novel approach. Furthermore, some recent researches on neutron capture therapy have focused on using gadolinium as an alternative or complementary for currently used boron, taking into account several advantages that gadolinium offers. Therefore, in this study, we carried out feasibility evaluation for both single and multiple injections of gadolinium-based MRI contrast agent incorporated in calcium phosphate nanoparticles as neutron capture therapy agent. In vivo evaluation was performed on colon carcinoma Col-26 tumor-bearing mice irradiated at nuclear reactor facility of Kyoto University Research Reactor Institute with average neutron fluence of 1.8 × 10(12) n/cm(2). Antitumor effectivity was evaluated based on tumor growth suppression assessed until 27 days after neutron irradiation, followed by histopathological analysis on tumor slice. The experimental results showed that the tumor growth of irradiated mice injected beforehand with Gd-DTPA-incorporating calcium phosphate-based nanoparticles was suppressed up to four times higher compared to the non-treated group, supported by the results of histopathological analysis. The results of antitumor effectivity observed on tumor-bearing mice after neutron irradiation indicated possible effectivity of gadolinium-based neutron capture therapy treatment.

Antitumor effect of manumycin on colorectal cancer cells by increasing the reactive oxygen species production and blocking PI3K-AKT pathway

Directory of Open Access Journals (Sweden)

Zhang JY

2016-05-01

Full Text Available Jingyu Zhang,1 Hua Jiang,2 Li Xie,1 Jing Hu,1 Li Li,1 Mi Yang,1 Lei Cheng,1 Baorui Liu,1 Xiaoping Qian1 1Department of the Comprehensive Cancer Center, Affiliated Nanjing Drum Tower Hospital, Nanjing Medical University, 2Department of Oncology, Affiliated Changzhou No 2 People’s Hospital, Nanjing Medical University, Nanjing, People’s Republic of China Abstract: Manumycin is a natural, well-tolerated microbial metabolite and is regarded as a farnesyltransferase inhibitor. Some data suggest that manumycin inhibits proliferation of diverse cancer cells through various pathways. However, the antitumor effect of manumycin on colorectal cancer (CRC remains unknown. In the present study, we investigated the antitumor effect of manumycin on CRC in vitro and in vivo. The results of cell viability assay revealed that the proliferation of the CRC cells was significantly inhibited by manumycin. Moreover, cell apoptosis induced by manumycin was also found in a time- and dose-dependent manner. Interestingly, treatment of the CRC cells with manumycin resulted in increased generation of reactive oxygen species. Subsequently, manumycin also decreased the phosphorylation of phosphatidylinositol 3-kinase (PI3K and AKT, as well as the expression of caspase-9 and poly(ADP-ribose polymerase (PARP in a time-dependent manner. In addition, we found that N-acetyl-L-cysteine (NAC attenuated the effect of manumycin on the PI3K-AKT pathway, and wortmannin reduced the effect of manumycin on caspase-9 and PARP expression. More importantly, the anticancer effect of manumycin was also observed in established tumor xenografts. Taken together, these findings supported the potential application of manumycin against colorectal carcinoma. Keywords: manumycin, colorectal cancer, PI3K-AKT pathway, ROS

Gold namoprtices enhance anti-tumor effect of radiotherapy to hypoxic tumor

Energy Technology Data Exchange (ETDEWEB)

Kim, Mi Sun; Lee, Eun Jung; Kim, Jae Won; Keum, Ki Chang; Koom, Woong Sub [Dept. of Radiation Oncology, Yonsei University College of Medicine, Seoul (Korea, Republic of); Chung, Ui Seok; Koh, Won Gun [Dept. of Chemical and Biomolecular Engineering, Yonsei University, Seoul (Korea, Republic of)

2016-09-15

Hypoxia can impair the therapeutic efficacy of radiotherapy (RT). Therefore, a new strategy is necessary for enhancing the response to RT. In this study, we investigated whether the combination of nanoparticles and RT is effective in eliminating the radioresistance of hypoxic tumors. Gold nanoparticles (GNPs) consisting of a silica core with a gold shell were used. CT26 colon cancer mouse model was developed to study whether the combination of RT and GNPs reduced hypoxia-induced radioresistance. Hypoxia inducible factor-1α (HIF-1α) was used as a hypoxia marker. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining were conducted to evaluate cell death. Hypoxic tumor cells had an impaired response to RT. GNPs combined with RT enhanced anti-tumor effect in hypoxic tumor compared with RT alone. The combination of GNPs and RT decreased tumor cell viability compare to RT alone in vitro. Under hypoxia, tumors treated with GNPs + RT showed a higher response than that shown by tumors treated with RT alone. When a reactive oxygen species (ROS) scavenger was added, the enhanced antitumor effect of GNPs + RT was diminished. In the present study, hypoxic tumors treated with GNPs + RT showed favorable responses, which might be attributable to the ROS production induced by GNPs + RT. Taken together, GNPs combined with RT seems to be potential modality for enhancing the response to RT in hypoxic tumors.

Gold namoprtices enhance anti-tumor effect of radiotherapy to hypoxic tumor

International Nuclear Information System (INIS)

Kim, Mi Sun; Lee, Eun Jung; Kim, Jae Won; Keum, Ki Chang; Koom, Woong Sub; Chung, Ui Seok; Koh, Won Gun

2016-01-01

Hypoxia can impair the therapeutic efficacy of radiotherapy (RT). Therefore, a new strategy is necessary for enhancing the response to RT. In this study, we investigated whether the combination of nanoparticles and RT is effective in eliminating the radioresistance of hypoxic tumors. Gold nanoparticles (GNPs) consisting of a silica core with a gold shell were used. CT26 colon cancer mouse model was developed to study whether the combination of RT and GNPs reduced hypoxia-induced radioresistance. Hypoxia inducible factor-1α (HIF-1α) was used as a hypoxia marker. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining were conducted to evaluate cell death. Hypoxic tumor cells had an impaired response to RT. GNPs combined with RT enhanced anti-tumor effect in hypoxic tumor compared with RT alone. The combination of GNPs and RT decreased tumor cell viability compare to RT alone in vitro. Under hypoxia, tumors treated with GNPs + RT showed a higher response than that shown by tumors treated with RT alone. When a reactive oxygen species (ROS) scavenger was added, the enhanced antitumor effect of GNPs + RT was diminished. In the present study, hypoxic tumors treated with GNPs + RT showed favorable responses, which might be attributable to the ROS production induced by GNPs + RT. Taken together, GNPs combined with RT seems to be potential modality for enhancing the response to RT in hypoxic tumors

Effect of electron beam-irradiation to b-glucan on its immunomodulating and antitumor activity

Energy Technology Data Exchange (ETDEWEB)

Jung, Yeon Hwan; Lee, Jung Lim; Yoo, Yung Choon [Konyand Univ., Daejeon (Korea, Republic of); Kim, Jae Hoon; Lee, Ju Woon [Korea Atomic Energy Research Institute, Daejeon (Korea, Republic of)

2010-07-01

In this study, in order investigated the effect of electron beam irradiation to b-glucan on its biological activities, we compared immunomodulating and antitumor activity between non-irradiated and electron beam-irradiated b-glucan. EB-glucan was irradiated by electron beam with 10, 30 and 50 kGy. Treatment with EB-glucan resulted in a slight increase of the proliferation of ConA-stimulated splenocytes, and the strongest activity was seen in 50 kGy-treated EB-glucan. EB-glucan teated with 50 kGy also showed increased secretion of cytokines such as IL-2 IFN-{gamma} and IL-6 from ConA-stimulated splenocytes. The activity of EB-glucan to enhance the proliferation of splenocytes and cytokine secretion from ConA-stimulated splenocytes was higher than that of NI-glucan. Furthermore, EB-glucan treated with 50 kGy showed higher activity to activate RAW 264.7 macrophages, comparing with that of NI-glucan. In experiments of antitumor activity, EB-glucan treated with 50 kGy prior to tumor inoculation inhibited an experimental lung metastasis produced by B16-BL6 melanoma cells in mice. But NI-glucan did show no effect. In addition, EB-glucan treated with 50 kGy induced a decrease a decrease of tumor growth in tumor-bearing mice. Collectivelt, these results indicates that electron beam irradiation {beta}-glucan leads its biological functions to enhance immunomodulating and antitumor activity.

Effect of electron beam-irradiation to b-glucan on its immunomodulating and antitumor activity

International Nuclear Information System (INIS)

Jung, Yeon Hwan; Lee, Jung Lim; Yoo, Yung Choon; Kim, Jae Hoon; Lee, Ju Woon

2010-01-01

In this study, in order investigated the effect of electron beam irradiation to b-glucan on its biological activities, we compared immunomodulating and antitumor activity between non-irradiated and electron beam-irradiated b-glucan. EB-glucan was irradiated by electron beam with 10, 30 and 50 kGy. Treatment with EB-glucan resulted in a slight increase of the proliferation of ConA-stimulated splenocytes, and the strongest activity was seen in 50 kGy-treated EB-glucan. EB-glucan teated with 50 kGy also showed increased secretion of cytokines such as IL-2 IFN-γ and IL-6 from ConA-stimulated splenocytes. The activity of EB-glucan to enhance the proliferation of splenocytes and cytokine secretion from ConA-stimulated splenocytes was higher than that of NI-glucan. Furthermore, EB-glucan treated with 50 kGy showed higher activity to activate RAW 264.7 macrophages, comparing with that of NI-glucan. In experiments of antitumor activity, EB-glucan treated with 50 kGy prior to tumor inoculation inhibited an experimental lung metastasis produced by B16-BL6 melanoma cells in mice. But NI-glucan did show no effect. In addition, EB-glucan treated with 50 kGy induced a decrease a decrease of tumor growth in tumor-bearing mice. Collectivelt, these results indicates that electron beam irradiation β-glucan leads its biological functions to enhance immunomodulating and antitumor activity

Hypoxia-targeting antitumor prodrugs and photosensitizers

International Nuclear Information System (INIS)

Zhang Zhouen; Nishimoto, S.I.

2006-01-01

Tumor hypoxia has been identified as a key subject for tumor therapy, since hypoxic tumor cells show resistance to treatment of tumor tissues by radiotherapy, chemotherapy and phototherapy. For improvement of tumor radiotherapy, we have proposed a series of radiation-activated prodrugs that could selectively release antitumor agent 5-fluorouracil or 5-fluorodeoxyuridine under hypoxic conditions. Recently, we attempted to develop two families of novel hypoxia-targeting antitumor agents, considering that tumor-hypoxic environment is favorable to biological and photochemical reductions. The first family of prodrugs was derived from camptothecin as a potent topoisomerase I inhibitor and several bioreductive motifs. These prodrugs could be activated by NADPH-cytochrome P450 reductase or DT-diaphorase to release free camptothecin, and thereby showed hypoxia-selective cytotoxictiy towards tumor cells. These prodrugs were also applicable to the real-time monitoring of activation and antitumor effect by fluorometry. Furthermore, the camptothecin-bioreductive motif conjugates was confirmed to show an oxygen-independent DAN photocleaving activity, which could overcome a drawback of back electron transfer occurring in the photosensitized one-electron oxidation of DNA. Thus, these camptothecin derivatives could be useful to both chemotherapy and phototherapy for hypoxic tumor cells. The second family of prodrugs harnessed UV light for cancer therapy, incorporating the antitumor agent 5-fluorourcil and the photolabile 2-nitrobenzyl chromophores. The attachment of a tumor-homing cyclic peptide CNGRC was also employed to construct the prototype of tumor-targeting photoactiaved antitumor prodrug. These novel prodrugs released high yield of 5-fluorourcil upon UV irradiation at λ ex =365 nm, while being quite stable in the dark. The photoactivation mechanism was also clarified by means of nanosecond laser flash photolysis. (authors)

Anti-tumor Effect of Rhaponticum uniflorum Ethyl Acetate Extract by Regulation of Peroxiredoxin1 and Epithelial-to-Mesenchymal Transition in Oral Cancer

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Hui Chen

2017-11-01

Full Text Available Objective: To explore whether Rhaponticum uniflorum (R. uniflorum had anti-tumor effects in oral cancer and investigate the molecular mechanisms involved in these anti-tumor effects.Methods: Chemical compositions of R. uniflorum ethyl acetate (RUEA extracts were detected by ultra-performance liquid chromatography-Q/time-of-flight mass spectrometry (UPLC-Q/TOF-MS, followed by pharmacology-based network prediction analysis. The effects of RUEA extracts on proliferation, apoptosis, migration, and invasion ability of human oral squamous cell carcinoma (OSCC cell line SCC15 were evaluated by CCK8 assay, Annexin V- fluorescein isothiocyanate/propidium iodide staining, wound healing assay, and Matrigel invasion assay, respectively. The mRNA and protein expression of peroxiredoxin1 (Prx1, the epithelial-to-mesenchymal transition (EMT marker E-cadherin, vimentin, and Snail were determined by quantitative real-time reverse transcription polymerase chain reaction and western blotting. A mouse xenograft model of SCC15 cells was established to further evaluate the effect of RUEA extracts in vivo. Immunohistochemical assessment of Ki67 and terminal deoxynucleotidyl transferase dUTP nick end labeling staining of apoptotic cells were performed on the tumor tissues to assess the effects of RUEA extracts on proliferation and apoptosis.Results: Fourteen compounds were identified from RUEA extracts by UPLC-Q/TOF-MS. The pharmacology-based network prediction analysis showed that Prx1 could be a potential binder of RUEA extracts. In SCC15 cells, RUEA extracts inhibited cell viability, induced apoptosis, and suppressed cell invasion and migration in a concentration-dependent manner. After treatment with RUEA extracts, the mRNA and protein expression of E-cadherin increased, whereas those of Prx1, vimentin, and Snail decreased. RUEA extracts also affected the EMT program and suppressed cell invasion and migration in Prx1 knockdown SCC15 cells. In an OSCC mouse

Properties of realgar bioleaching using an extremely acidophilic bacterium and its antitumor mechanism as an anticancer agent

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Peng Chen

Full Text Available Abstract Realgar is a naturally occurring arsenic sulfide (or Xionghuang, in Chinese. It contains over 90% tetra-arsenic tetrasulfide (As4S4. Currently, realgar has been confirmed the antitumor activities, both in vitro and in vivo, of realgar extracted using Acidithiobacillus ferrooxidans (A. ferrooxidans. Bioleaching, a new technology to greatly improve the use rate of arsenic extraction from realgar using bacteria, is a novel methodology that addressed a limitation of the traditional method for realgar preparation. The present systematic review reports on the research progress in realgar bioleaching and its antitumor mechanism as an anticancer agent. A total of 93 research articles that report on the biological activity of extracts from realgar using bacteria and its preparation were presented in this review. The realgar bioleaching solution (RBS works by inducing apoptosis when it is used to treat tumor cells in vitro and in vivo. When it is used to treat animal model organisms in vivo, such as mice and Caenorhabditis elegans, tumor tissues grew more slowly, with mass necrosis. Meanwhile, the agent also showed obvious inhibition of tumor cell growth. Bioleaching technology greatly improves the utilization of realgar and is a novel methodology to improve the traditional method.

Homeostatic T Cell Expansion to Induce Anti-Tumor Autoimmunity in Breast Cancer

National Research Council Canada - National Science Library

Baccala, Roberto

2007-01-01

... that (a) homeostatic T-cell proliferation consistently elicits anti-tumor responses; (b) irradiation is more effective than Tcell depletion by antibodies in inducing anti-tumor responses mediated by homeostatic T-cell proliferation...

Pulse radiolysis study of the reduction mechanism of an antitumor antibiotic, mitomycin C

International Nuclear Information System (INIS)

Machtalere, G.; Houee-Levin, C.; Gardes-Albert, M.; Ferradini, C.; Hickel, B.

1988-01-01

Mitomycin C is a quinonic antitumor metabolized in vivo by one-electron reduction. We have studied the mechanism of the one-electron reduction of this drug by pulse radiolysis using C00 .- free radicals as reductants. Semiquinonic and hydroquinonic intermediates are formed. The hydroquinonic form undergoes a methanol elimination leading to a transient which can disappear in one of two ways: by either internal redox reaction or hydrolysis of the aziridine. 17 refs [fr

Antitumor Activity and Mechanism of a Reverse Transcriptase Inhibitor, Dapivirine, in Glioblastoma.

Science.gov (United States)

Liu, Weiwen; Song, Xian-Lu; Zhao, Shan-Chao; He, Minyi; Wang, Hai; Chen, Ziyang; Xiang, Wei; Yi, Guozhong; Qi, Songtao; Liu, Yawei

2018-01-01

Dapivirine is one of reverse transcriptase inhibitors (RTIs). It is the prototype of diarylpyrimidines (DAPY), formerly known as TMC120 or DAPY R147681 (IUPAC name: 4- [[4-(2, 4, 6-trimethylphenyl) amino]-2-pyrimidinyl] amino]-benzonitrile; CAS no.244767-67-7). The purpose of this study is to investigate the antitumor activity of dapivirine, one of the RTIs, on U87 glioblastoma (GBM) cells in vitro and in vivo . U87 GBM cells were cultured and treated with or without dapivirine. Cell viability was evaluated by CCK-8 (Cell Counting Kit 8, CCK-8) assay; apoptosis was analyzed by flow cytometry; cell migration was evaluated by Boyden Chamber assay; Western blotting was performed to detect proteins related to apoptosis, epithelial-to-mesenchymal transition and autophagy. PathScan intracellular signaling array kit was used to detect important and well-characterized signaling molecules. Tumor xenograft model in nude mice was used to evaluate the antitumorigenic effect in vivo . Dapivirine weakened proliferation of glioma cells and induced the apoptosis of U87 glioblastoma cells. Furthermore, dapivirine regulated autophagy and induced Akt, Bad and SAPK/JNK activations. Moreover, the inhibition of glioma cell growth by dapivirine was also observed in nude mice in vivo . In summary, in our study dapivirine exposure induces stress, resulting in JNK and PI3K/Akt pathway activation through diminished inhibition of the apoptosis and autophagy cascade in U87 GBM cells, which inhibits cell growth in vitro and in vivo .

Anticancer effects of saponin and saponin–phospholipid complex of Panax notoginseng grown in Vietnam

OpenAIRE

Thu Dang Kim; Hai Nguyen Thanh; Duong Nguyen Thuy; Loi Vu Duc; Thu Vu Thi; Hung Vu Manh; Patcharee Boonsiri; Tung Bui Thanh

2016-01-01

Objective: To evaluate the antitumor activity both in vitro and in vivo of saponin–phospholipid complex of Panax notoginseng. Methods: The in vitro cytotoxic effect of saponins extract and saponin–phospholipid complex against human lung cancer NCI-H460 and breast cancer cell lines BT474 was examined using MTS assay. For in vivo evaluation of antitumor potential, saponin and saponin–phospholipid complex were administered orally in rats induced mammary carcinogenesis by 7,12-dimethylbenz(a)a...

A visualized investigation at the atomic scale of the antitumor effect of magnetic nanomedicine on gastric cancer cells.

Science.gov (United States)

Liu, Xiaokang; Deng, Xia; Li, Xinghua; Xue, Desheng; Zhang, Haoli; Liu, Tao; Liu, Qingfang; Mellors, Nigel J; Li, Yumin; Peng, Yong

2014-07-01

Discovering which anticancer drugs attack which organelle(s) of cancer cells is essential and significant, not only for understanding their therapeutic and adverse effects, but also to enable the development of new-generation therapeutics. Here, we show that novel Fe3O4-carboxymethyl cellulose-5-fluorouracil (Fe3O4-CMC-5FU) nanomedicine can apparently enhance the antitumor effect on gastric cancer cells, and its mechanism of killing the SGC-7901 gastric cancer cells can be directly observed at the atomic scale. The novel nanomedicine was prepared using the traditional antitumor drug 5FU to chemically bond onto the functionalized Fe3O4 nanoparticles (Fe3O4-CMC-5FU nanomedicine), and then was fed into SGC-7901 gastric cancer cells. The inorganic Fe3O4 nanoparticles were used to track the distribution and antitumor effect of the nanomedicine within individual SGC-7901 gastric cancer cells. Atomic-level observation and tracking the elemental distribution inside individual cells proved that the magnetic nanomedicine killed the gastric cells mainly by attacking their mitochondria. The enhanced therapeutic efficacy derives from the localized high concentration and poor mobility of the aggregated Fe3O4-CMC-5FU nanomedicine in the cytoplasm. A brand new mechanism of Fe3O4-CMC-5FU nanomedicine killing SGC-7901 gastric cancer cells by attacking their mitochondria was discovered, which is different from the classical mechanism utilized by traditional medicine 5FU, which kills gastric cancer cells by damaging their DNA. Our work might provide a partial solution in nanomedicines or even modern anticancer medicine for the visualized investigation of their antitumor effect.

Antitumor Effects and Biological Mechanism of Action of the Aqueous Extract of the Camptotheca acuminata Fruit in Human Endometrial Carcinoma Cells

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Chi-Shian Lin

2014-01-01

Full Text Available The aqueous extracts of the leaves and fruit of Camptotheca acuminata have long been used in traditional Chinese medicine (TCM for treating cancer patients. The chemotherapeutic drug, camptothecin (CPT, and related analogs were first isolated from C. acuminata in the 1970s. Although the antitumor effects of CPT have been characterized in recent years, the antitumor effects of aqueous extracts of C. acuminata have not been clarified. The aims of our current study were to determine the tumor-suppression efficiency of an aqueous extract of the fruit of C. acuminata (AE-CA in the human endometrial carcinoma cell lines, HEC-1A, HEC-1B, and KLE, and compare its antitumor effects with those of CPT. Cell viability assays indicated that a dosage of AE-CA containing 0.28 mg/mL of CPT demonstrated enhanced cytotoxicity, compared with CPT treatment. The effects of AE-CA on the induction of cell cycle arrest, the accumulation of cyclin-A2 and -B1, and the activation of caspase-3 and caspase-7 were similar to those of CPT. Furthermore, AE-CA exhibited a synergistic effect on the cytotoxicity of cisplatin in HEC-1A and HEC-1B cells. These results indicated that AE-CA is a potent antitumor agent and can be combined with cisplatin for the treatment of human endometrial cancer.

Curcumin-induced HDAC inhibition and attenuation of medulloblastoma growth in vitro and in vivo

International Nuclear Information System (INIS)

Lee, Seung Joon; Krauthauser, Candice; Maduskuie, Victoria; Fawcett, Paul T; Olson, James M; Rajasekaran, Sigrid A

2011-01-01

Medulloblastoma is the most common brain tumor in children, and its prognosis is worse than for many other common pediatric cancers. Survivors undergoing treatment suffer from serious therapy-related side effects. Thus, it is imperative to identify safer, effective treatments for medulloblastoma. In this study we evaluated the anti-cancer potential of curcumin in medulloblastoma by testing its ability to induce apoptosis and inhibit tumor growth in vitro and in vivo using established medulloblastoma models. Using cultured medulloblastoma cells, tumor xenografts, and the Smo/Smo transgenic medulloblastoma mouse model, the antitumor effects of curcumin were tested in vitro and in vivo. Curcumin induced apoptosis and cell cycle arrest at the G2/M phase in medulloblastoma cells. These effects were accompanied by reduced histone deacetylase (HDAC) 4 expression and activity and increased tubulin acetylation, ultimately leading to mitotic catastrophe. In in vivo medulloblastoma xenografts, curcumin reduced tumor growth and significantly increased survival in the Smo/Smo transgenic medulloblastoma mouse model. The in vitro and in vivo data suggest that curcumin has the potential to be developed as a therapeutic agent for medulloblastoma

Induction of antitumor immunity through xenoplacental immunization

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Agadjanyan Michael G

2006-05-01

Full Text Available Abstract Historically cancer vaccines have yielded suboptimal clinical results. We have developed a novel strategy for eliciting antitumor immunity based upon homology between neoplastic tissue and the developing placenta. Placenta formation shares several key processes with neoplasia, namely: angiogenesis, activation of matrix metalloproteases, and active suppression of immune function. Immune responses against xenoantigens are well known to break self-tolerance. Utilizing xenogeneic placental protein extracts as a vaccine, we have successfully induced anti-tumor immunity against B16 melanoma in C57/BL6 mice, whereas control xenogeneic extracts and B16 tumor extracts where ineffective, or actually promoted tumor growth, respectively. Furthermore, dendritic cells were able to prime tumor immunity when pulsed with the placental xenoantigens. While vaccination-induced tumor regression was abolished in mice depleted of CD4 T cells, both CD4 and CD8 cells were needed to adoptively transfer immunity to naïve mice. Supporting the role of CD8 cells in controlling tumor growth are findings that only freshly isolated CD8 cells from immunized mice were capable of inducing tumor cell caspases-3 activation ex vivo. These data suggest feasibility of using xenogeneic placental preparations as a multivalent vaccine potently targeting not just tumor antigens, but processes that are essential for tumor maintenance of malignant potential.

Antitumor Activity and Mechanism of a Reverse Transcriptase Inhibitor, Dapivirine, in Glioblastoma

OpenAIRE

Liu, Weiwen; Song, Xian-lu; Zhao, Shan-chao; He, Minyi; Wang, Hai; Chen, Ziyang; Xiang, Wei; Yi, Guozhong; Qi, Songtao; Liu, Yawei

2018-01-01

Ethnopharmacological relevance: Dapivirine is one of reverse transcriptase inhibitors (RTIs). It is the prototype of diarylpyrimidines (DAPY), formerly known as TMC120 or DAPY R147681 (IUPAC name: 4- [[4-(2, 4, 6-trimethylphenyl) amino]-2-pyrimidinyl] amino]-benzonitrile; CAS no.244767-67-7). Aim: The purpose of this study is to investigate the antitumor activity of dapivirine, one of the RTIs, on U87 glioblastoma (GBM) cells in vitro and in vivo. Materials and Methods: U87 GBM cells were cul...

Anti-EGFR-iRGD recombinant protein conjugated silk fibroin nanoparticles for enhanced tumor targeting and antitumor efficiency

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Bian X

2016-05-01

Full Text Available Xinyu Bian,* Puyuan Wu,* Huizi Sha, Hanqing Qian, Qing Wang, Lei Cheng, Yang Yang, Mi Yang, Baorui LiuComprehensive Cancer Center of Drum-Tower Hospital, Medical School of Nanjing University, Clinical Cancer Institute of Nanjing University, Nanjing, People’s Republic of China*These authors contributed equally to this workAbstract: In this study, we report a novel kind of targeting with paclitaxel (PTX-loaded silk fibroin nanoparticles conjugated with iRGD–EGFR nanobody recombinant protein (anti-EGFR-iRGD. The new nanoparticles (called A-PTX-SF-NPs were prepared using the carbodiimide-mediated coupling procedure and their characteristics were evaluated. The cellular cytotoxicity and cellular uptake of A-PTX-SF-NPs were also investigated. The results in vivo suggested that NPs conjugated with the recombinant protein exhibited more targeting and anti-neoplastic property in cells with high EGFR expression. In the in vivo antitumor efficacy assay, the A-PTX-SF-NPs group showed slower tumor growth and smaller tumor volumes than PTX-SF-NPs in a HeLa xenograft mouse model. A real-time near-infrared fluorescence imaging study showed that A-PTX-SF-NPs could target the tumor more effectively. These results suggest that the anticancer activity and tumor targeting of A-PTX-SF-NPs were superior to those of PTX-SF-NPs and may have the potential to be used for targeted delivery for tumor therapies. Keywords: EGFR, nanobody, iRGD, recombinant protein, targeting drug carriers, antitumor efficiency

The Antitumor Effect and Hepatotoxicity of a Hexokinase II Inhibitor 3-Bromopyruvate: In Vivo Investigation of Intraarterial Administration in a Rabbit VX2 Hepatoma Model

International Nuclear Information System (INIS)

Jae, Hwan Jun; Chung, Jin Wook; Park, Hee Sun; Lee, Min Jong; Lee, Ki Chang; Kim, Hyo Cheol; Yoon, Jung Hwan; Park, Jae Hyung; Chung, He Son

2009-01-01

The purpose of this study was to compare the antitumor effect and hepatotoxicity of an intraarterial delivery of low-dose and high-dose 3-bromopyruvate (3-BrPA) and those of a conventional Lipiodol-doxorubicin emulsion in a rabbit VX2 hepatoma model. This experiment was approved by the animal care committee at our institution. VX2 carcinoma was implanted in the livers of 36 rabbits. Transcatheter intraarterial administration was performed using low dose 3- BrPA (25 mL in a 1 mM concentration, n = 10), high dose 3-BrPA (25 mL in a 5 mM concentration, n = 10) and Lipiodol-doxorubicin emulsion (1.6 mg doxorubicin/ 0.4 mL Lipiodol, n = 10), and six rabbits were treated with normal saline alone as a control group. One week later, the proportion of tumor necrosis was calculated based on histopathologic examination. The hepatotoxicity was evaluated by biochemical analysis. The differences between these groups were statistically assessed with using Mann-Whitney U tests and Kruskal-Wallis tests. The tumor necrosis rate was significantly higher in the high dose group (93% ± 7.6 [mean ± SD]) than that in the control group (48% ± 21.7) (p = 0.0002), but the tumor necrosis rate was not significantly higher in the low dose group (62% ± 20.0) (p = 0.2780). However, the tumor necrosis rate of the high dose group was significantly lower than that of the Lipiodol-doxorubicin treatment group (99% ± 2.7) (p = 0.0015). The hepatotoxicity observed in the 3-BrPA groups was comparable to that of the Lipiodol-doxorubicin group. Even though intraarterial delivery of 3-BrPA shows a dose-related antitumor effect, single session treatment seems to have limited efficacy when compared with the conventional method

The antitumor effect and hepatotoxicity of a hexokinase II inhibitor 3-bromopyruvate: in vivo investigation of intraarterial administration in a rabbit VX2 hepatoma model.

Science.gov (United States)

Jae, Hwan Jun; Chung, Jin Wook; Park, Hee Sun; Lee, Min Jong; Lee, Ki Chang; Kim, Hyo-Cheol; Yoon, Jung Hwan; Chung, Hesson; Park, Jae Hyung

2009-01-01

The purpose of this study was to compare the antitumor effect and hepatotoxicity of an intraarterial delivery of low-dose and high-dose 3-bromopyruvate (3-BrPA) and those of a conventional Lipiodol-doxorubicin emulsion in a rabbit VX2 hepatoma model. This experiment was approved by the animal care committee at our institution. VX2 carcinoma was implanted in the livers of 36 rabbits. Transcatheter intraarterial administration was performed using low dose 3-BrPA (25 mL in a 1 mM concentration, n = 10), high dose 3-BrPA (25 mL in a 5 mM concentration, n = 10) and Lipiodol-doxorubicin emulsion (1.6 mg doxorubicin/ 0.4 mL Lipiodol, n = 10), and six rabbits were treated with normal saline alone as a control group. One week later, the proportion of tumor necrosis was calculated based on histopathologic examination. The hepatotoxicity was evaluated by biochemical analysis. The differences between these groups were statistically assessed with using Mann-Whitney U tests and Kruskal-Wallis tests. The tumor necrosis rate was significantly higher in the high dose group (93% +/- 7.6 [mean +/- SD]) than that in the control group (48% +/- 21.7) (p = 0.0002), but the tumor necrosis rate was not significantly higher in the low dose group (62% +/- 20.0) (p = 0.2780). However, the tumor necrosis rate of the high dose group was significantly lower than that of the Lipiodol-doxorubicin treatment group (99% +/- 2.7) (p = 0.0015). The hepatotoxicity observed in the 3-BrPA groups was comparable to that of the Lipiodol-doxorubicin group. Even though intraarterial delivery of 3-BrPA shows a dose-related antitumor effect, single session treatment seems to have limited efficacy when compared with the conventional method.

The Antitumor Effect and Hepatotoxicity of a Hexokinase II Inhibitor 3-Bromopyruvate: In Vivo Investigation of Intraarterial Administration in a Rabbit VX2 Hepatoma Model

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Jae, Hwan Jun; Chung, Jin Wook; Park, Hee Sun; Lee, Min Jong; Lee, Ki Chang; Kim, Hyo Cheol; Yoon, Jung Hwan; Park, Jae Hyung [Seoul National University Hospital, Seoul (Korea, Republic of); Chung, He Son [Korea Institute of Science and Technology, Seoul (Korea, Republic of)

2009-12-15

The purpose of this study was to compare the antitumor effect and hepatotoxicity of an intraarterial delivery of low-dose and high-dose 3-bromopyruvate (3-BrPA) and those of a conventional Lipiodol-doxorubicin emulsion in a rabbit VX2 hepatoma model. This experiment was approved by the animal care committee at our institution. VX2 carcinoma was implanted in the livers of 36 rabbits. Transcatheter intraarterial administration was performed using low dose 3- BrPA (25 mL in a 1 mM concentration, n = 10), high dose 3-BrPA (25 mL in a 5 mM concentration, n = 10) and Lipiodol-doxorubicin emulsion (1.6 mg doxorubicin/ 0.4 mL Lipiodol, n = 10), and six rabbits were treated with normal saline alone as a control group. One week later, the proportion of tumor necrosis was calculated based on histopathologic examination. The hepatotoxicity was evaluated by biochemical analysis. The differences between these groups were statistically assessed with using Mann-Whitney U tests and Kruskal-Wallis tests. The tumor necrosis rate was significantly higher in the high dose group (93% +- 7.6 [mean +- SD]) than that in the control group (48% +- 21.7) (p = 0.0002), but the tumor necrosis rate was not significantly higher in the low dose group (62% +- 20.0) (p = 0.2780). However, the tumor necrosis rate of the high dose group was significantly lower than that of the Lipiodol-doxorubicin treatment group (99% +- 2.7) (p = 0.0015). The hepatotoxicity observed in the 3-BrPA groups was comparable to that of the Lipiodol-doxorubicin group. Even though intraarterial delivery of 3-BrPA shows a dose-related antitumor effect, single session treatment seems to have limited efficacy when compared with the conventional method

Proton pump inhibitors induce a caspase-independent antitumor effect against human multiple myeloma.

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Canitano, Andrea; Iessi, Elisabetta; Spugnini, Enrico Pierluigi; Federici, Cristina; Fais, Stefano

2016-07-01

Multiple Myeloma (MM) is the second most common hematological malignancy and is responsive to a limited number of drugs. Unfortunately, to date, despite the introduction of novel drugs, no relevant increase in survival rates has been obtained. Proton pump inhibitors (PPIs) have been shown to have significant antitumor action as single agents as well as in combination with chemotherapy. This study investigates the potential anti-tumor effectiveness of two PPIs, Lansoprazole and Omeprazole, against human MM cells. We found that Lansoprazole exerts straightforward efficacy against myeloma cells, even at suboptimal concentrations (50 µM), while Omeprazole has limited cytotoxic action. The Lansoprazole anti-MM effect was mostly mediated by a caspase-independent apoptotic-like cytotoxicity, with only a secondary anti-proliferative action. This study provides clear evidence supporting the use of Lansoprazole in the strive against MM with an efficacy proven much higher than current therapeutical approaches and without reported side effects. It is however conceivable that, consistent with the results obtained in other human tumors, Lansoprazole may well be combined with existing anti-myeloma therapies with the aim to improve the low level of efficacy of the current strategies. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Antitumoral, antioxidant, and antimelanogenesis potencies of Hawthorn, a potential natural agent in the treatment of melanoma.

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Mustapha, Nadia; Mokdad-Bzéouich, Imèn; Maatouk, Mouna; Ghedira, Kamel; Hennebelle, Thierry; Chekir-Ghedira, Leila

2016-06-01

The lack of an efficient agent that does not have the disadvantage of low activity (kojic acid), high cytotoxicity, and mutagenicity (hydroquinone), poor skin penetration (arbutin), or low stability in formulation (glabridin) led us to continue our research on new antipigmentation/skin-lightening agents. Therefore, research of natural products that can modulate the metabolism of pigmentation is of great interest. Otherwise, malignant melanoma is one of the most aggressive forms of skin cancer, with high metastatic potential, and currently, there is no effective chemotherapy against invasive melanoma. Therefore, it is necessary to develop new drugs with potent activity and weak side effects against melanoma. The in-vitro anticancer effect of hawthorn was analyzed against B16F10 melanoma cells using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The effect of isolated compounds from hawthorn on melanogenesis in B16F10 melanoma cells was investigated by measuring the amounts of melanin and tyrosinase spectrophotometrically at 475 nm. Balb/c mice models inoculated with B16F10 mouse tumor cells were used to evaluate the in-vivo antitumoral potential of hawthorn by assessing its effect on the growth of transplanted tumors. The antioxidant potential of tested samples was evaluated in B16F10 and primary human keratinocyte cells using a cellular antioxidant activity assay. Hawthorn tested samples inhibited effectively the growth of melanoma cells in vitro. Furthermore, it appears that tested samples from hawthorn reduced melanogenesis by inhibiting the tyrosinase activity of B16F10 cells in a dose-dependent manner. In-vivo studies showed that hawthorn total oligomer flavonoids extract treatment at a dose of 150 mg/kg body weight for 21 days in implanted tumor mice resulted in significant inhibition of the tumor growth volume and weight. In addition, tested samples showed significant cellular antioxidant capacity against the reactive oxygen species

Effects of extraction methods on the yield, chemical structure and anti-tumor activity of polysaccharides from Cordyceps gunnii mycelia.

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Zhu, Zhen-Yuan; Dong, Fengying; Liu, Xiaocui; Lv, Qian; YingYang; Liu, Fei; Chen, Ling; Wang, Tiantian; Wang, Zheng; Zhang, Yongmin

2016-04-20

This study was to investigate the effects of different extraction methods on the yield, chemical structure and antitumor activity of polysaccharides from Cordyceps gunnii (C. gunnii) mycelia. Five extraction methods were used to extract crude polysaccharides (CPS), which include room-temperature water extraction (RWE), hot-water extraction (HWE), microwave-assisted extraction (MAE), ultrasound-assisted extraction (UAE) and cellulase-assisted extraction (CAE). Then Sephadex G-100 was used for purification of CPS. As a result, the antitumor activities of CPS and PPS on S180 cells were evaluated. Five CPS and purified polysaccharides (PPS) were obtained. The yield of CPS by microwave-assisted extraction (CPSMAE) was the highest and its anti-tumor activity was the best and its macromolecular polysaccharide (3000-1000kDa) ratio was the largest. The PPS had the same monosaccharide composition, but their obvious difference was in the antitumor activity and the physicochemical characteristics, such as intrinsic viscosity, specific rotation, scanning electron microscopy and circular dichroism spectra. Copyright © 2015 Elsevier Ltd. All rights reserved.

Antitumor activity of Chlorella sorokiniana and Scenedesmus sp. microalgae native of Nuevo León State, México.

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Reyna-Martinez, Raul; Gomez-Flores, Ricardo; López-Chuken, Ulrico; Quintanilla-Licea, Ramiro; Caballero-Hernandez, Diana; Rodríguez-Padilla, Cristina; Beltrán-Rocha, Julio Cesar; Tamez-Guerra, Patricia

2018-01-01

Cancer cases result in 13% of all deaths worldwide. Unwanted side effects in patients under conventional treatments have led to the search for beneficial alternative therapies. Microalgae synthesize compounds with known in vitro and in vivo biological activity against different tumor cell lines. Therefore, native microalgae from the State of Nuevo Leon, Mexico may become a potential source of antitumor agents. The aim of the present study was to evaluate the in vitro cytotoxic effect of Nuevo Leon regional Chlorella sorokiniana (Chlorellales: Chlorellaceae) and Scenedesmus sp. (Chlorococcales: Scenedesmaceae). Native microalgae crude organic extracts cytotoxicity against murine L5178Y-R lymphoma cell line and normal lymphocyte proliferation were evaluated using the MTT reduction colorimetric assay. Cell death pathway was analyzed by acridine orange and ethidium bromide staining, DNA degradation in 2% agarose gel electrophoresis and caspases activity. Results indicated significant ( p  < 0.05) 61.89% ± 3.26% and 74.77% ± 1.84% tumor cytotoxicity by C. sorokiniana and Scenedesmus sp. methanol extracts, respectively, at 500 µg/mL, by the mechanism of apoptosis. This study contributes to Mexican microalgae biodiversity knowledge and their potential as antitumor agent sources.

Antitumor activity of Chlorella sorokiniana and Scenedesmus sp. microalgae native of Nuevo León State, México

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Raul Reyna-Martinez

2018-02-01

Full Text Available Cancer cases result in 13% of all deaths worldwide. Unwanted side effects in patients under conventional treatments have led to the search for beneficial alternative therapies. Microalgae synthesize compounds with known in vitro and in vivo biological activity against different tumor cell lines. Therefore, native microalgae from the State of Nuevo Leon, Mexico may become a potential source of antitumor agents. The aim of the present study was to evaluate the in vitro cytotoxic effect of Nuevo Leon regional Chlorella sorokiniana (Chlorellales: Chlorellaceae and Scenedesmus sp. (Chlorococcales: Scenedesmaceae. Native microalgae crude organic extracts cytotoxicity against murine L5178Y-R lymphoma cell line and normal lymphocyte proliferation were evaluated using the MTT reduction colorimetric assay. Cell death pathway was analyzed by acridine orange and ethidium bromide staining, DNA degradation in 2% agarose gel electrophoresis and caspases activity. Results indicated significant (p < 0.05 61.89% ± 3.26% and 74.77% ± 1.84% tumor cytotoxicity by C. sorokiniana and Scenedesmus sp. methanol extracts, respectively, at 500 µg/mL, by the mechanism of apoptosis. This study contributes to Mexican microalgae biodiversity knowledge and their potential as antitumor agent sources.

R-2HG Exhibits Anti-tumor Activity by Targeting FTO/m6A/MYC/CEBPA Signaling.

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Su, Rui; Dong, Lei; Li, Chenying; Nachtergaele, Sigrid; Wunderlich, Mark; Qing, Ying; Deng, Xiaolan; Wang, Yungui; Weng, Xiaocheng; Hu, Chao; Yu, Mengxia; Skibbe, Jennifer; Dai, Qing; Zou, Dongling; Wu, Tong; Yu, Kangkang; Weng, Hengyou; Huang, Huilin; Ferchen, Kyle; Qin, Xi; Zhang, Bin; Qi, Jun; Sasaki, Atsuo T; Plas, David R; Bradner, James E; Wei, Minjie; Marcucci, Guido; Jiang, Xi; Mulloy, James C; Jin, Jie; He, Chuan; Chen, Jianjun

2018-01-11

R-2-hydroxyglutarate (R-2HG), produced at high levels by mutant isocitrate dehydrogenase 1/2 (IDH1/2) enzymes, was reported as an oncometabolite. We show here that R-2HG also exerts a broad anti-leukemic activity in vitro and in vivo by inhibiting leukemia cell proliferation/viability and by promoting cell-cycle arrest and apoptosis. Mechanistically, R-2HG inhibits fat mass and obesity-associated protein (FTO) activity, thereby increasing global N 6 -methyladenosine (m 6 A) RNA modification in R-2HG-sensitive leukemia cells, which in turn decreases the stability of MYC/CEBPA transcripts, leading to the suppression of relevant pathways. Ectopically expressed mutant IDH1 and S-2HG recapitulate the effects of R-2HG. High levels of FTO sensitize leukemic cells to R-2HG, whereas hyperactivation of MYC signaling confers resistance that can be reversed by the inhibition of MYC signaling. R-2HG also displays anti-tumor activity in glioma. Collectively, while R-2HG accumulated in IDH1/2 mutant cancers contributes to cancer initiation, our work demonstrates anti-tumor effects of 2HG in inhibiting proliferation/survival of FTO-high cancer cells via targeting FTO/m 6 A/MYC/CEBPA signaling. Copyright © 2017 Elsevier Inc. All rights reserved.

Two new phenolic compounds and antitumor activities of asparinin A from Asparagus officinalis.

Science.gov (United States)

Li, Xue-Mei; Cai, Jin-Long; Wang, Le; Wang, Wen-Xiang; Ai, Hong-Lian; Mao, Zi-Chao

2017-02-01

Two new phenolic acid compounds, asparoffin C (1) and asparoffin D (2), together with four known compounds, asparenyol (3), gobicusin B (4), 1-methoxy-2-hydroxy-4-[5-(4-hydroxyphenoxy)-3-penten-1-ynyl] phenol (5), and asparinin A (6), have been isolated from the stems of Asparagus officinalis. The structures were established by extensive spectroscopic methods (MS and 1D and 2D NMR). Compound 6 has obvious antitumor activities both in vitro and in vivo.

Lurbinectedin induces depletion of tumor-associated macrophages, an essential component of its in vivo synergism with gemcitabine, in pancreatic adenocarcinoma mouse models

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Céspedes, María Virtudes; Guillén, María José; López-Casas, Pedro Pablo; Sarno, Francesca; Gallardo, Alberto; Álamo, Patricia; Cuevas, Carmen; Hidalgo, Manuel; Galmarini, Carlos María; Allavena, Paola; Avilés, Pablo; Mangues, Ramón

2016-01-01

ABSTRACT We explored whether the combination of lurbinectedin (PM01183) with the antimetabolite gemcitabine could result in a synergistic antitumor effect in pancreatic ductal adenocarcinoma (PDA) mouse models. We also studied the contribution of lurbinectedin to this synergism. This drug presents a dual pharmacological effect that contributes to its in vivo antitumor activity: (i) specific binding to DNA minor grooves, inhibiting active transcription and DNA repair; and (ii) specific depletion of tumor-associated macrophages (TAMs). We evaluated the in vivo antitumor activity of lurbinectedin and gemcitabine as single agents and in combination in SW-1990 and MIA PaCa-2 cell-line xenografts and in patient-derived PDA models (AVATAR). Lurbinectedin-gemcitabine combination induced a synergistic effect on both MIA PaCa-2 [combination index (CI)=0.66] and SW-1990 (CI=0.80) tumor xenografts. It also induced complete tumor remissions in four out of six patient-derived PDA xenografts. This synergism was associated with enhanced DNA damage (anti-γ-H2AX), cell cycle blockage, caspase-3 activation and apoptosis. In addition to the enhanced DNA damage, which is a consequence of the interaction of the two drugs with the DNA, lurbinectedin induced TAM depletion leading to cytidine deaminase (CDA) downregulation in PDA tumors. This effect could, in turn, induce an increase of gemcitabine-mediated DNA damage that was especially relevant in high-density TAM tumors. These results show that lurbinectedin can be used to develop ‘molecularly targeted’ combination strategies. PMID:27780828

Lurbinectedin induces depletion of tumor-associated macrophages, an essential component of its in vivo synergism with gemcitabine, in pancreatic adenocarcinoma mouse models

Directory of Open Access Journals (Sweden)

María Virtudes Céspedes

2016-12-01

Full Text Available We explored whether the combination of lurbinectedin (PM01183 with the antimetabolite gemcitabine could result in a synergistic antitumor effect in pancreatic ductal adenocarcinoma (PDA mouse models. We also studied the contribution of lurbinectedin to this synergism. This drug presents a dual pharmacological effect that contributes to its in vivo antitumor activity: (i specific binding to DNA minor grooves, inhibiting active transcription and DNA repair; and (ii specific depletion of tumor-associated macrophages (TAMs. We evaluated the in vivo antitumor activity of lurbinectedin and gemcitabine as single agents and in combination in SW-1990 and MIA PaCa-2 cell-line xenografts and in patient-derived PDA models (AVATAR. Lurbinectedin-gemcitabine combination induced a synergistic effect on both MIA PaCa-2 [combination index (CI=0.66] and SW-1990 (CI=0.80 tumor xenografts. It also induced complete tumor remissions in four out of six patient-derived PDA xenografts. This synergism was associated with enhanced DNA damage (anti-γ-H2AX, cell cycle blockage, caspase-3 activation and apoptosis. In addition to the enhanced DNA damage, which is a consequence of the interaction of the two drugs with the DNA, lurbinectedin induced TAM depletion leading to cytidine deaminase (CDA downregulation in PDA tumors. This effect could, in turn, induce an increase of gemcitabine-mediated DNA damage that was especially relevant in high-density TAM tumors. These results show that lurbinectedin can be used to develop ‘molecularly targeted’ combination strategies.

Taming the Wildness of "Trojan-Horse" Peptides by Charge-Guided Masking and Protease-Triggered Demasking for the Controlled Delivery of Antitumor Agents.

Science.gov (United States)

Shi, Nian-Qiu; Qi, Xian-Rong

2017-03-29

Cell-penetrating peptide (CPP), also called "Trojan Horse" peptide, has become a successful approach to deliver various payloads into cells for achieving the intracellular access. However, the "Trojan Horse" peptide is too wild, not just to "Troy", but rather widely distributed in the body. Thus, there is an urgent need to tame the wildness of "Trojan Horse" peptide for targeted delivery of antineoplastic agents to the tumor site. To achieve this goal, we exploit a masked CPP-doxorubicin conjugate platform for targeted delivery of chemotherapeutic drugs using charge-guided masking and protease-triggered demasking strategies. In this platform, the cell-penetrating function of the positively CPP (d-form nonaarginine) is abrogated by a negatively shielding peptide (masked CPP), and between them is a cleavable substrate peptide by the protease (MMP-2/9). Protease-triggered demasking would occur when the masked CPP reached the MMP-2/9-riched tumor. The CPP-doxorubicin conjugate (CPP-Dox) and the masked CPP-Dox conjugate (mCPP-Dox) were used as models for the evaluation of masking and demasking processes. It was found that exogenous MMP-2/9 could effectively trigger the reversion of CPP-cargo in this conjugate, and this trigger adhered to the Michaelis-Menten kinetics profile. This conjugate was sensitive to the trigger of endogenous MMP-2/9 and could induce enhanced cytotoxicity toward MMP-2/9-rich tumor cells. In vivo antitumor efficacy revealed that this masked conjugate had considerable antitumor activity and could inhibit the tumor growth at a higher level relative to CPP-cargo. Low toxicity in vivo showed the noticeably decreased wildness of this conjugate toward normal tissues and more controllable entry of antitumor agents into "Troy". On the basis of analyses in vitro and in vivo, this mCPP-cargo conjugate delivery system held an improved selectivity toward MMP-2/9-rich tumors and would be a promising strategy for tumor-targeted treatment.

TTI-621 (SIRPαFc): A CD47-Blocking Innate Immune Checkpoint Inhibitor with Broad Antitumor Activity and Minimal Erythrocyte Binding.

Science.gov (United States)

Petrova, Penka S; Viller, Natasja Nielsen; Wong, Mark; Pang, Xinli; Lin, Gloria H Y; Dodge, Karen; Chai, Vien; Chen, Hui; Lee, Vivian; House, Violetta; Vigo, Noel T; Jin, Debbie; Mutukura, Tapfuma; Charbonneau, Marilyse; Truong, Tran; Viau, Stephane; Johnson, Lisa D; Linderoth, Emma; Sievers, Eric L; Maleki Vareki, Saman; Figueredo, Rene; Pampillo, Macarena; Koropatnick, James; Trudel, Suzanne; Mbong, Nathan; Jin, Liqing; Wang, Jean C Y; Uger, Robert A

2017-02-15

Purpose: The ubiquitously expressed transmembrane glycoprotein CD47 delivers an anti-phagocytic (do not eat) signal by binding signal-regulatory protein α (SIRPα) on macrophages. CD47 is overexpressed in cancer cells and its expression is associated with poor clinical outcomes. TTI-621 (SIRPαFc) is a fully human recombinant fusion protein that blocks the CD47-SIRPα axis by binding to human CD47 and enhancing phagocytosis of malignant cells. Blockade of this inhibitory axis using TTI-621 has emerged as a promising therapeutic strategy to promote tumor cell eradication. Experimental Design: The ability of TTI-621 to promote macrophage-mediated phagocytosis of human tumor cells was assessed using both confocal microscopy and flow cytometry. In vivo antitumor efficacy was evaluated in xenograft and syngeneic models and the role of the Fc region in antitumor activity was evaluated using SIRPαFc constructs with different Fc tails. Results: TTI-621 enhanced macrophage-mediated phagocytosis of both hematologic and solid tumor cells, while sparing normal cells. In vivo , TTI-621 effectively controlled the growth of aggressive AML and B lymphoma xenografts and was efficacious in a syngeneic B lymphoma model. The IgG1 Fc tail of TTI-621 plays a critical role in its antitumor activity, presumably by engaging activating Fcγ receptors on macrophages. Finally, TTI-621 exhibits minimal binding to human erythrocytes, thereby differentiating it from CD47 blocking antibodies. Conclusions: These data indicate that TTI-621 is active across a broad range of human tumors. These results further establish CD47 as a critical regulator of innate immune surveillance and form the basis for clinical development of TTI-621 in multiple oncology indications. Clin Cancer Res; 23(4); 1068-79. ©2016 AACR . ©2016 American Association for Cancer Research.

Pyrvinium targets the unfolded protein response to hypoglycemia and its anti-tumor activity is enhanced by combination therapy.

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De-Hua Yu

Full Text Available We identified pyrvinium pamoate, an old anthelminthic medicine, which preferentially inhibits anchorage-independent growth of cancer cells over anchorage-dependent growth (approximately 10 fold. It was also reported by others to have anti-tumor activity in vivo and selective toxicity against cancer cells under glucose starvation in vitro, but with unknown mechanism. Here, we provide evidence that pyrvinium suppresses the transcriptional activation of GRP78 and GRP94 induced by glucose deprivation or 2-deoxyglucose (2DG, a glycolysis inhibitor, but not by tunicamycin or A23187. Other UPR pathways induced by glucose starvation, e.g. XBP-1, ATF4, were also found suppressed by pyrvinium. Constitutive expression of GRP78 via transgene partially protected cells from pyrvinium induced cell death under glucose starvation, suggesting that suppression of the UPR is involved in pyrvinium mediated cytotoxicity under glucose starvation. Xenograft experiments showed rather marginal overall anti-tumor activity for pyrvinium as a monotherapy. However, the combination of pyrvinium and Doxorubicin demonstrated significantly enhanced efficacy in vivo, supporting a mechanistic treatment concept based on tumor hypoglycemia and UPR.

In Vivo Imaging of Natural Killer Cell Trafficking in Tumors

NARCIS (Netherlands)

Galli, Filippo; Rapisarda, Anna Serafina; Stabile, Helena; Malviya, Gaurav; Manni, Isabella; Bonanno, Elena; Piaggio, Giulia; Gismondi, Angela; Santoni, Angela; Signore, Alberto

2015-01-01

Natural killer cells (NKs) are important effectors of the innate immune system, with marked antitumor activity. Imaging NK trafficking in vivo may be relevant to following up the efficacy of new therapeutic approaches aiming at increasing tumor-infiltrating NKs (TINKs). The specific aims of present

Regorafenib: Antitumor Activity upon Mono and Combination Therapy in Preclinical Pediatric Malignancy Models.

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Daudigeos-Dubus, Estelle; Le Dret, Ludivine; Lanvers-Kaminsky, Claudia; Bawa, Olivia; Opolon, Paule; Vievard, Albane; Villa, Irène; Pagès, Mélanie; Bosq, Jacques; Vassal, Gilles; Zopf, Dieter; Geoerger, Birgit

2015-01-01

The multikinase inhibitor regorafenib (BAY 73-4506) exerts both anti-angiogenic and anti-tumorigenic activity in adult solid malignancies mainly advanced colorectal cancer and gastrointestinal stromal tumors. We intended to explore preclinically the potential of regorafenib against solid pediatric malignancies alone and in combination with anticancer agents to guide the pediatric development plan. In vitro effects on cell proliferation were screened against 33 solid tumor cell lines of the Innovative Therapies for Children with Cancer (ITCC) panel covering five pediatric solid malignancies. Regorafenib inhibited cell proliferation with a mean half maximal growth inhibition of 12.5 μmol/L (range 0.7 μmol/L to 28 μmol/L). In vivo, regorafenib was evaluated alone at 10 or 30 mg/kg/d or in combination with radiation, irinotecan or the mitogen-activated protein kinase kinase (MEK) inhibitor refametinib against various tumor types, including patient-derived brain tumor models with an amplified platelet-derived growth factor receptor A (PDGFRA) gene. Regorafenib alone significantly inhibited tumor growth in all xenografts derived from nervous system and connective tissue tumors. Enhanced effects were observed when regorafenib was combined with irradiation and irinotecan against PDGFRA amplified IGRG93 glioma and IGRM57 medulloblastoma respectively, resulting in 100% tumor regressions. Antitumor activity was associated with decreased tumor vascularization, inhibition of PDGFR signaling, and induction of apoptotic cell death. Our work demonstrates that regorafenib exhibits significant antitumor activity in a wide spectrum of preclinical pediatric models through inhibition of angiogenesis and induction of apoptosis. Furthermore, radio- and chemosensitizing effects were observed with DNA damaging agents in PDGFR amplified tumors.

Selective potentiation of the antitumor radiation effect by means of short-term hyperglycemia

International Nuclear Information System (INIS)

Yarmonenko, S.P.; Shapot, V.S.; Voloshina, E.A.; Gorozhanskaya, Eh.G.; Dyuskaliev, Zh.D.; Krimker, V.M.

1981-01-01

Experiments on mice have shown that short-term induced hyperglycemia caused by 5-fold intraperitoneal administration of glucose at a dose of 2.6 and 1.3 g/kg increases notably the radiation injury to a solid type of Ehrlich carcinoma. Short-term induced hyperglycemia is mostly effective after irradiation. During irradiation together with its antitumor effect enhanced in the presence of short-term induced hyperglycemia there is observed selective protection of the normal tissues resulting from a decrease of oxygen pressure in them

Epitope diversification driven by non-tumor epitope-specific Th1 and Th17 mediates potent antitumor reactivity.

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Ichikawa, Kosuke; Kagamu, Hiroshi; Koyama, Kenichi; Miyabayashi, Takao; Koshio, Jun; Miura, Satoru; Watanabe, Satoshi; Yoshizawa, Hirohisa; Narita, Ichiei

2012-09-21

MHC class I-restricted peptide-based vaccination therapies have been conducted to treat cancer patients, because CD8⁺ CTL can efficiently induce apoptosis of tumor cells in an MHC class I-restricted epitope-specific manner. Interestingly, clinical responders are known to demonstrate reactivity to epitopes other than those used for vaccination; however, the mechanism underlying how antitumor T cells with diverse specificity are induced is unclear. In this study, we demonstrated that dendritic cells (DCs) that engulfed apoptotic tumor cells in the presence of non-tumor MHC class II-restricted epitope peptides, OVA(323-339), efficiently presented tumor-associated antigens upon effector-dominant CD4⁺ T cell balance against regulatory T cells (Treg) for the OVA(323-339) epitope. Th1 and Th17 induced tumor-associated antigens presentation of DC, while Th2 ameliorated tumor-antigen presentation for CD8⁺ T cells. Blocking experiments with anti-IL-23p19 antibody and anti-IL-23 receptor indicated that an autocrine mechanism of IL-23 likely mediated the diverted tumor-associated antigens presentation of DC. Tumor-associated antigens presentation of DC induced by OVA(323-339) epitope-specific CD4⁺ T cells resulted in facilitated antitumor immunity in both priming and effector phase in vivo. Notably, this immunotherapy did not require pretreatment to reduce Treg induced by tumor. This strategy may have clinical implications for designing effective antitumor immunotherapies. Copyright © 2012 Elsevier Ltd. All rights reserved.

Melatonin enhances the anti-tumor effect of fisetin by inhibiting COX-2/iNOS and NF-κB/p300 signaling pathways.

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Canhui Yi

Full Text Available Melatonin is a hormone identified in plants and pineal glands of mammals and possesses diverse physiological functions. Fisetin is a bio-flavonoid widely found in plants and exerts antitumor activity in several types of human cancers. However, the combinational effect of melatonin and fisetin on antitumor activity, especially in melanoma treatment, remains unclear. Here, we tested the hypothesis that melatonin could enhance the antitumor activity of fisetin in melanoma cells and identified the underlying molecular mechanisms. The combinational treatment of melanoma cells with fisetin and melatonin significantly enhanced the inhibitions of cell viability, cell migration and clone formation, and the induction of apoptosis when compared with the treatment of fisetin alone. Moreover, such enhancement of antitumor effect by melatonin was found to be mediated through the modulation of the multiply signaling pathways in melanoma cells. The combinational treatment of fisetin with melatonin increased the cleavage of PARP proteins, triggered more release of cytochrome-c from the mitochondrial inter-membrane, enhanced the inhibition of COX-2 and iNOS expression, repressed the nuclear localization of p300 and NF-κB proteins, and abrogated the binding of NF-κB on COX-2 promoter. Thus, these results demonstrated that melatonin potentiated the anti-tumor effect of fisetin in melanoma cells by activating cytochrome-c-dependent apoptotic pathway and inhibiting COX-2/iNOS and NF-κB/p300 signaling pathways, and our study suggests the potential of such a combinational treatment of natural products in melanoma therapy.

Melatonin Enhances the Anti-Tumor Effect of Fisetin by Inhibiting COX-2/iNOS and NF-κB/p300 Signaling Pathways

Science.gov (United States)

Yu, Zhenlong; Xiao, Yao; Wang, Jingshu; Qiu, Huijuan; Yu, Wendan; Tang, Ranran; Yuan, Yuhui; Guo, Wei; Deng, Wuguo

2014-01-01

Melatonin is a hormone identified in plants and pineal glands of mammals and possesses diverse physiological functions. Fisetin is a bio-flavonoid widely found in plants and exerts antitumor activity in several types of human cancers. However, the combinational effect of melatonin and fisetin on antitumor activity, especially in melanoma treatment, remains unclear. Here, we tested the hypothesis that melatonin could enhance the antitumor activity of fisetin in melanoma cells and identified the underlying molecular mechanisms. The combinational treatment of melanoma cells with fisetin and melatonin significantly enhanced the inhibitions of cell viability, cell migration and clone formation, and the induction of apoptosis when compared with the treatment of fisetin alone. Moreover, such enhancement of antitumor effect by melatonin was found to be mediated through the modulation of the multiply signaling pathways in melanoma cells. The combinational treatment of fisetin with melatonin increased the cleavage of PARP proteins, triggered more release of cytochrome-c from the mitochondrial inter-membrane, enhanced the inhibition of COX-2 and iNOS expression, repressed the nuclear localization of p300 and NF-κB proteins, and abrogated the binding of NF-κB on COX-2 promoter. Thus, these results demonstrated that melatonin potentiated the anti-tumor effect of fisetin in melanoma cells by activating cytochrome-c-dependent apoptotic pathway and inhibiting COX-2/iNOS and NF-κB/p300 signaling pathways, and our study suggests the potential of such a combinational treatment of natural products in melanoma therapy. PMID:25000190

Increased oxidative stress mediates the antitumor effect of PARP inhibition in ovarian cancer

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Dong Hou

2018-07-01

Full Text Available PARP inhibitors have been widely tested in clinical trials, especially for the treatment of breast cancer and ovarian cancer, and were shown to be highly successful. Because PARP primarily functions in sensing and repairing DNA strand breaks, the therapeutic effect of PARP inhibition is generally believed to be attributed to impaired DNA repair. We here report that oxidative stress is also increased by PARP inhibition and mediates the antitumor effect. We showed that PARP1 is highly expressed in specimens of high grade serous ovarian carcinoma and its activity is required for unperturbed proliferation of ovarian cancer cells. Inhibition or depletion of PARP leads to not only an increase in DNA damage, but also an elevation in the levels of reactive oxygen species (ROS. Importantly, antioxidant N-acetylcysteine (NAC significantly attenuated the induction of DNA damage and the perturbation of proliferation by PARP inhibition or depletion. We further showed that NADPH oxidases 1 and 4 were significantly upregulated by PARP inhibition and were partially responsible for the induction of oxidative stress. Depletion of NOX1 and NOX4 partially rescued the growth inhibition of PARP1-deficient tumor xenografts. Our findings suggest that in addition to compromising the repair of DNA damage, PARP inhibition or depletion may exert extra antitumor effect by elevating oxidative stress in ovarian cancer cells. Keywords: PARP1, Oxidative stress, NADPH oxidases, Ovarian cancer

Lym-1 Chimeric Antigen Receptor T Cells Exhibit Potent Anti-Tumor Effects against B-Cell Lymphoma

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Long Zheng

2017-12-01

Full Text Available T cells expressing chimeric antigen receptors (CARs recognizing CD19 epitopes have produced remarkable anti-tumor effects in patients with B-cell malignancies. However, cancer cells lacking recognized epitopes can emerge, leading to relapse and death. Thus, CAR T cells targeting different epitopes on different antigens could improve immunotherapy. The Lym-1 antibody targets a conformational epitope of Human Leukocyte Antigen-antigen D Related (HLA-DR on the surface of human B-cell lymphomas. Lym-1 CAR T cells were thus generated for evaluation of cytotoxic activity towards lymphoma cells in vitro and in vivo. Human T cells from healthy donors were transduced to express a Lym-1 CAR, and assessed for epitope-driven function in culture and towards Raji xenografts in NOD-scidIL2Rgammanull (NSG mice. Lym-1 CAR T cells exhibited epitope-driven activation and lytic function against human B-cell lymphoma cell lines in culture and mediated complete regression of Raji/Luciferase-Green fluorescent protein (Raji/Luc-GFP in NSG mice with similar or better reactivity than CD19 CAR T cells. Lym-1 CAR transduction of T cells is a promising immunotherapy for patients with Lym-1 epitope positive B-cell malignancies.

Binding and internalization of NGR-peptide-targeted liposomal doxorubicin (TVT-DOX) in CD13-expressing cells and its antitumor effects.

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Garde, Seema V; Forté, André J; Ge, Michael; Lepekhin, Eugene A; Panchal, Chandra J; Rabbani, Shafaat A; Wu, Jinzi J

2007-11-01

In an effort to develop new agents and molecular targets for the treatment of cancer, aspargine-glycine-arginine (NGR)-targeted liposomal doxorubicin (TVT-DOX) is being studied. The NGR peptide on the surface of liposomal doxorubicin (DOX) targets an aminopeptidase N (CD13) isoform, specific to the tumor neovasculature, making it a promising strategy. To further understand the molecular mechanisms of action, we investigated cell binding, kinetics of internalization as well as cytotoxicity of TVT-DOX in vitro. We demonstrate the specific binding of TVT-DOX to CD13-expressing endothelial [human umbilical vein endothelial cells (HUVEC) and Kaposi sarcoma-derived endothelial cells (SLK)] and tumor (fibrosarcoma, HT-1080) cells in vitro. Following binding, the drug was shown to internalize through the endosomal pathway, eventually leading to the localization of doxorubicin in cell nuclei. TVT-DOX showed selective toxicity toward CD13-expressing HUVEC, sparing the CD13-negative colon-cancer cells, HT-29. Additionally, the nontargeted counterpart of TVT-DOX, Caelyx, was less cytotoxic to the CD13-positive HUVECs demonstrating the advantages of NGR targeting in vitro. The antitumor activity of TVT-DOX was tested in nude mice bearing human prostate-cancer xenografts (PC3). A significant growth inhibition (up to 60%) of PC3 tumors in vivo was observed. Reduction of tumor vasculature following treatment with TVT-DOX was also apparent. We further compared the efficacies of TVT-DOX and free doxorubicin in the DOX-resistant colon-cancer model, HCT-116, and observed the more pronounced antitumor effects of the TVT-DOX formulation over free DOX. The potential utility of TVT-DOX in a variety of vascularized solid tumors is promising.

Radiation effects on tumor-specific DTH response, 2

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Nobusawa, Hiroshi; Hachisu, Reiko.

1991-01-01

Tumor-specific immunity was induced in C3H mice by immunizing with syngeneic MH134 hepatoma cells. Radiation sensitivity of anti-tumor activity of immunized spleen cells were examined and compared with the radiation sensitivity of the delayed-type hypersensitivity (DTH)-response. The spleen cells were irradiated in vitro, then mixed with the tumor cells. DTH-response intensity was determined from the footpad increment twenty-four hours after inoculation of tumor cells with immunized spleen cells. Anti-tumor activity of the spleen cells, based on growth inhibition of tumor cells, was measured by a cytostatic test in vivo with diffusion chambers. Tumor-specific DTH response was suppressed dose-dependently in the range of 12-24 Gy irradiation. No suppression was observed below 12 Gy. Without irradiation, growth of tumor cells was inhibited by immunized spleen cells more effectively than by normal spleen cells. Anti-tumor activity of immunized and normal spleen cells was diminished by irradiation doses of 20 Gy and 10 Gy, respectively. Comparing our report with others that analyzed the type of anti-tumor effector cells induced in this experimental system, we concluded that tumor-specific anti-tumor activity (tumor growth inhibition in vivo) that was radiosensitive at 10-20 Gy depended on a DTH-response. (author)

Antitumor effect of a new nano-vector with miRNA-135a on malignant glioma

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Liang C

2017-12-01

Full Text Available Chaofeng Liang,1,* Weitong Sun,2,* Haiyong He,1,* Baoyu Zhang,1 Cong Ling,1 Bocheng Wang,1 Tengchao Huang,1 Bo Hou,1 Ying Guo1 1Department of Neurosurgery, 3rd Affiliated Hospital of Sun Yat-sen University, Sun Yat-sen University, Guangdong, China; 2The Pharmaceutical College of Jiamusi University, Jiamusi University, Jiamusi, China *These authors contributed equally to this work Introduction: MiR-135a is found to selectively induce apoptosis in glioma cell but not in normal neurons and glial cells. However, low transfection efficacy limits its application in vivo as other miRNAs. We prepared a new kind of nano-vector based on polyethylene glycol methyl ether (mPEG and hyper-branched polyethylenimine (hy-PEI in order to improve the miRNA delivery system into the glioma cells. Methods: The mPEG-g-PEI/miR-135a was constructed and detected by 1H NMR and FTIR analyses. Transmission electron microscope was utilized for its characteristics. Stability and release efficiency was assessed by electrophoresis. Biocompatibility was observed and analyzed through co-culture with astrocytes and malignant glioma cells (C6. Transfection rate was monitored by laser confocal microscopy and flow cytometry. The antitumor effect of mPEG-g-PEI/miR-135a to C6 was confirmed in vivo by MR scanning, pathology and survival curve. RT-PCR was used to assay transfection efficiency of mPEG-g-PEI/miR-135a in vitro and in vivo. And Western blotting was used to assess the expressions of the targeted proteins of miR-135a.Results: In this experiment, we found the optimal N/P ratio of mPEG-g-PEI/miR-135a was about 6 judged by Zeta potential, particle size and encapsulation ability. The stability of mPEG-g-PEI/miR-135a in serum and the release efficiency in acid(pH=5.0 of mPEG-g-PEI/miR-135a were simulated the environment in vivo and in tumor. The mPEG-g-PEI nano-vector was co-cultured with malignant glioma cell C6 and normal astrocytes in vitro and showed good biocompatibility

Rhenium–platinum antitumor systems

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A. V. Shtemenko

2017-04-01

Full Text Available This review provides an overlook of design (in short, antitumor and other biological activity of quadruple-bonded cluster dirhenium(III compounds and their synergism with cisplatin. In particular, we describe the work of the rhenium-platinum antitumor system (introduction of rhenium and platinum compounds. Among known metal-based anticancer drugs and drug candidates dirhenium(III compounds differ profoundly due to their strong antiradical and antioxidant properties determined by quadruple bond unsaturation. Such advantages of metal complexes as more expressed redox chemical propertie should be exploited for creating more efficient anticancer drugs. Combination of drugs leads to synergistic effects and/or to lowe­ring toxicity of platinides and is very promising in cancer chemotherapy. The review covers the follo­wing items: design of quadruple bonded dirhenium(III clusters, their spectral and antiradical properties (in short; interaction of the dirhenium(III compounds with lipids and formation of liposomes; interaction of the dirhenium(III compounds with erythrocytes and their antihemolytic activity in the models of hemolytic anemia; anticancer activity of dirhenium clusters and work of the rhenium-platinum antitumor system; antianemic and antioxidant properties of the dirhenium(III compounds in the model of tumor growth; interaction of the dirhenium(III compounds with nucleobases and DNA. Some modern trends in the field of bioinorganic and medicinal chemi­stry are also considered regarding their connection to the rhenium-platinum system efficiency: use of combinational therapy and nanomaterials; involvement of some biologically active ligands and redox-activation strategy, etc.

Aspirin Has Antitumor Effects via Expression of Calpain Gene in Cervical Cancer Cells

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Sang Koo Lee

2008-01-01

Full Text Available Aspirin and other nonsteroidal anti-inflammatory drugs show efficacy in the prevention of cancers. It is known that they can inhibit cyclooxygenases, and some studies have shown that they can induce apoptosis. Our objective in this study was to investigate the mechanism by which aspirin exerts its apoptosis effects in human cervical cancer HeLa cells. The effect of aspirin on the gene expression was studied by differential mRNA display RT-PCR. Among the isolated genes, mu-type calpain gene was upregulated by aspirin treatment. To examine whether calpain mediates the antitumor effects, HeLa cells were stably transfected with the mammalian expression vector pCR3.1 containing mu-type calpain cDNA (pCRCAL/HeLa, and tumor formations were measured in nude mice. When tumor burden was measured by day 49, HeLa cells and pCR/HeLa cells (vector control produced tumors of 2126 mm3 and 1638 mm3, respectively, while pCRCAL/HeLa cells produced markedly smaller tumor of 434 mm3 in volume. The caspase-3 activity was markedly elevated in pCRCAL/HeLa cells. The increased activity levels of caspase-3 in pCRCAL/HeLa cells, in parallel with the decreased tumor formation, suggest a correlation between caspase-3 activity and calpain protein. Therefore, we conclude that aspirin-induced calpain mediates an antitumor effect via caspase-3 in cervical cancer cells.

Human adipose tissue-derived mesenchymal stem cells inhibit T-cell lymphoma growth in vitro and in vivo.

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Ahn, Jin-Ok; Chae, Ji-Sang; Coh, Ye-Rin; Jung, Woo-Sung; Lee, Hee-Woo; Shin, Il-Seob; Kang, Sung-Keun; Youn, Hwa-Young

2014-09-01

Human mesenchymal stem cells (hMSCs) are thought to be one of the most reliable stem cell sources for a variety of cell therapies. This study investigated the anti-tumor effect of human adipose tissue-derived mesenchymal stem cells (hAT-MSCs) on EL4 murine T-cell lymphoma in vitro and in vivo. The growth-inhibitory effect of hAT-MSCs on EL4 tumor cells was evaluated using a WST-1 cell proliferation assay. Cell-cycle arrest and apoptosis were investigated by flow cytometry and western blot. To evaluate an anti-tumor effect of hAT-MSCs on T-cell lymphoma in vivo, CM-DiI-labeled hAT-MSCs were circumtumorally injected in tumor-bearing nude mice, and tumor size was measured. hAT-MSCs inhibited T-cell lymphoma growth by altering cell-cycle progression and inducing apoptosis in vitro. hAT-MSCs inhibited tumor growth in tumor-bearing nude mice and prolonged survival time. Immunofluorescence analysis showed that hAT-MSCs migrated to tumor sites. hAT-MSCs suppress the growth of T-cell lymphoma, suggesting a therapeutic option for T-cell lymphoma. Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Antitumor Effect of Burchellin Derivatives Against Neuroblastoma.

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Kurita, Masahiro; Takada, Tomomi; Wakabayashi, Noriko; Asami, Satoru; Ono, Shinichi; Uchiyama, Taketo; Suzuki, Takashi

2018-02-01

Neuroblastoma is one of the most commonly encountered malignant solid tumors in the pediatric age group. We examined the antitumor effects of five burchellin derivatives against human neuroblastoma cell lines. We evaluated cytotoxicity by the MTT assay for four human neuroblastoma and two normal cell lines. We also performed analysis of the apoptotic induction effect by flow cytometry, and examined the expression levels of apoptosis- and cell growth-related proteins by western blot analysis. We found that one of the burchellin derivatives (compound 4 ) exerted cytotoxicity against the neuroblastoma cell lines. Compound 4 induced caspase-dependent apoptosis via a mitochondrial pathway. The apoptosis mechanisms induced by compound 4 involved caspase-3, -7 and -9 activation and poly (ADP-ribose) polymerase cleavage. In addition, compound 4 induced cell death through inhibition of the cell growth pathway (via extracellular signal-regulated kinase 1 and 2, AKT8 virus oncogene cellular homolog, and signal transducer and activator of transcription 3). Compound 4 exerted cellular cytotoxicity against neuroblastoma cells via induction of caspase-dependent apoptosis, and may offer promise for further development as a useful drug for the treatment of advanced neuroblastoma. Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Comparative toxicity and efficacy of engineered anthrax lethal toxin variants with broad anti-tumor activities

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Peters, Diane E.; Hoover, Benjamin; Cloud, Loretta Grey; Liu, Shihui; Molinolo, Alfredo A.; Leppla, Stephen H.; Bugge, Thomas H.

2014-01-01

We have previously designed and characterized versions of anthrax lethal toxin that are selectively cytotoxic in the tumor microenvironment and which display broad and potent anti-tumor activities in vivo. Here, we have performed the first direct comparison of the safety and efficacy of three engineered anthrax lethal toxin variants requiring activation by either matrix-metalloproteinases (MMPs), urokinase plasminogen activator (uPA) or co-localized MMP/uPA activities. C57BL/6J mice were challenged with six doses of engineered toxins via intraperitoneal (I.P.) or intravenous (I.V.) dose routes to determine the maximum tolerated dose for six administrations (MTD6) and dose-limiting toxicities. Efficacy was evaluated using the B16-BL6 syngraft model of melanoma; mice bearing established tumors were treated with six I.P. doses of toxin and tumor measurements and immunohistochemistry, paired with terminal blood work, were used to elaborate upon the anti-tumor mechanism and relative efficacy of each variant. We found that MMP-, uPA- and dual MMP/uPA-activated anthrax lethal toxins exhibited the same dose-limiting toxicity; dose-dependent GI toxicity. In terms of efficacy, all three toxins significantly reduced primary B16-BL6 tumor burden, ranging from 32% to 87% reduction, and they also delayed disease progression as evidenced by dose-dependent normalization of blood work values. While target organ toxicity and effective doses were similar amongst the variants, the dual MMP/uPA-activated anthrax lethal toxin exhibited the highest I.P. MTD6 and was 1.5–3-fold better tolerated than the single MMP- and uPA-activated toxins. Overall, we demonstrate that this dual MMP/uPA-activated anthrax lethal toxin can be administered safely and is highly effective in a preclinical model of melanoma. This modified bacterial cytotoxin is thus a promising candidate for further clinical development and evaluation for use in treating human cancers. - Highlights: • Toxicity and anti-tumor

Comparative toxicity and efficacy of engineered anthrax lethal toxin variants with broad anti-tumor activities

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Peters, Diane E. [Proteases and Tissue Remodeling Section, Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD (United States); Program of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, MA (United States); Hoover, Benjamin [Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD (United States); Cloud, Loretta Grey [Proteases and Tissue Remodeling Section, Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD (United States); Liu, Shihui [Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD (United States); Molinolo, Alfredo A. [Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD (United States); Leppla, Stephen H. [Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD (United States); Bugge, Thomas H., E-mail: thomas.bugge@nih.go [Proteases and Tissue Remodeling Section, Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD (United States)

2014-09-01

We have previously designed and characterized versions of anthrax lethal toxin that are selectively cytotoxic in the tumor microenvironment and which display broad and potent anti-tumor activities in vivo. Here, we have performed the first direct comparison of the safety and efficacy of three engineered anthrax lethal toxin variants requiring activation by either matrix-metalloproteinases (MMPs), urokinase plasminogen activator (uPA) or co-localized MMP/uPA activities. C57BL/6J mice were challenged with six doses of engineered toxins via intraperitoneal (I.P.) or intravenous (I.V.) dose routes to determine the maximum tolerated dose for six administrations (MTD6) and dose-limiting toxicities. Efficacy was evaluated using the B16-BL6 syngraft model of melanoma; mice bearing established tumors were treated with six I.P. doses of toxin and tumor measurements and immunohistochemistry, paired with terminal blood work, were used to elaborate upon the anti-tumor mechanism and relative efficacy of each variant. We found that MMP-, uPA- and dual MMP/uPA-activated anthrax lethal toxins exhibited the same dose-limiting toxicity; dose-dependent GI toxicity. In terms of efficacy, all three toxins significantly reduced primary B16-BL6 tumor burden, ranging from 32% to 87% reduction, and they also delayed disease progression as evidenced by dose-dependent normalization of blood work values. While target organ toxicity and effective doses were similar amongst the variants, the dual MMP/uPA-activated anthrax lethal toxin exhibited the highest I.P. MTD6 and was 1.5–3-fold better tolerated than the single MMP- and uPA-activated toxins. Overall, we demonstrate that this dual MMP/uPA-activated anthrax lethal toxin can be administered safely and is highly effective in a preclinical model of melanoma. This modified bacterial cytotoxin is thus a promising candidate for further clinical development and evaluation for use in treating human cancers. - Highlights: • Toxicity and anti-tumor

Curcumin-induced HDAC inhibition and attenuation of medulloblastoma growth in vitro and in vivo

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Olson James M

2011-04-01

Full Text Available Abstract Background Medulloblastoma is the most common brain tumor in children, and its prognosis is worse than for many other common pediatric cancers. Survivors undergoing treatment suffer from serious therapy-related side effects. Thus, it is imperative to identify safer, effective treatments for medulloblastoma. In this study we evaluated the anti-cancer potential of curcumin in medulloblastoma by testing its ability to induce apoptosis and inhibit tumor growth in vitro and in vivo using established medulloblastoma models. Methods Using cultured medulloblastoma cells, tumor xenografts, and the Smo/Smo transgenic medulloblastoma mouse model, the antitumor effects of curcumin were tested in vitro and in vivo. Results Curcumin induced apoptosis and cell cycle arrest at the G2/M phase in medulloblastoma cells. These effects were accompanied by reduced histone deacetylase (HDAC 4 expression and activity and increased tubulin acetylation, ultimately leading to mitotic catastrophe. In in vivo medulloblastoma xenografts, curcumin reduced tumor growth and significantly increased survival in the Smo/Smo transgenic medulloblastoma mouse model. Conclusions The in vitro and in vivo data suggest that curcumin has the potential to be developed as a therapeutic agent for medulloblastoma.

A ruthenium(II) complex inhibits tumor growth in vivo with fewer side-effects compared with cisplatin.

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Wang, Jin-Quan; Zhang, Ping-Yu; Ji, Liang-Nian; Chao, Hui

2015-05-01

The antitumor activity of a ruthenium(II) polypyridyl complex, Δ-[Ru(bpy)2(HPIP)](ClO4)2 (Δ-Ru1, where bpy=2,2'-bipyridine, HPIP=2-(2-hydroxyphenyl)imidazo[4,5-f][1,10]phenanthroline), was evaluated. The in vivo experiments showed that Δ-Ru1 inhibited the growth of a human cervical carcinoma cell line (HeLa) xenotransplanted into nude mice with efficiency similar to that of cisplatin. Histopathology examination of the tumors from treated xenograft models was consistent with apoptosis in tumor cells. Importantly, in striking contrast with cisplatin, Δ-Ru1 did not cause any detectable side effects on the kidney, liver, peripheral neuronal system, or the hematological system at the pharmacologically effective dose. The preclinical studies reported here provide support for the clinical use of Δ-Ru1 as an exciting new drug candidate with lower toxicity than cisplatin, endowed with proapoptotic properties. Copyright © 2015 Elsevier Inc. All rights reserved.

The Antitumor Effects of Triterpenoid Saponins from the Anemone flaccida and the Underlying Mechanism

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Lin-Tao Han

2013-01-01

Full Text Available Anemone flaccida Fr. Schmidt, a family of ancient hopanoids, have been used as traditional Asian herbs for the treatments of inflammation and convulsant diseases. Previous study on HeLa cells suggested that triterpenoid saponins from Anemone flaccida Fr. Schmidt may have potential antitumor effect due to their apoptotic activities. Here, we confirmed the apoptotic activities of the following five triterpenoid saponins: glycoside St-I4a (1, glycoside St-J (2, anhuienoside E (3, hedera saponin B (4, and flaccidoside II (5 on human BEL-7402 and HepG2 hepatoma cell lines, as well as the model of HeLa cells treated with lipopolysaccharide (LPS. We found that COX-2/PGE2 signaling pathway, which plays key roles in the development of cancer, is involved in the antitumor activities of these saponins. These data provide the evidence that triterpenoid saponins can induce apoptosis via COX-2/PGE2 pathway, implying a preventive role of saponins from Anemone flaccida in tumor.

Inhibition of heat-shock protein 90 sensitizes liver cancer stem-like cells to magnetic hyperthermia and enhances anti-tumor effect on hepatocellular carcinoma-burdened nude mice

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Yang, Rui; Tang, Qiusha; Miao, Fengqin; An, Yanli; Li, Mengfei; Han, Yong; Wang, Xihui; Wang, Juan; Liu, Peidang; Chen, Rong

2015-01-01

Purpose To explore the thermoresistance and expression of heat-shock protein 90 (HSP90) in magnetic hyperthermia-treated human liver cancer stem-like cells (LCSCs) and the effects of a heat-shock protein HSP90 inhibitor 17-allylamino-17-demethoxgeldanamycin (17-AAG) on hepatocellular carcinoma-burdened nude mice. Methods CD90+ LCSCs were isolated by magnetic-activated cell sorting from BEL-7404. Spheroid formation, proliferation, differentiation, drug resistance, and tumor formation assays were performed to identify stem cell characteristics. CD90-targeted thermosensitive magnetoliposomes (TMs)-encapsulated 17-AAG (CD90@17-AAG/TMs) was prepared by reverse-phase evaporation and its characteristics were studied. Heat tolerance in CD90+ LCSCs and the effect of CD90@17-AAG/TMs-mediated heat sensitivity were examined in vitro and in vivo. Results CD90+ LCSCs showed significant stem cell-like properties. The 17-AAG/TMs were successfully prepared and were spherical in shape with an average size of 128.9±7.7 nm. When exposed to magnetic hyperthermia, HSP90 was up-regulated in CD90+ LCSCs. CD90@17-AAG/TMs inhibited the activity of HSP90 and increased the sensitivity of CD90+ LCSCs to magnetic hyperthermia. Conclusion The inhibition of HSP90 could sensitize CD90+ LCSCs to magnetic hyperthermia and enhance its anti-tumor effects in vitro and in vivo. PMID:26677324

A novel STAT inhibitor, OPB-31121, has a significant antitumor effect on leukemia with STAT-addictive oncokinases

International Nuclear Information System (INIS)

Hayakawa, F; Sugimoto, K; Harada, Y; Hashimoto, N; Ohi, N; Kurahashi, S; Naoe, T

2013-01-01

Signal transduction and activator of transcription (STAT) proteins are extracellular ligand-responsive transcription factors that mediate cell proliferation, apoptosis, differentiation, development and the immune response. Aberrant signals of STAT induce uncontrolled cell proliferation and apoptosis resistance and are strongly involved in cancer. STAT has been identified as a promising target for antitumor drugs, but to date most trials have not been successful. Here, we demonstrated that a novel STAT inhibitor, OPB-31121, strongly inhibited STAT3 and STAT5 phosphorylation without upstream kinase inhibition, and induced significant growth inhibition in various hematopoietic malignant cells. Investigation of various cell lines suggested that OPB-31121 is particularly effective against multiple myeloma, Burkitt lymphoma and leukemia harboring BCR–ABL, FLT3/ITD and JAK2 V617F, oncokinases with their oncogenicities dependent on STAT3/5. Using an immunodeficient mouse transplantation system, we showed the significant antitumor effect of OPB-31121 against primary human leukemia cells harboring these aberrant kinases and its safety for normal human cord blood cells. Finally, we demonstrated a model to overcome drug resistance to upstream kinase inhibitors with a STAT inhibitor. These results suggested that OPB-31121 is a promising antitumor drug. Phase I trials have been performed in Korea and Hong Kong, and a phase I/II trial is underway in Japan

Toxic effect of nonylphenol on the marine macroalgae Gracilaria lemaneiformis (Gracilariales, Rhodophyta): antioxidant system and antitumor activity.

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Zhong, Mingqin; Yin, Pinghe; Zhao, Ling

2017-04-01

The objective of the present work was to evaluate the toxic effect of nonylphenol (NP) on the antioxidant response and antitumor activity of Gracilaria lemaneiformis. An obvious oxidative damage was observed in this study. The thallus exposed to NP showed 1.2-2.0-fold increase in lipid peroxide and displayed a maximum level of 16.58 μmol g -1 Fw on 0.6 mg L -1 for 15-day exposure. The activities of antioxidant enzymes such as superoxide dismutase (SOD) and catalase (CAT) enhanced significantly by 1.1-3.2-fold and subsequently diminished at the high concentrations and prolonged exposure. The results of DNA damage in comet assay also supported that NP was obviously toxic on G. lemaneiformis with increasing the percentage of tail DNA in a dose-dependent manner. Furthermore, the ethanol extract of G. lemaneiformis (EEGL) did exhibit antitumor potential against HepG-2 cells. While decreased in cell inhibition, ROS generation, apoptosis, and caspase-3 in HepG-2 cells treated with the EEGL were observed when G. lemaneiformis was exposed to NP for 15 days, and which were related to exposure concentration of NP. These suggested that NP has strongly toxic effect on the antitumor activity of G. lemaneiformis. The results revealed in this study imply that macroalgae can be useful biomarkers to evaluate marine pollutions.

Targeting PEPT1: a novel strategy to improve the antitumor efficacy of doxorubicin in human hepatocellular carcinoma therapy.

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Gong, Yanxia; Wu, Xiang; Wang, Tao; Zhao, Jia; Liu, Xi; Yao, Zhi; Zhang, Qingyu; Jian, Xu

2017-06-20

Proton coupled oligopeptide transporter 1 (PEPT1) is a member of the peptide transporter superfamily and plays important role in the absorption of oligopeptide and peptidomimetic drugs. Our previous research verified that PEPT1 expressed specifically in human Hepatocellular carcinoma (HCC) tissue and cell lines and showed potential transport activity to be a new candidate of the tumor therapeutic target. In this study, we aim to explore the feasibility of a novel tumor target therapeutic strategy: Targeting PEPT1 to improve the antitumor efficacy of Doxorubicin in human HCC therapy. First, Doxorubicin was conjugated with Glycylglycylglycine (Gly-Gly-Gly) - a tripeptide which was known as the substrate of PEPT1 and characterized by HPLC and MS successfully. Doxorubicin-tripeptide conjugate was then observed to clarify the target delivery by PEPT1 and the antitumor effect on human hepatocarcinoma in vivo and in vitro. Furthermore, the improvement of the toxic and side effect of Doxorubicin after conjugation was also evaluated by some biochemical tests. Our results reveal that targeting PEPT1 may contribute to the efficient delivery of Doxorubicin to hepatocarcinoma cells and the reduction of drug toxicity. PEPT1 has the prospect to be a novel target of HCC therapy.

In vitro and in vivo evaluation of SN-38 nanocrystals with different particle sizes

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Chen M

2017-08-01

Full Text Available Min Chen,1,2 Wanqing Li,3 Xun Zhang,1 Ye Dong,1 Yabing Hua,1 Hui Zhang,1 Jing Gao,1 Liang Zhao,2 Ying Li,1 Aiping Zheng1 1State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, 2School of Pharmacy, Jinzhou Medical University, Jinzhou, 3School of Preclinical Medicine, Beijing University of Chinese Medicine, Beijing, People’s Republic of China Abstract: 7-Ethyl-10-hydroxycamptothecin (SN-38 is a potent broad-spectrum antitumor drug derived from irinotecan hydrochloride (CPT-11. Due to its poor solubility and instability of the active lactone ring, its clinical use is significantly limited. As one of the most promising formulations for poorly water-soluble drugs, nanocrystals have attracted increasing attention. In order to solve these problems and evaluate the antitumor effect of SN-38 in vitro and in vivo, two nanocrystals with markedly different particle sizes were prepared. Dynamic light scattering and transmission electron microscopy were used to investigate the two nanocrystals. The particle sizes of SN-38 nanocrystals A (SN-38/NCs-A and SN-38 nanocrystals B (SN-38/NCs-B were 229.5±1.99 and 799.2±14.44 nm, respectively. X-ray powder diffraction analysis showed that the crystalline state of SN-38 did not change in the size reduction process. An accelerated dissolution velocity of SN-38 was achieved by nanocrystals, and release rate of SN-38/NCs-A was significantly faster than that of SN-38/NCs-B. Cellular uptake, cellular cytotoxicity, pharmacokinetics, animal antitumor efficacy, and tissue distribution were subsequently examined. As a result, enhanced intracellular accumulation in HT1080 cells and cytotoxicity on different tumor cells were observed for SN-38/NCs-A compared to that for SN-38/NCs-B and solution. Besides, compared to the SN-38 solution, SN-38/NCs-A had a higher bioavailability after intravenous injection; while the bioavailability of SN-38/NCs-B was even lower than

Antitumor effects of a sirtuin inhibitor, tenovin-6, against gastric cancer cells via death receptor 5 up-regulation.

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Sachiko Hirai

Full Text Available Up-regulated sirtuin 1 (SIRT1, an NAD+-dependent class III histone deacetylase, deacetylates p53 and inhibits its transcriptional activity, leading to cell survival. SIRT1 overexpression has been reported to predict poor survival in some malignancies, including gastric cancer. However, the antitumor effect of SIRT1 inhibition remains elusive in gastric cancer. Here, we investigated the antitumor mechanisms of a sirtuin inhibitor, tenovin-6, in seven human gastric cancer cell lines (four cell lines with wild-type TP53, two with mutant-type TP53, and one with null TP53. Interestingly, tenovin-6 induced apoptosis in all cell lines, not only those with wild-type TP53, but also mutant-type and null versions, accompanied by up-regulation of death receptor 5 (DR5. In the KatoIII cell line (TP53-null, DR5 silencing markedly attenuated tenovin-6-induced apoptosis, suggesting that the pivotal mechanism behind its antitumor effects is based on activation of the death receptor signal pathway. Although endoplasmic reticulum stress caused by sirtuin inhibitors was reported to induce DR5 up-regulation in other cancer cell lines, we could not find marked activation of its related molecules, such as ATF6, PERK, and CHOP, in gastric cancer cells treated with tenovin-6. Tenovin-6 in combination with docetaxel or SN-38 exerted a slight to moderate synergistic cytotoxicity against gastric cancer cells. In conclusion, tenovin-6 has potent antitumor activity against human gastric cancer cells via DR5 up-regulation. Our results should be helpful for the future clinical development of sirtuin inhibitors.

Oil-in-water biocompatible microemulsion as a carrier for the antitumor drug compound methyl dihydrojasmonate

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Silva GB

2015-01-01

Full Text Available Gisela Bevilacqua Rolfsen Ferreira da Silva,1 Maria Virginia Scarpa,1 Iracilda Zepone Carlos,2 Marcela Bassi Quilles,2 Raphael Carlos Comeli Lia,3 Eryvaldo Socrates Tabosa do Egito,4 Anselmo Gomes de Oliveira1 1Departamento de Fármacos e Medicamentos, 2Departamento de Análises Clínicas, UNESP–Universidade Estadual Paulista, Faculdade de Ciências Farmacêuticas, PPG em Nanotecnologia Farmacêutica, Rodovia Araraquara-Jaú Km 01, Araraquara, SP, Brazil; 3Instituto de Patologia Cirúrgica e Citopatologia (IPC, Araraquara, SP, Brazil; 4UFRN–Universidade Federal do Rio Grande do Norte, Programa de Pós-graduação em Ciências da Saúde, Natal, RN, Brazil Abstract: Methyl dihydrojasmonate (MJ has been studied because of its application as an antitumor drug compound. However, as MJ is a poorly water-soluble compound, a suitable oil-in-water microemulsion (ME has been studied in order to provide its solubilization in an aqueous media and to allow its administration by the parenteral route. The ME used in this work was characterized on the pseudo-ternary phase diagram by dynamic light scattering and rheological measurements. Regardless of the drug presence, the droplet size was directly dependent on the oil/surfactant (O/S ratio. Furthermore, the drug incorporation into the ME significantly increased the ME diameter, mainly at low O/S ratios. The rheological evaluation of the systems showed that in the absence of drug a Newtonian behavior was observed. On the other hand, in the presence of MJ the ME systems revealed pseudoplastic behavior, independently of the O/S ratio. The in vivo studies demonstrated that not only was the effect on the tumor inhibition inversely dependent on the MJ-loaded ME administered dose, but also it was slightly higher than the doxorubicin alone, which was used as the positive control. Additionally, a small antiangiogenic effect for MJ-loaded ME was found at doses in which it possesses antitumor activity. MJ revealed to

The effect of anti-tumor necrosis factor alpha agents on postoperative anastomotic complications in Crohn's disease

DEFF Research Database (Denmark)

El-Hussuna, Alaa Abdul-Hussein H; Krag, Aleksander; Olaison, Gunnar

2013-01-01

Patients with Crohn's disease treated with anti-tumor necrosis factor alpha agents may have an increased risk of surgical complications.......Patients with Crohn's disease treated with anti-tumor necrosis factor alpha agents may have an increased risk of surgical complications....

Enhanced antitumor activity of surface-modified iron oxide nanoparticles and an α-tocopherol derivative in a rat model of mammary gland carcinosarcoma.

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Horák, Daniel; Pustovyy, Vitaliy Igorovych; Babinskyi, Andrii Valeriyovich; Palyvoda, Olga Mikhailovna; Chekhun, Vasyl Fedorovich; Todor, Igor Nikolaevich; Kuzmenko, Oleksandr Ivanovich

2017-01-01

Maghemite (γ-Fe 2 O 3 ) nanoparticles were obtained by coprecipitation of ferrous and ferric salts in an alkaline medium followed by oxidation; the nanoparticles were coated with poly( N,N -dimethylacrylamide) (PDMA) and characterized by transmission electron microscopy, attenuated total reflection (ATR) Fourier transform infrared (FTIR) spectroscopy, dynamic light scattering, thermogravimetric and elemental analyses, and magnetic measurements in terms of particle morphology, size, polydispersity, amount of coating, and magnetization, respectively. The effects of α-tocopherol (Toc) and its phenolic (Toc-6-OH) and acetate (Toc-6-Ac) derivatives on Fe 2+ release from γ-Fe 2 O 3 @PDMA, as well as from γ-Fe 2 O 3 and CuFe 2 O 4 nanoparticles (controls), were examined in vitro using 1,10-phenanthroline. The presence of tocopherols enhanced spontaneous Fe 2+ release from nanoparticles, with Toc-6-OH exhibiting more activity than neat Toc. All of the nanoparticles tested were found to initiate blood lipid oxidation in a concentration-dependent manner, as determined by analysis of 2-thiobarbituric acid reactive species. Wistar rats with Walker-256 carcinosarcoma (a model of mammary gland carcinosarcoma) received Toc-6-Ac, magnetic nanoparticles, or their combination per os, and the antitumor activity of each treatment was determined in vivo. γ-Fe 2 O 3 @PDMA nanoparticles exhibited increased antitumor activity compared to both commercial CuFe 2 O 4 particles and the antitumor drug doxorubicin. Moreover, increased antitumor activity was observed after combined administration of γ-Fe 2 O 3 @PDMA nanoparticles and Toc-6-Ac; however, levels of bilirubin, aspartate aminotransferase, and white bloods normalized and did not differ from those of the intact controls. The antitumor activity of the γ-Fe 2 O 3 nanoparticles strongly correlated with Fe 2+ release from the nanoparticles but not with nanoparticle-initiated lipid peroxidation in vitro.

Regorafenib: Antitumor Activity upon Mono and Combination Therapy in Preclinical Pediatric Malignancy Models.

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Estelle Daudigeos-Dubus

Full Text Available The multikinase inhibitor regorafenib (BAY 73-4506 exerts both anti-angiogenic and anti-tumorigenic activity in adult solid malignancies mainly advanced colorectal cancer and gastrointestinal stromal tumors. We intended to explore preclinically the potential of regorafenib against solid pediatric malignancies alone and in combination with anticancer agents to guide the pediatric development plan. In vitro effects on cell proliferation were screened against 33 solid tumor cell lines of the Innovative Therapies for Children with Cancer (ITCC panel covering five pediatric solid malignancies. Regorafenib inhibited cell proliferation with a mean half maximal growth inhibition of 12.5 μmol/L (range 0.7 μmol/L to 28 μmol/L. In vivo, regorafenib was evaluated alone at 10 or 30 mg/kg/d or in combination with radiation, irinotecan or the mitogen-activated protein kinase kinase (MEK inhibitor refametinib against various tumor types, including patient-derived brain tumor models with an amplified platelet-derived growth factor receptor A (PDGFRA gene. Regorafenib alone significantly inhibited tumor growth in all xenografts derived from nervous system and connective tissue tumors. Enhanced effects were observed when regorafenib was combined with irradiation and irinotecan against PDGFRA amplified IGRG93 glioma and IGRM57 medulloblastoma respectively, resulting in 100% tumor regressions. Antitumor activity was associated with decreased tumor vascularization, inhibition of PDGFR signaling, and induction of apoptotic cell death. Our work demonstrates that regorafenib exhibits significant antitumor activity in a wide spectrum of preclinical pediatric models through inhibition of angiogenesis and induction of apoptosis. Furthermore, radio- and chemosensitizing effects were observed with DNA damaging agents in PDGFR amplified tumors.

Composition and mechanism of anti-tumor effects of Hericium erinaceus mushroom extracts in tumor-bearing mice

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We investigated anti-tumor effects of the following four extracts of freeze-dried Hericium erinaceus mushrooms in Balb/c mice intracutaneously transplanted on the backs with CT-26 colon cancer cells: HWE, hot-water extraction by boiling in water for 3 h; MWE, microwaving in 50% ethanol/water at 60 W...

EVALUATION OF THE ANTITUMOR AND ANTICACHEXIA ACTIVITY OF GRATIOLA OFFICINALIS L. EXTRACT IN RATS WITH TRANSPLANTED SARCOMA 45

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N. A. Navolokin

2016-01-01

Full Text Available Cachexia is a severe complication of cancer and currently there are no drugs that would effectively deal with exhaustion and intoxication in various diseases.Materials and methods. In this paper a study and evaluation of the antitumor and anticachexia activities of the extract of Gratiola officinalis l. in rats with transplanted sarcoma 45 in experiment in vivo was conducted. Gratiola officinalis l. extract is received by patented method and is not toxic to animals. The study was conducted on 40 white male rats line Wistar weighing 150 ± 50 g. Animals were divided into 4 groups (10 rats per group: control group, comparison group with sarcoma without affecting, group with sarcoma with intramuscular and group with sarcoma with oral administration of the extract in a dosage of 110 mg/kg. The extract was administered intramuscularly or orally 72 hours after transplantation of sarcoma 45. The tumor volume and the weight of the animals were assessed daily.Results. The extract of leaves and flowers of Gratiola officinalis l. obtained by patented method has a strong antitumor activity, reducing the growth rate of the tumor and causing marked changes in the tumor, as well as providing stable anticachexia effect. Index of tumor weight inhibition was 70.6 % on average. Intramuscular administration was more effective in reducing of tumor growth, but less effectively increases the weight of animals than oral administration. In both administration methods Gratiola officinalis extract has no toxic effect on peripheral blood. We have previously found that the extract has antioxidant activity so that anticachexia effect is pathogenic, meaning it occurs by reducing toxicity.Conclusions. Gratiola officinalis extract has a broad spectrum of biological activity, in particular antitumor, anticachexia, it is not toxic, so it is advisable to investigate as a promising tool for the treatment of tumor diseases and cancer cachexia, and cachexia caused by other chronic

Jungle Honey Enhances Immune Function and Antitumor Activity

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Miki Fukuda

2011-01-01

Full Text Available Jungle honey (JH is collected from timber and blossom by wild honey bees that live in the tropical forest of Nigeria. JH is used as a traditional medicine for colds, skin inflammation and burn wounds as well as general health care. However, the effects of JH on immune functions are not clearly known. Therefore, we investigated the effects of JH on immune functions and antitumor activity in mice. Female C57BL/6 mice were injected with JH (1 mg/mouse/day, seven times intra-peritoneal. After seven injections, peritoneal cells (PC were obtained. Antitumor activity was assessed by growth of Lewis Lung Carcinoma/2 (LL/2 cells. PC numbers were increased in JH-injected mice compared to control mice. In Dot Plot analysis by FACS, a new cell population appeared in JH-injected mice. The percent of Gr-1 surface antigen and the intensity of Gr-1 antigen expression of PC were increased in JH-injected mice. The new cell population was neutrophils. JH possessed chemotactic activity for neutrophils. Tumor incidence and weight were decreased in JH-injected mice. The ratio of reactive oxygen species (ROS producing cells was increased in JH-injected mice. The effective component in JH was fractionized by gel filtration using HPLC and had an approximate molecular weight (MW of 261. These results suggest that neutrophils induced by JH possess potent antitumor activity mediated by ROS and the effective immune component of JH is substrate of MW 261.

Antitumor activity of doxorubicine-loaded nanoemulsion against ...

African Journals Online (AJOL)

Pharmacotherapy Group, Faculty of Pharmacy, University of Benin, Benin City, 300001 Nigeria. All rights ... Keywords: Doxorubicine, Anti-tumor activity, Mean survival time, Heart histology, Nanoemulsion, Lipid profile .... the standard kit methods using fully Automated ..... effects of this new formulation in human patients.

Investigation of HIFU-induced anti-tumor immunity in a murine tumor model

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Lyerly H Kim

2007-07-01

Full Text Available Abstract Background High intensity focused ultrasound (HIFU is an emerging non-invasive treatment modality for localized treatment of cancers. While current clinical strategies employ HIFU exclusively for thermal ablation of the target sites, biological responses associated with both thermal and mechanical damage from focused ultrasound have not been thoroughly investigated. In particular, endogenous danger signals from HIFU-damaged tumor cells may trigger the activation of dendritic cells. This response may play a critical role in a HIFU-elicited anti-tumor immune response which can be harnessed for more effective treatment. Methods Mice bearing MC-38 colon adenocarcinoma tumors were treated with thermal and mechanical HIFU exposure settings in order to independently observe HIFU-induced effects on the host's immunological response. In vivo dendritic cell activity was assessed along with the host's response to challenge tumor growth. Results Thermal and mechanical HIFU were found to increase CD11c+ cells 3.1-fold and 4-fold, respectively, as compared to 1.5-fold observed for DC injection alone. In addition, thermal and mechanical HIFU increased CFSE+ DC accumulation in draining lymph nodes 5-fold and 10-fold, respectively. Moreover, focused ultrasound treatments not only caused a reduction in the growth of primary tumors, with tumor volume decreasing by 85% for thermal HIFU and 43% for mechanical HIFU, but they also provided protection against subcutaneous tumor re-challenge. Further immunological assays confirmed an enhanced CTL activity and increased tumor-specific IFN-γ-secreting cells in the mice treated by focused ultrasound, with cytotoxicity induced by mechanical HIFU reaching as high as 27% at a 10:1 effector:target ratio. Conclusion These studies present initial encouraging results confirming that focused ultrasound treatment can elicit a systemic anti-tumor immune response, and they suggest that this immunity is closely related to

Antitumor activity of Bulgarian herb Tribulus terrestris L. on human breast cancer cells

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Svetla Angelova

2013-01-01

Full Text Available Medicinal plants have been intensively studied as a source of antitumor compounds. Due to the beneficial climate conditions Bulgarian herbs have high pharmacological potential. Currently, the antitumor effect of the Bulgarian medicinal plant Tribulus terrestris L. on human cancer cell lines is not studied. The main active compounds of the plant are the steroid saponins.The present study aims to analyze the effect on cell viability and apoptotic activity of total extract and saponin fraction of Bulgarian Tribulus terrestris L. on human breast cancer (MCF7 and normal (MCF10A cell lines. Antitumor effect was established by МТТ cell viability assay and assessment of apoptotic potential was done through analysis of genomic integrity (DNA fragmentation assay and analysis of morphological cell changes (Fluorescence microscopy. The results showed that total extract of the herb has a marked dose-dependent inhibitory effect on viability of MCF7 cells (half maximal inhibitory concentration is 15 μg/ml. Cell viability of MCF10A was moderately decreased without visible dose-dependent effect. The saponin fraction has increased inhibitory effect on breast cancer cells compared to total extract. Morphological changes and DNA fragmentation were observed as markers for early and late apoptosis predominantly in tumor cells after treatment. Apoptotic processes were intensified with the increase of treatment duration.The obtained results are the first showing selective antitumor activity of Bulgarian Tribulus terrestris L. on human cancer cells in vitro. Apoptotic processes are involved in the antitumor mechanisms induced by the herb. This results give directions for future investigations concerning detailed assessment of its pharmacological potential.

Enhancement of anti-tumor activity of hybrid peptide in conjugation with carboxymethyl dextran via disulfide linkers.

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Gaowa, Arong; Horibe, Tomohisa; Kohno, Masayuki; Tabata, Yasuhiko; Harada, Hiroshi; Hiraoka, Masahiro; Kawakami, Koji

2015-05-01

To improve the anti-tumor activity of EGFR2R-lytic hybrid peptide, we prepared peptide-modified dextran conjugates with the disulfide bonds between thiolated carboxymethyl dextran (CMD-Cys) and cysteine-conjugated peptide (EGFR2R-lytic-Cys). In vitro release studies showed that the peptide was released from the CMD-s-s-peptide conjugate in a concentration-dependent manner in the presence of glutathione (GSH, 2μM-2mM). The CMD-s-s-peptide conjugate exhibited a similar cytotoxic activity with free peptide alone against human pancreatic cancer BxPC-3 cells in vitro. Furthermore, it was shown that the CMD-s-s-peptide conjugates were highly accumulated in tumor tissue in a mouse xenograft model using BxPC-3 cells, and the anti-tumor activity of the conjugate was more effective than that of the free peptide. In addition, the plasma concentrations of peptide were moderately increased and the elimination half-life of the peptide was prolonged after intravenous injection of CMD-s-s-peptide conjugates. These results demonstrated that the conjugate based on thiolated CMD polymer would be potentially useful carriers for the sustained release of the hybrid peptide in vivo. Copyright © 2015 Elsevier B.V. All rights reserved.

Snake venom L-amino acid oxidases: an overview on their antitumor effects

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2014-01-01

The L-amino acid oxidases (LAAOs) constitute a major component of snake venoms and have been widely studied due to their widespread presence and various effects, such as apoptosis induction, cytotoxicity, induction and/or inhibition of platelet aggregation, hemorrhage, hemolysis, edema, as well as antimicrobial, antiparasitic and anti-HIV activities. The isolated and characterized snake venom LAAOs have become important research targets due to their potential biotechnological applications in pursuit for new drugs of interest in the scientific and medical fields. The current study discusses the antitumor effects of snake venom LAAOs described in the literature to date, highlighting the mechanisms of apoptosis induction proposed for this class of proteins. PMID:24940304

In Vitro and In Vivo Evaluation of Microparticulate Drug Delivery Systems Composed of Macromolecular Prodrugs

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Yoshiharu Machida

2008-08-01

Full Text Available Macromolecular prodrugs are very useful systems for achieving controlled drug release and drug targeting. In particular, various macromolecule-antitumor drug conjugates enhance the effectiveness and improve the toxic side effects. Also, polymeric micro- and nanoparticles have been actively examined and their in vivo behaviors elucidated, and it has been realized that their particle characteristics are very useful to control drug behavior. Recently, researches based on the combination of the concepts of macromolecular prodrugs and micro- or nanoparticles have been reported, although they are limited. Macromolecular prodrugs enable drugs to be released at a certain controlled release rate based on the features of the macromolecule-drug linkage. Micro- and nanoparticles can control in vivo behavior based on their size, surface charge and surface structure. These merits are expected for systems produced by the combination of each concept. In this review, several micro- or nanoparticles composed of macromolecule-drug conjugates are described for their preparation, in vitro properties and/or in vivo behavior.

Intensification of the antitumoral effect of ionizing radiations in combined use of metronidazole and hyperglycemia

International Nuclear Information System (INIS)

Vinskaya, N.P.; Voloshina, E.A.; Vygodskaya, A.L.; Yarmonenko, S.P.

1984-01-01

The authors have shown that a more pronounced antitumor effect of radiation in the combined use of metronidazole and induced short-term hyperglycemia (STH) may result not only from the summation of the two effects: the sensitizing effect of metronidazole and decreased viability of irradiated cells caused by STH but also from the intensified cytotoxic effect of metronidazole on hypoxic tumor cells. It was also noted that when hypoxic cells subjected to the sensitizing effect of electron acceptor sensitizers are found in the normal (skin) and tumorous tissues, STH use following irradiation in the presence of metronidazole enchances selectively the tumor radiation effect

3D printed constructs with antibacterial or antitumor activity for surgical treatment of bone defects in cancer patients

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Sergeeva, N. S.; Sviridova, I. K.; Komlev, V. S.; Karalkin, P. A.; Kirsanova, V. A.; Akhmedova, S. A.; Shanskij, Ya. D.; Kuvshinova, E. A.; Fedotov, A. Yu.; Teterina, A. Yu.; Barinov, S. M.

2017-09-01

The concept of functionalization with bioactive molecules and drugs is one of the most advanced areas of modern bone tissue biomaterial science in terms of enhancement of their osteoconductive and therapeutic properties. The purpose of this study was to develop the approaches for 3D printing of sodium alginate /gelatin /octacalcium phosphate-based constructs with antibacterial and antitumor activity intended for bone defects replacement in the patients with malignant diseases. In this work, we evaluated the drug release kinetic and physicochemical characteristics of the constructs, as well as their specific activity, biocompatibility and osteoplastic properties in in vitro and in vivo tests. The experimental results proved the principal possibility of creating the biocompatible bone substitutes with antibacterial/antitumor activity and maintaining osteoconductive properties by means of 3D printing method.

Evaluation of biodistribution and anti-tumor effect of a dimeric RGD peptide-paclitaxel conjugate in mice with breast cancer

International Nuclear Information System (INIS)

Cao, Qizhen; Li, Zi-Bo; Chen, Kai; Wu, Zhanhong; He, Lina; Chen, Xiaoyuan; Neamati, Nouri

2008-01-01

Targeting drugs to receptors involved in tumor angiogenesis has been demonstrated as a novel and promising approach to improve cancer treatment. In this study, we evaluated the anti-tumor efficacy of a dimeric RGD peptide-paclitaxel conjugate (RGD2-PTX) in an orthotopic MDA-MB-435 breast cancer model. To assess the effect of conjugation and the presence of drug moiety on the MDA-MB-435 tumor and normal tissue uptake, the biodistribution of 3 H-RGD2-PTX was compared with that of 3 H-PTX. The treatment effect of RGD2-PTX and RGD2+PTX was measured by tumor size, 18 F-FDG/PET, 18 F-FLT/PET, and postmortem histopathology. By comparing the biodistribution of 3 H-RGD2-PTX and 3 H-PTX, we found that 3 H-RGD2-PTX had higher initial tumor exposure dose and prolonged tumor retention than 3 H-PTX. Metronomic low-dose treatment of breast cancer indicated that RGD2-PTX is significantly more effective than PTX+RGD2 combination and solvent control. Although in vivo 18 F-FLT/PET imaging and ex vivo Ki67 staining indicated little effect of the PTX-based drug on cell proliferation, 18 F-FDG/PET imaging showed significantly reduced tumor metabolism in the RGD2-PTX-treated mice versus those treated with RGD2+PTX and solvent control. Terminal uridine deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining also showed that RGD2-PTX treatment also had significantly higher cell apoptosis ratio than the other two groups. Moreover, the microvessel density was significantly reduced after RGD2-PTX treatment as determined by CD31 staining. Our results demonstrate that integrin-targeted delivery of paclitaxel allows preferential cytotoxicity to integrin-expressing tumor cells and tumor vasculature. The targeted delivery strategies developed in this study may also be applied to other chemotherapeutics for selective tumor killing. (orig.)

Mechanisms Underlying the Anti-Aging and Anti-Tumor Effects of Lithocholic Bile Acid

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Anthony Arlia-Ciommo

2014-09-01

Full Text Available Bile acids are cholesterol-derived bioactive lipids that play essential roles in the maintenance of a heathy lifespan. These amphipathic molecules with detergent-like properties display numerous beneficial effects on various longevity- and healthspan-promoting processes in evolutionarily distant organisms. Recent studies revealed that lithocholic bile acid not only causes a considerable lifespan extension in yeast, but also exhibits a substantial cytotoxic effect in cultured cancer cells derived from different tissues and organisms. The molecular and cellular mechanisms underlying the robust anti-aging and anti-tumor effects of lithocholic acid have emerged. This review summarizes the current knowledge of these mechanisms, outlines the most important unanswered questions and suggests directions for future research.

Antioxidant Intake and Antitumor Therapy: Toward Nutritional Recommendations for Optimal Results

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Mut-Salud, Nuria; Álvarez, Pablo Juan; Garrido, Jose Manuel; Carrasco, Esther; Aránega, Antonia; Rodríguez-Serrano, Fernando

2016-01-01

The role of the induction of oxidative stress as the mechanism of action of many antitumor drugs is acquiring an increasing interest. In such cases, the antitumor therapy success may be conditioned by the antioxidants present in our own body, which can be synthesized de novo (endogenous) or incorporated through the diet and nutritional supplements (exogenous). In this paper, we have reviewed different aspects of antioxidants, including their classification, natural sources, importance in diet, consumption of nutritional supplements, and the impact of antioxidants on health. Moreover, we have focused especially on the study of the interaction between antioxidants and antitumor therapy, considering both radiotherapy and chemotherapy. In this regard, we found that the convenience of administration of antioxidants during cancer treatment still remains a very controversial issue. In general terms, antioxidants could promote or suppress the effectiveness of antitumor treatment and even protect healthy tissues against damage induced by oxidative stress. The effects may depend on many factors discussed in the paper. These factors should be taken into consideration in order to achieve precise nutritional recommendations for patients. The evidence at the moment suggests that the supplementation or restriction of exogenous antioxidants during cancer treatment, as appropriate, could contribute to improving its efficiency. PMID:26682013

Antioxidant Intake and Antitumor Therapy: Toward Nutritional Recommendations for Optimal Results

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Nuria Mut-Salud

2016-01-01

Full Text Available The role of the induction of oxidative stress as the mechanism of action of many antitumor drugs is acquiring an increasing interest. In such cases, the antitumor therapy success may be conditioned by the antioxidants present in our own body, which can be synthesized de novo (endogenous or incorporated through the diet and nutritional supplements (exogenous. In this paper, we have reviewed different aspects of antioxidants, including their classification, natural sources, importance in diet, consumption of nutritional supplements, and the impact of antioxidants on health. Moreover, we have focused especially on the study of the interaction between antioxidants and antitumor therapy, considering both radiotherapy and chemotherapy. In this regard, we found that the convenience of administration of antioxidants during cancer treatment still remains a very controversial issue. In general terms, antioxidants could promote or suppress the effectiveness of antitumor treatment and even protect healthy tissues against damage induced by oxidative stress. The effects may depend on many factors discussed in the paper. These factors should be taken into consideration in order to achieve precise nutritional recommendations for patients. The evidence at the moment suggests that the supplementation or restriction of exogenous antioxidants during cancer treatment, as appropriate, could contribute to improving its efficiency.

Anti-tumor effects of brucine immuno-nanoparticles on hepatocellular carcinoma

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Qin JM

2012-01-01

Full Text Available Jian-Min Qin1, Pei-Hao Yin1, Qi Li1, Zhong-Qiu Sa1, Xia Sheng1, Lin Yang1, Tao Huang1, Min Zhang1, Ke-Pan Gao2, Qing-Hua Chen2, Jing-Wei Ma3, He-Bai Shen31Department of General Surgery, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, 2National Pharmaceutical Engineering Research Center; Shanghai Institute of Pharmaceutical Industry, 3Department of Physical Chemistry, Shanghai Normal University, Shanghai, People's Republic of ChinaBackground: Hepatocellular carcinoma is difficult to diagnose early, and most patients are already in the late stages of the disease when they are admitted to hospital. The total 5-year survival rate is less than 5%. Recent studies have showed that brucine has a good anti-tumor effect, but high toxicity, poor water solubility, short half-life, narrow therapeutic window, and a toxic dose that is close to the therapeutic dose, which all limit its clinical application. This study evaluated the effects of brucine immuno-nanoparticles (BIN on hepatocellular carcinoma.Materials and methods: Anionic polymerization, chemical modification technology, and phacoemulsification technology were used to prepare a carboxylated polyethylene glycol-polylactic acid copolymer carrier material. Chemical coupling technology was utilized to develop anti-human AFP McAb-polyethylene glycol-polylactic acid copolymer BIN. The size, shape, zeta potential, drug loading, encapsulation efficiency, and release of these immune-nanoparticles were studied in vitro. The targeting, and growth, invasion, and metastasis inhibitory effects of this treatment on liver cancer SMMC-7721 cells were tested.Results: BIN were of uniform size with an average particle size of 249 ± 77 nm and zeta potential of -18.7 ± 4.19 mV. The encapsulation efficiency was 76.0% ± 2.3% and the drug load was 5.6% ± 0.2%. Complete uptake and even distribution around the liver cancer cell membrane were observed.Conclusion: BIN had even size distribution, was

Gemcitabine-loaded albumin nanospheres (GEM-ANPs) inhibit PANC-1 cells in vitro and in vivo

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Li, Ji; Di, Yang; Jin, Chen; Fu, Deliang; Yang, Feng; Jiang, Yongjian; Yao, Lie; Hao, Sijie; Wang, Xiaoyi; Subedi, Sabin; Ni, Quanxing

2013-04-01

With the development of nanotechnology, special attention has been given to the nanomaterial application in tumor treatment. Here, a modified desolvation-cross-linking method was successfully applied to fabricate gemcitabine-loaded albumin nanospheres (GEM-ANPs), with 110 and 406 nm of mean diameter, respectively. The aim of this study was to assess the drug distribution, side effects, and antitumor activity of GEM-ANPs in vivo. The metabolic viability and flow cytometry analysis revealed that both GEM-ANPs, especially 406-nm GEM-ANPs, could effectively inhibit the metabolism and proliferation and promote the apoptosis of human pancreatic carcinoma (PANC-1) in vitro. Intravenous injection of 406-nm GEM-ANPs exhibited a significant increase of gemcitabine in the pancreas, liver, and spleen of Sprague-Dawley rats ( p PANC-1-induced tumor mice, intravenous injection of 406-nm GEM-ANPs also could effectively reduce the tumor volume by comparison with free gemcitabine. With these findings, albumin nanosphere-loading approach might be efficacious to improve the antitumor activity of gemcitabine, and the efficacy is associated with the size of GEM-ANPs.

Tertiary Lymphoid Structures in Cancer: Drivers of Antitumor Immunity, Immunosuppression, or Bystander Sentinels in Disease?

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Colbeck, Emily Jayne; Ager, Ann; Gallimore, Awen; Jones, Gareth Wyn

2017-01-01

Secondary lymphoid organs are integral to initiation and execution of adaptive immune responses. These organs provide a setting for interactions between antigen-specific lymphocytes and antigen-presenting cells recruited from local infected or inflamed tissues. Secondary lymphoid organs develop as a part of a genetically preprogrammed process during embryogenesis. However, organogenesis of secondary lymphoid tissues can also be recapitulated in adulthood during de novo lymphoid neogenesis of tertiary lymphoid structures (TLSs). These ectopic lymphoid-like structures form in the inflamed tissues afflicted by various pathological conditions, including cancer, autoimmunity, infection, or allograft rejection. Studies are beginning to shed light on the function of such structures in different disease settings, raising important questions regarding their contribution to progression or resolution of disease. Data show an association between the tumor-associated TLSs and a favorable prognosis in various types of human cancer, attracting the speculation that TLSs support effective local antitumor immune responses. However, definitive evidence for the role for TLSs in fostering immune responses in vivo are lacking, with current data remaining largely correlative by nature. In fact, some more recent studies have even demonstrated an immunosuppressive, tumor-promoting role for cancer-associated TLSs. In this review, we will discuss what is known about the development of cancer-associated TLSs and the current understanding of their potential role in the antitumor immune response. PMID:29312327

Triclosan treatment decreased the antitumor effect of sorafenib on hepatocellular carcinoma cells

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Wu M

2018-05-01

Full Text Available Man Wu,1,2 Guanren Zhao,2 Xiaomei Zhuang,1 Tianhong Zhang,1 Ce Zhang,2 Wenpeng Zhang,1 Zhenqing Zhang1 1State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, China; 2Department of Pharmacy, The 309th Hospital of PLA, Beijing, China Background: Triclosan is a widely applied antimicrobial agent which affects the endocrine system and homeostasis; it may also promote the cirrhosis and hepatocellular carcinoma (HCC growth in a mice model. The exact roles of triclosan in regulating human hepatocellular carcinoma development and treatment remain unknown. Methods: MHCC97-H, a highly aggressive HCC cell line, was treated with indicated concentration of triclosan or sorafenib. The expression of drug-resistance genes was examined by qPCR. The clearance or metabolism of sorafenib was determined by liquid chromatograph-mass spectrometer/mass spectrometer (LC-MS/MS. MTT assay was used to examine the MHCC97-H cell proliferation. Nude mice were used to exam the anti-tumor effect of sorafenib on subcutaneous and intrahepatic growth of MHCC97-H cells. Results: In the present study, triclosan could induce the expression of drug-resistance genes in MHCC97-H cells (a highly aggressive HCC cell line, accelerate the clearance of sorafenib, and attenuate the anti-proliferation effect of this molecular targeted agent in MHCC97-H cells. Triclosan decreased the antitumor effect of sorafenib on subcutaneous and intrahepatic growth of MHCC97-H in nude mice. Conclusion: By discovering the fact that triclosan treatment enhances sorafenib resistance in HCC cells, this work suggests exposure of triclosan is detrimental to HCC patients during chemotherapy. Keywords: HCC, triclosan, sorafenib resistance, drug clearance 

Anti-podocalyxin antibody exerts antitumor effects via antibody-dependent cellular cytotoxicity in mouse xenograft models of oral squamous cell carcinoma.

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Itai, Shunsuke; Ohishi, Tomokazu; Kaneko, Mika K; Yamada, Shinji; Abe, Shinji; Nakamura, Takuro; Yanaka, Miyuki; Chang, Yao-Wen; Ohba, Shun-Ichi; Nishioka, Yasuhiko; Kawada, Manabu; Harada, Hiroyuki; Kato, Yukinari

2018-04-27

Podocalyxin (PODXL) overexpression is associated with progression, metastasis, and poor outcomes in cancers. We recently produced the novel anti-PODXL monoclonal antibody (mAb) PcMab-47 (IgG 1 , kappa). Herein, we engineered PcMab-47 into 47-mG 2a , a mouse IgG 2a -type mAb, to add antibody-dependent cellular cytotoxicity (ADCC). We further developed 47-mG 2a -f, a core fucose-deficient type of 47-mG 2a to augment its ADCC. Immunohistochemical analysis of oral cancer tissues using PcMab-47 and 47-mG 2a revealed that the latter stained oral squamous cell carcinoma (OSCC) cells in a cytoplasmic pattern at a much lower concentration. PcMab-47 and 47-mG 2a detected PODXL in 163/201 (81.1%) and in 197/201 (98.0%) OSCC samples, respectively. 47-mG 2a -f also detected PODXL in OSCCs at a similar frequency as 47-mG 2a . In vitro analysis revealed that both 47-mG 2a and 47-mG 2a -f exhibited strong complement-dependent cytotoxicity (CDC) against CHO/hPODXL cells. In contrast, 47-mG 2a -f exhibited much stronger ADCC than 47-mG 2a against OSCC cells, indicating that ADCC and CDC of those anti-PODXL mAbs depend on target cells. In vivo analysis revealed that both 47-mG 2a and 47-mG 2a -f exerted antitumor activity in CHO/hPODXL xenograft models at a dose of 100 μg or 500 μg/mouse/week administered twice. 47-mG 2a -f, but not 47-mG 2a , exerted antitumor activity in SAS and HSC-2 xenograft models at a dose of 100 μg/mouse/week administered three times. Although both 47-mG 2a and 47-mG 2a -f exerted antitumor activity in HSC-2 xenograft models at a dose of 500 μg/mouse/week administered twice, 47-mG 2a -f also showed higher antitumor activity than 47-mG 2a . These results suggested that a core fucose-deficient anti-PODXL mAb could be useful for antibody-based therapy against PODXL-expressing OSCCs.

Blocking Indolamine-2,3-Dioxygenase Rebound Immune Suppression Boosts Antitumor Effects of Radio-Immunotherapy in Murine Models and Spontaneous Canine Malignancies.

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Monjazeb, Arta M; Kent, Michael S; Grossenbacher, Steven K; Mall, Christine; Zamora, Anthony E; Mirsoian, Annie; Chen, Mingyi; Kol, Amir; Shiao, Stephen L; Reddy, Abhinav; Perks, Julian R; T N Culp, William; Sparger, Ellen E; Canter, Robert J; Sckisel, Gail D; Murphy, William J

2016-09-01

Previous studies demonstrate that intratumoral CpG immunotherapy in combination with radiotherapy acts as an in-situ vaccine inducing antitumor immune responses capable of eradicating systemic disease. Unfortunately, most patients fail to respond. We hypothesized that immunotherapy can paradoxically upregulate immunosuppressive pathways, a phenomenon we term "rebound immune suppression," limiting clinical responses. We further hypothesized that the immunosuppressive enzyme indolamine-2,3-dioxygenase (IDO) is a mechanism of rebound immune suppression and that IDO blockade would improve immunotherapy efficacy. We examined the efficacy and immunologic effects of a novel triple therapy consisting of local radiotherapy, intratumoral CpG, and systemic IDO blockade in murine models and a pilot canine clinical trial. In murine models, we observed marked increase in intratumoral IDO expression after treatment with radiotherapy, CpG, or other immunotherapies. The addition of IDO blockade to radiotherapy + CpG decreased IDO activity, reduced tumor growth, and reduced immunosuppressive factors, such as regulatory T cells in the tumor microenvironment. This triple combination induced systemic antitumor effects, decreasing metastases, and improving survival in a CD8(+) T-cell-dependent manner. We evaluated this novel triple therapy in a canine clinical trial, because spontaneous canine malignancies closely reflect human cancer. Mirroring our mouse studies, the therapy was well tolerated, reduced intratumoral immunosuppression, and induced robust systemic antitumor effects. These results suggest that IDO maintains immune suppression in the tumor after therapy, and IDO blockade promotes a local antitumor immune response with systemic consequences. The efficacy and limited toxicity of this strategy are attractive for clinical translation. Clin Cancer Res; 22(17); 4328-40. ©2016 AACR. ©2016 American Association for Cancer Research.

Antitumor and radiation protection effects of β-1,3-D-glucan extracted from yeast (saccharomyces cerevisiae)

International Nuclear Information System (INIS)

Yoshimura, Akinobu; Hasegawa, Takeo; Monzen, Hajime; Takahashi, Tohru

2003-01-01

Various natural extracts are manufactured and on sale as health food products, which are raising popular consciousness of being fit, because they are considered effective or suppressible for cancer. In the current experiment, we measured the immunological activity, antitumor effects, and radioprotective effects of β-1,3-D-glucan (Macroglucan) extracted from bread yeast. Macroglucan of 0, 200, 400, and 800 mg/kg were administered intraperitoneally to C3H/HeJ mice, respectively. The antitumor effects of Macroglucan were examined by measuring natural killer (NK) and lymphokine activated killer (LAK) cell activity and tumor volume. Change in weight, survival, and microscopic manifestation of the intestine were evaluated in the C3H/HeJ mice received total body irradiation to measure radioprotective effect of Macroglucan. According to measurements of cellular cytotoxicity, levels of NK and LAK cell activity were significantly higher in the group administered Macroglucan than in the control group. Macroglucan's role in immunological activity was suggested by the observed suppression of tumor growth in the Macroglucan-administered group. That group also experienced suppression of weight loss after irradiation in the experiment for radioprotection, and a consequent increase in the survival rate compared with the control group. Protective effects appeared in photomicrographs of the intestinal cells. These results confirmed Macroglucan's radioprotective effects. These effects may be related to the suppression of infection accompanying immunological activation due to Macroglucan administration, antioxidant activity, and radical scavenging capacity. (author)

Antitumor Immunity Is Controlled by Tetraspanin Proteins

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Fleur Schaper

2018-05-01

Full Text Available Antitumor immunity is shaped by the different types of immune cells that are present in the tumor microenvironment (TME. In particular, environmental signals (for instance, soluble factors or cell–cell contact transmitted through the plasma membrane determine whether immune cells are activated or inhibited. Tetraspanin proteins are emerging as central building blocks of the plasma membrane by their capacity to cluster immune receptors, enzymes, and signaling molecules into the tetraspanin web. Whereas some tetraspanins (CD81, CD151, CD9 are widely and broadly expressed, others (CD53, CD37, Tssc6 have an expression pattern restricted to hematopoietic cells. Studies using genetic mouse models have identified important immunological functions of these tetraspanins on different leukocyte subsets, and as such, may be involved in the immune response against tumors. While multiple studies have been performed with regards to deciphering the function of tetraspanins on cancer cells, the effect of tetraspanins on immune cells in the antitumor response remains understudied. In this review, we will focus on tetraspanins expressed by immune cells and discuss their potential role in antitumor immunity. New insights in tetraspanin function in the TME and possible prognostic and therapeutic roles of tetraspanins will be discussed.

Fractionated photothermal antitumor therapy with multidye nanoparticles

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Gutwein LG

2012-01-01

Full Text Available Luke G Gutwein1, Amit K Singh2, Megan A Hahn2, Michael C Rule3, Jacquelyn A Knapik4, Brij M Moudgil2, Scott C Brown2, Stephen R Grobmyer11Division of Surgical Oncology, Department of Surgery, College of Medicine, 2Particle Engineering Research Center, 3Cell and Tissue Analysis Core, McKnight Brain Institute, 4Department of Pathology, University of Florida, Gainesville, FL, USAPurpose: Photothermal therapy is an emerging cancer treatment paradigm which involves highly localized heating and killing of tumor cells, due to the presence of nanomaterials that can strongly absorb near-infrared (NIR light. In addition to having deep penetration depths in tissue, NIR light is innocuous to normal cells. Little is known currently about the fate of nanomaterials post photothermal ablation and the implications thereof. The purpose of this investigation was to define the intratumoral fate of nanoparticles (NPs after photothermal therapy in vivo and characterize the use of novel multidye theranostic NPs (MDT-NPs for fractionated photothermal antitumor therapy.Methods: The photothermal and fluorescent properties of MDT-NPs were first characterized. To investigate the fate of nanomaterials following photothermal ablation in vivo, novel MDT-NPs and a murine mammary tumor model were used. Intratumoral injection of MDT-NPs and real-time fluorescence imaging before and after fractionated photothermal therapy was performed to study the intratumoral fate of MDT-NPs. Gross tumor and histological changes were made comparing MDT-NP treated and control tumor-bearing mice.Results: The dual dye-loaded mesoporous NPs (ie, MDT-NPs; circa 100 nm retained both their NIR absorbing and NIR fluorescent capabilities after photoactivation. In vivo MDT-NPs remained localized in the intratumoral position after photothermal ablation. With fractionated photothermal therapy, there was significant treatment effect observed macroscopically (P = 0.026 in experimental tumor-bearing mice

Antitumor effect of combination of the inhibitors of two new oncotargets: proton pumps and reverse transcriptase.

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Lugini, Luana; Sciamanna, Ilaria; Federici, Cristina; Iessi, Elisabetta; Spugnini, Enrico Pierluigi; Fais, Stefano

2017-01-17

Tumor therapy needs new approaches in order to improve efficacy and reduce toxicity of the current treatments. The acidic microenvironment and the expression of high levels of endogenous non-telomerase reverse transcriptase (RT) are common features of malignant tumor cells. The anti-acidic proton pump inhibitor Lansoprazole (LAN) and the non-nucleoside RT inhibitor Efavirenz (EFV) have shown independent antitumor efficacy. LAN has shown to counteract drug tumor resistance. We tested the hypothesis that combination of LAN and EFV may improve the overall antitumor effects. We thus pretreated human metastatic melanoma cells with LAN and then with EFV, both in 2D and 3D spheroid models. We evaluated the treatment effect by proliferation and cell death/apoptosis assays in classical and in pulse administration experiments. The action of EFV was negatively affected by the tumor microenvironmental acidity, and LAN pretreatment overcame the problem. LAN potentiated the cytotoxicity of EFV to melanoma cells and, when administered during the drug interruption period, prevented the replacement of tumor cell growth.This study supports the implementation of the current therapies with combination of Proton Pumps and Reverse Transcriptase inhibitors.

Antitumor HPV E7-specific CTL activity elicited by in vivo engineered exosomes produced through DNA inoculation

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Di Bonito P

2017-06-01

-injected mice was formally demonstrated by the E7-specific CD8+ T-cell immune response we detected in mice inoculated with exosomes isolated from plasma of mice inoculated with the Nefmut/E7 vector. Finally, we provide evidence that the injection of Nefmut/E7 DNA led to the generation of effective antigen-specific cytotoxic T lymphocytes whose activity was likely part of the potent, therapeutic antitumor effect we observed in mice implanted with TC-1 tumor cells. In summary, we established a novel method to generate immunogenic exosomes in vivo by the intramuscular inoculation of DNA vectors expressing the exosome-anchoring protein Nefmut and its derivatives. Keywords: nanovesicles, cytotoxic T lymphocytes, HIV-1 Nef, DNA vectors

Enhanced antitumor activity of 3-bromopyruvate in combination with rapamycin in vivo and in vitro.

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Zhang, Qi; Pan, Jing; Lubet, Ronald A; Komas, Steven M; Kalyanaraman, Balaraman; Wang, Yian; You, Ming

2015-04-01

3-Bromopyruvate (3-BrPA) is an alkylating agent and a well-known inhibitor of energy metabolism. Rapamycin is an inhibitor of the serine/threonine protein kinase mTOR. Both 3-BrPA and rapamycin show chemopreventive efficacy in mouse models of lung cancer. Aerosol delivery of therapeutic drugs for lung cancer has been reported to be an effective route of delivery with little systemic distribution in humans. In this study, 3-BrPA and rapamycin were evaluated in combination for their preventive effects against lung cancer in mice by aerosol treatment, revealing a synergistic ability as measured by tumor multiplicity and tumor load compared treatment with either single-agent alone. No evidence of liver toxicity was detected by monitoring serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) enzymes. To understand the mechanism in vitro experiments were performed using human non-small cell lung cancer (NSCLC) cell lines. 3-BrPA and rapamycin also synergistically inhibited cell proliferation. Rapamycin alone blocked the mTOR signaling pathway, whereas 3-BrPA did not potentiate this effect. Given the known role of 3-BrPA as an inhibitor of glycolysis, we investigated mitochondrial bioenergetics changes in vitro in 3-BrPA-treated NSCLC cells. 3-BrPA significantly decreased glycolytic activity, which may be due to adenosine triphosphate (ATP) depletion and decreased expression of GAPDH. Our results demonstrate that rapamycin enhanced the antitumor efficacy of 3-BrPA, and that dual inhibition of mTOR signaling and glycolysis may be an effective therapeutic strategy for lung cancer chemoprevention. ©2015 American Association for Cancer Research.

Antitumor effect of novel anti-podoplanin antibody NZ-12 against malignant pleural mesothelioma in an orthotopic xenograft model.

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Abe, Shinji; Kaneko, Mika Kato; Tsuchihashi, Yuki; Izumi, Toshihiro; Ogasawara, Satoshi; Okada, Naoto; Sato, Chiemi; Tobiume, Makoto; Otsuka, Kenji; Miyamoto, Licht; Tsuchiya, Koichiro; Kawazoe, Kazuyoshi; Kato, Yukinari; Nishioka, Yasuhiko

2016-09-01

Podoplanin (aggrus) is highly expressed in several types of cancers, including malignant pleural mesothelioma (MPM). Previously, we developed a rat anti-human podoplanin mAb, NZ-1, and a rat-human chimeric anti-human podoplanin antibody, NZ-8, derived from NZ-1, which induced antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity against podoplanin-positive MPM cell lines. In this study, we showed the antitumor effect of NZ-1, NZ-8, and NZ-12, a novel rat-human chimeric anti-human podoplanin antibody derived from NZ-1, in an MPM orthotopic xenograft SCID mouse model. Treatment with NZ-1 and rat NK (CD161a(+) ) cells inhibited the growth of tumors and the production of pleural effusion in NCI-H290/PDPN or NCI-H226 orthotopic xenograft mouse models. NZ-8 and human natural killer (NK) (CD56(+) ) cells also inhibited tumor growth and pleural effusion in MPM orthotopic xenograft mice. Furthermore, NZ-12 induced potent ADCC mediated by human MNC, compared with either NZ-1 or NZ-8. Antitumor effects were observed following treatment with NZ-12 and human NK (CD56(+) ) cells in MPM orthotopic xenograft mice. In addition, combined immunotherapy using the ADCC activity of NZ-12 mediated by human NK (CD56(+) ) cells with pemetrexed, led to enhanced antitumor effects in MPM orthotopic xenograft mice. These results strongly suggest that combination therapy with podoplanin-targeting immunotherapy using both NZ-12 and pemetrexed might provide an efficacious therapeutic strategy for the treatment of MPM. © 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Ginsenoside Rh2 enhances the antitumor immunological response of a melanoma mice model.

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Wang, Meng; Yan, Shi-Ju; Zhang, Hong-Tao; Li, Nan; Liu, Tao; Zhang, Ying-Long; Li, Xiao-Xiang; Ma, Qiong; Qiu, Xiu-Chun; Fan, Qing-Yu; Ma, Bao-An

2017-02-01

The treatment of malignant tumors following surgery is important in preventing relapse. Among all the post-surgery treatments, immunomodulators have demonstrated satisfactory effects on preventing recurrence according to recent studies. Ginsenoside is a compound isolated from panax ginseng, which is a famous traditional Chinese medicine. Ginsenoside aids in killing tumor cells through numerous processes, including the antitumor processes of ginsenoside Rh2 and Rg1, and also affects the inflammatory processes of the immune system. However, the role that ginsenoside serves in antitumor immunological activity remains to be elucidated. Therefore, the present study aimed to analyze the effect of ginsenoside Rh2 on the antitumor immunological response. With a melanoma mice model, ginsenoside Rh2 was demonstrated to inhibit tumor growth and improved the survival time of the mice. Ginsenoside Rh2 enhanced T-lymphocyte infiltration in the tumor and triggered cytotoxicity in spleen lymphocytes. In addition, the immunological response triggered by ginsenoside Rh2 could be transferred to other mice. In conclusion, the present study provides evidence that ginsenoside Rh2 treatment enhanced the antitumor immunological response, which may be a potential therapy for melanoma.

Enhanced antitumor efficacy of doxorubicin-encapsulated halloysite nanotubes

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Li K

2017-12-01

Full Text Available Kai Li,1,* Yongxing Zhang,2,* Mengting Chen,1 Yangyang Hu,1 Weiliang Jiang,1 Li Zhou,1 Sisi Li,1 Min Xu,1 Qinghua Zhao,2 Rong Wan1 1Department of Gastroenterology, Shanghai First People’s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China; 2Department of Orthopaedics, Shanghai First People’s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China *These authors contributed equally to this work Abstract: To improve the antitumor efficacy of doxorubicin (DOX and provide novel clinical treatment of gastric cancer, halloysite nanotubes (HNTs loaded with DOX were encapsulated by soybean phospholipid (LIP and the formed HNTs/DOX/LIP was systematically characterized via different techniques. The in vitro anticancer activity of HNTs/DOX/LIP was examined using an MTT assay. The antitumor efficacy and biocompatibility were monitored by measuring the tumor volume and assessing the blood routine and serum biochemistry using an ectopic implantation cancer model. The results show that when the concentration of HNTs was 3 mg/mL and the concentration of DOX was 1 mg/mL the optimal DOX loading efficiency was as high as 22.01%±0.43%. In vitro drug release behavior study demonstrated that HNTs/DOX/LIP shows a pH-responsive release property with fast drug release under acidic conditions (pH =5.4. MTT assays and in vivo experimental results revealed that HNTs/DOX/LIP exhibits a significantly higher inhibitory efficacy on the growth of mouse gastric cancer cells than free DOX at the same drug concentration. In addition, the life span of tumor-bearing mice in the HNTs/DOX/LIP-treated group was obviously prolonged compared with the control groups. Moreover, HNTs/DOX/LIP possessed excellent hemocompatibility as shown in the blood and histology studies. These findings indicated that the formed HNTs/DOX/LIP possesses higher antitumor efficacy and may be used as a targeted

Sodium Phenylbutyrate Inhibits Tumor Growth and the Epithelial-Mesenchymal Transition of Oral Squamous Cell Carcinoma In Vitro and In Vivo.

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Qian, Kun; Sun, Laiyu; Zhou, Guoqing; Ge, Haixia; Meng, Yue; Li, Jingfen; Li, Xiao; Fang, Xinqiang

2018-05-01

Sodium phenylbutyrate (SPB) as a salt of 4-phenylbutyric acid (4-PBA) has been reported to be an ammonia scavenger, histone deacetylase inhibitor, and an endoplasmic reticulum stress inhibitor in various diseases, including neurological diseases, inflammatory disorders, and carcinogenesis. Although phenylbutyrate showed effective antitumor properties in many cancers, its role in oral squamous cell carcinoma (OSCC) remains further characterized. Thus, the OSCC cell lines CAL27, HSC3, and SCC4 were treated with a series of doses of SPB for different times. The IC 50 of three cell lines for SPB was determined to be 4.0, 3.7, and 3.0 mM. The CCK-8 assay indicated that the treatment of SPB induced continuous inhibition of cell vitality of three cell lines. Apoptosis was assessed by Hoechst assay that showed that SPB could significantly promote cell apoptosis. Moreover, the apoptosis-related pathway was analyzed, and the results showed that the expression of antiapoptosis factor BCL-2 was downregulated by SPB but the cleavage of caspase-3 was increased. Meanwhile, it was found that SPB also impaired the migration and invasion of OSCC cells in vitro. Mechanistically, the transforming growth factor-β (TGFB) related epithelial-mesenchymal transition (EMT) was inhibited by SPB with decreased mesenchymal marker N-cadherin and increased epithelial marker E-cadherin. Furthermore, the antitumor effect of SPB in vivo was also demonstrated. The administration of SPB induced remarkably tumor regression with decreased tumor volume, and the TGFB level and EMT phenotype in vivo were also inhibited. These data demonstrated that the treatment of SPB could function as antitumor therapeutics for OSCC.

Anti-tumor activity of polysaccharides extracted from Senecio ...

African Journals Online (AJOL)

Purpose: To optimize the extraction conditions of polysaccharides from the root of Senecio scandens Buch,-Ham. (PRS) and evaluate its anti-tumor effect on hepatocellular carcinoma. Methods: Response surface methodology (RSM) applied with a Box-Behnken design (BBD, three levels and three factors) was employed to ...

Study on the Immunomodulation Effect of Isodon japonicus Extract via Splenocyte Function and NK Anti-Tumor Activity

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Kyung-A Hwang

2012-04-01

Full Text Available Here we investigated the potential immune-enhancing activity of Isodon japonicus on murine splenocyte and natural-killer (NK cells in vitro. The ethanol extract of I. japonicus significantly enhanced the proliferation of splenocyte and induced the significant enhancement of NK cells’ activity against tumor cells (YAC-1. In addition, I. japonicus increased the production of interferon (IFN-γ and tumor necrosis factor (TNF-α, suggesting that the increase in NK cell cytotoxicity could be due to the enhancement of the NK cell production of both cytokines. Taken together, I. japonicus extract inhibited the growth of human leukemia cells (K562 by 74%. Our observation indicated that the anti-tumor effects of I. japonicus may be attributed to its ability to serve as a stimulant of NK anti-tumor activity. In addition, our results support the development of functional food studies on I. japonicus.

Inhibition of angiogenesis: a novel antitumor mechanism of the herbal compound arctigenin.

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Gu, Yuan; Scheuer, Claudia; Feng, Dilu; Menger, Michael D; Laschke, Matthias W

2013-09-01

Arctigenin, a functional ingredient of several traditional Chinese herbs, has been reported to have potential antitumor activity. However, its mechanisms of action are still not well elucidated. Because the establishment and metastatic spread of tumors is crucially dependent on angiogenesis, here we investigated whether arctigenin inhibits tumor growth by disturbing blood vessel formation. For this purpose, human dermal microvascular endothelial cells were exposed to different arctigenin doses to study their viability, proliferation, protein expression, migration, and tube formation compared with vehicle-treated controls. In addition, arctigenin action on vascular sprouting was analyzed in an aortic ring assay. Furthermore, we studied direct arctigenin effects on CT26.WT colon carcinoma cells. Spheroids of these tumor cells were transplanted into the dorsal skinfold chamber of arctigenin-treated and vehicle-treated BALB/c mice for the in-vivo analysis of tumor vascularization and growth by intravital fluorescence microscopy, histology, and immunohistochemistry. We found that noncytotoxic doses of arctigenin dose dependently reduced the proliferation of human dermal microvascular endothelial cells without affecting their migratory and tube-forming capacity. Arctigenin treatment also resulted in a decreased cellular expression of phosphorylated serine/threonine protein kinase AKT, vascular endothelial growth factor receptor 2, and proliferating cell nuclear antigen and inhibited vascular sprouting from aortic rings. In addition, proliferation, but not secretion of vascular endothelial growth factor, was decreased in arctigenin-treated tumor cells. Finally, arctigenin suppressed the vascularization and growth of engrafting CT26.WT tumors in the dorsal skinfold chamber model. Taken together, these results show for the first time an antiangiogenic action of arctigenin, which may contribute considerably toward its antitumor activity.

Theoretical Study of Phosphoethanolamine: A Synthetic Anticancer Agent with Broad Antitumor Activity

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Vitor Prates Lorenzo

2016-01-01

Full Text Available Cancer is a major public health problem with limited success of available treatments, pointing to the need for new strategies to be developed. Phosphoethanolamine exhibits broad antitumor activity in a variety of tumor cells and potent inhibitor effects on tumor progress in vivo. Once-used organophosphates inhibit acetylcholinesterase (AChE, resulting in toxic effects to the user. As this group is present in phosphoethanolamine, we perform prediction of the in silico metabolism of phosphoethanolamine and submit this series to a docking study on AChE. A total of 10 metabolites were indicated by the prediction, including ammonia and hydroxylamine, which were not included in the study. Using a group of 8 organophosphorus whose pIC50 values ranged from 5.92 to 9.47 as template, we observed that no compound present in the phosphoethanolamine series had a binding energy lower than that of organophosphorus, suggesting that the series has low inhibitory power on AChE. In light of this, we conclude that phosphoethanolamine and its predicted metabolites do not significantly inhibit AChE to cause a cholinergic crisis. This finding highlights the importance of investigating this compound as lead for potential anticancer agents.

pH-sensitive polymeric cisplatin-ion complex with styrene-maleic acid copolymer exhibits tumor-selective drug delivery and antitumor activity as a result of the enhanced permeability and retention effect.

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Saisyo, Atsuyuki; Nakamura, Hideaki; Fang, Jun; Tsukigawa, Kenji; Greish, Khaled; Furukawa, Hiroyuki; Maeda, Hiroshi

2016-02-01

Cisplatin (CDDP) is widely used to treat various cancers. However, its distribution to normal tissues causes serious adverse effects. For this study, we synthesized a complex of styrene-maleic acid copolymer (SMA) and CDDP (SMA-CDDP), which formed polymeric micelles, to achieve tumor-selective drug delivery based on the enhanced permeability and retention (EPR) effect. SMA-CDDP is obtained by regulating the pH of the reaction solution of SMA and CDDP. The mean SMA-CDDP particle size was 102.5 nm in PBS according to electrophoretic light scattering, and the CDDP content was 20.1% (w/w). The release rate of free CDDP derivatives from the SMA-CDDP complex at physiological pH was quite slow (0.75%/day), whereas it was much faster at pH 5.5 (4.4%/day). SMA-CDDP thus had weaker in vitro toxicity at pH 7.4 but higher cytotoxicity at pH 5.5. In vivo pharmacokinetic studies showed a 5-fold higher tumor concentration of SMA-CDDP than of free CDDP. SMA-CDDP had more effective antitumor potential but lower toxicity than did free CDDP in mice after i.v. administration. Administration of parental free CDDP at 4 mg/kg×3 caused a weight loss of more than 5%; SMA-CDDP at 60 mg/kg (CDDP equivalent)×3 caused no significant weight change but markedly suppressed S-180 tumor growth. These findings together suggested using micelles of the SMA-CDDP complex as a cancer chemotherapeutic agent because of beneficial properties-tumor-selective accumulation and relatively rapid drug release at the acidic pH of the tumor-which resulted in superior antitumor effects and fewer side effects compared with free CDDP. Copyright © 2015 Elsevier B.V. All rights reserved.

Effect of Paris saponin on antitumor and immune function in U14 ...

African Journals Online (AJOL)

bearing mice, and reduced the serum IL-4 level. The Paris saponin can inhibit U14 cell growth and prolong survival time of mice; it is speculated that the Paris saponin may express its anti-tumor activity by improving the body's immune system.

Zoledronic acid enhances antitumor efficacy of liposomal doxorubicin.

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Hattori, Yoshiyuki; Shibuya, Kazuhiko; Kojima, Kaori; Miatmoko, Andang; Kawano, Kumi; Ozaki, Kei-Ichi; Yonemochi, Etsuo

2015-07-01

Previously, we found that the injection of zoledronic acid (ZOL) into mice bearing tumor induced changes of the vascular structure in the tumor. In this study, we examined whether ZOL treatment could decrease interstitial fluid pressure (IFP) via change of tumor vasculature, and enhance the antitumor efficacy of liposomal doxorubicin (Doxil®). When ZOL solution was injected at 40 µg/mouse per day for three consecutive days into mice bearing murine Lewis lung carcinoma LLC tumor, depletion of macrophages in tumor tissue and decreased density of tumor vasculature were observed. Furthermore, ZOL treatments induced inflammatory cytokines such as interleukin (IL)-10 and -12, granulocyte-macrophage colony-stimulating factor (GM-CSF) and tumor necrosis factor (TNF)-α in serum of LLC tumor-bearing mice, but not in normal mice, indicating that ZOL treatments might induce an inflammatory response in tumor tissue. Furthermore, ZOL treatments increased antitumor activity by Doxil in mice bearing a subcutaneous LLC tumor, although they did not significantly increase the tumor accumulation of doxorubicin (DXR). These results suggest that ZOL treatments might increase the therapeutic efficacy of Doxil via improvement of DXR distribution in a tumor by changing the tumor vasculature. ZOL treatment can be an alternative approach to increase the antitumor effect of liposomal drugs.

Dll4 blockade potentiates the anti-tumor effects of VEGF inhibition in renal cell carcinoma patient-derived xenografts.

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Kiersten Marie Miles

Full Text Available The Notch ligand Delta-like 4 (Dll4 is highly expressed in vascular endothelium and has been shown to play a pivotal role in regulating tumor angiogenesis. Blockade of the Dll4-Notch pathway in preclinical cancer models has been associated with non-productive angiogenesis and reduced tumor growth. Given the cross-talk between the vascular endothelial growth factor (VEGF and Delta-Notch pathways in tumor angiogenesis, we examined the activity of a function-blocking Dll4 antibody, REGN1035, alone and in combination with anti-VEGF therapy in renal cell carcinoma (RCC.Severe combined immunodeficiency (SCID mice bearing patient-derived clear cell RCC xenografts were treated with REGN1035 and in combination with the multi-targeted tyrosine kinase inhibitor sunitinib or the VEGF blocker ziv-aflibercept. Immunohistochemical and immunofluorescent analyses were carried out, as well as magnetic resonance imaging (MRI examinations pre and 24 hours and 2 weeks post treatment. Single agent treatment with REGN1035 resulted in significant tumor growth inhibition (36-62% that was equivalent to or exceeded the single agent anti-tumor activity of the VEGF pathway inhibitors sunitinib (38-54% and ziv-aflibercept (46%. Importantly, combination treatments with REGN1035 plus VEGF inhibitors resulted in enhanced anti-tumor effects (72-80% growth inhibition, including some tumor regression. Magnetic resonance imaging showed a marked decrease in tumor perfusion in all treatment groups. Interestingly, anti-tumor efficacy of the combination of REGN1035 and ziv-aflibercept was also observed in a sunitinib resistant ccRCC model.Overall, these findings demonstrate the potent anti-tumor activity of Dll4 blockade in RCC patient-derived tumors and a combination benefit for the simultaneous targeting of the Dll4 and VEGF signaling pathways, highlighting the therapeutic potential of this treatment modality in RCC.

Study of Antitumor Activity of Sodium Phenylbutyrate, Histon Deacetylase Inhibitor, on Ehrlich Carcinoma Model.

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Fadeev, N P; Kharisov, R I; Kovan'ko, E G; Pustovalov, Yu I

2015-09-01

Antitumor activity of sodium phenylbutyrate was studied on 120 outbred female mice with transplanted Ehrlich ascites carcinoma. The animals received the drug in doses of 400, 800, and 1200 mg/kg with drinking water daily for 21 days. The antitumor effect was evaluated by tumor growth inhibition and lifespan prolongation. Phenylbutyrate in the dose of 800 mg/kg was most effective. The drug inhibited the tumor growth by 71%, prolonged the lifespan of animals by 28, and was low-toxic.

Smart thermosensitive liposomes for effective solid tumor therapy and in vivo imaging.

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Kevin Affram

Full Text Available In numerous studies, liposomes have been used to deliver anticancer drugs such as doxorubicin to local heat-triggered tumor. Here, we investigate: (i the ability of thermosensitive liposomal nanoparticle (TSLnp as a delivery system to deliver poorly membrane-permeable anticancer drug, gemcitabine (Gem to solid pancreatic tumor with the aid of local mild hyperthermia and, (ii the possibility of using gadolinium (Magnevist® loaded-TSLnps (Gd-TSLnps to increase magnetic resonance imaging (MRI contrast in solid tumor. In this study, we developed and tested gemcitabine-loaded thermosensitive liposomal nanoparticles (Gem-TSLnps and gadolinium-loaded thermosensitive liposomal nanoparticles (Gd-TSLnps both in in-vitro and in-vivo. The TSLnps exhibited temperature-dependent release of Gem, at 40-42°C, 65% of Gem was released within 10 min, whereas < 23% Gem leakage occurred at 37°C after a period of 2 h. The pharmacokinetic parameters and tissue distribution of both Gem-TSLnps and Gd-TSLnps were significantly greater compared with free Gem and Gd, while Gem-TSLnps plasma clearance was reduced by 17-fold and that of Gd-TSLpns was decreased by 2-fold. Area under the plasma concentration time curve (AUC of Gem-TSLnps (35.17± 0.04 μghr/mL was significantly higher than that of free Gem (2.09 ± 0.01 μghr/mL whereas, AUC of Gd-TSLnps was higher than free Gd by 3.9 fold high. TSLnps showed significant Gem accumulation in heated tumor relative to free Gem. Similar trend of increased Gd-TSLnps accumulation was observed in non-heated tumor compared to that of free Gd; however, no significant difference in MRI contrast enhancement between free Gd and Gd-TSLnps ex-vivo tumor images was observed. Despite Gem-TSLnps dose being half of free Gem dose, antitumor efficacy of Gem-TSLnps was comparable to that of free Gem(Gem-TSLnps 10 mg Gem/kg compared with free Gem 20 mg/kg. Overall, the findings suggest that TSLnps may be used to improve Gem delivery and enhance

Combined treatment with D-allose, docetaxel and radiation inhibits the tumor growth in an in vivo model of head and neck cancer

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Hoshikawa, Hiroshi; Kamitori, Kazuyo; Indo, Kanako; Mori, Terushige; Kamata, Mizuna; Takahashi, Tomoko; Tokuda, Masaaki

2018-01-01

The present study was designed to evaluate the effect of one rare sugar, D-allose, on normal human cells and cutaneous tissue, and to investigate the radiosensitizing and chemosensitizing potential of D-allose in an in vivo model of head and neck cancer. Results indicated that D-allose did not inhibit the growth of normal human fibroblasts TIG-1 cells, and no apoptotic changes were observed after D-allose and D-glucose treatment. The mRNA expression levels of thioredoxin interacting protein (TXNIP) in TIG-1 cells after D-allose treatment increased by 2-fold (50.4 to 106.5). Conversely, the mRNA expression levels of TXNIP in HSC3 cancer cells increased by 74-fold (1.5 to 110.6), and the thioredoxin (TRX)/TXNIP ratio was markedly reduced from 61.7 to 1.4 following D-allose treatment. Combined multiple treatments with docetaxel, radiation and D-allose resulted in the greatest antitumor response in the in vivo model. Hyperkeratosis, epidermal thickening and tumor necrosis factor-α immunostaining were observed following irradiation treatment, but these pathophysiological reactions were reduced following D-allose administration. Thus, the present findings suggest that D-allose may enhance the antitumor effects of chemoradiotherapy whilst sparing normal tissues. PMID:29456721

Zoledronic acid produces combinatory anti-tumor effects with cisplatin on mesothelioma by increasing p53 expression levels.

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Shinya Okamoto

Full Text Available We examined anti-tumor effects of zoledronic acid (ZOL, one of the bisphosphonates agents clinically used for preventing loss of bone mass, on human mesothelioma cells bearing the wild-type p53 gene. ZOL-treated cells showed activation of caspase-3/7, -8 and -9, and increased sub-G1 phase fractions. A combinatory use of ZOL and cisplatin (CDDP, one of the first-line anti-cancer agents for mesothelioma, synergistically or additively produced the cytotoxicity on mesothelioma cells. Moreover, the combination achieved greater anti-tumor effects on mesothelioma developed in the pleural cavity than administration of either ZOL or CDDP alone. ZOL-treated cells as well as CDDP-treated cells induced p53 phosphorylation at Ser 15, a marker of p53 activation, and up-regulated p53 protein expression levels. Down-regulation of p53 levels with siRNA however did not influence the ZOL-mediated cytotoxicity but negated the combinatory effects by ZOL and CDDP. In addition, ZOL treatments augmented cytotoxicity of adenoviruses expressing the p53 gene on mesothelioma. These data demonstrated that ZOL-mediated augmentation of p53, which was not linked with ZOL-induced cytotoxicity, played a role in the combinatory effects with a p53 up-regulating agent, and suggests a possible clinical use of ZOL to mesothelioma with anti-cancer agents.

Enhanced antitumor efficacy of poly(D,L-lactide-co-glycolide-based methotrexate-loaded implants on sarcoma 180 tumor-bearing mice

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Gao L

2017-10-01

Full Text Available Li Gao,1,2 Lunyang Xia,3 Ruhui Zhang,1 Dandan Duan,3 Xiuxiu Liu,2 Jianjian Xu,2 Lan Luo1 1State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 2School of Biological and Medical Engineering, Hefei University of Technology, Hefei, 3Laboratory of Pharmaceutical Research, Anhui Zhongren Science and Technology Co., Ltd., Hefei, People’s Republic of China Purpose: Methotrexate is widely used in chemotherapy for a variety of malignancies. However, severe toxicity, poor pharmacokinetics, and narrow safety margin of methotrexate limit its clinical application. The aim of this study was to develop sustained-release methotrexate-loaded implants and evaluate antitumor activity of the implants after intratumoral implantation. Materials and methods: We prepared the implants containing methotrexate, poly(D,L-lactide-co-glycolide, and polyethylene glycol 4000 with the melt-molding technique. The implants were characterized with regards to drug content, morphology, in vitro, and in vivo release profiles. Differential scanning calorimetry (DSC and Fourier transform infrared spectroscopy (FTIR were carried out to investigate the physicochemical properties of the implants. Furthermore, the antitumor activity of the implants was tested in a sarcoma 180 mouse model. Results: The implants were prepared as solid rods. Scanning electron microscopy images showed a smooth surface of the implant, suggesting that methotrexate was homogeneously dispersed in the polymeric matrix. The results of DSC and FTIR indicated that no significant interaction between methotrexate and the polymer was observed in the implants. Both in vitro and in vivo release profiles of the implants were characterized by burst release followed by sustained release of methotrexate. Intratumoral implantation of methotrexate-loaded implants could efficiently delay tumor growth. Moreover, an increase in the dose of implants led to a higher tumor

Prevention of graft-versus-host-disease with preserved graft-versus-leukemia-effect by ex vivo and in vivo modulation of CD4(+) T-cells.

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Fricke, Stephan; Hilger, Nadja; Fricke, Christian; Schönfelder, Uta; Behre, Gerhard; Ruschpler, Peter; Boldt, Andreas; Oelkrug, Christopher; Sack, Ulrich; Emmrich, Frank

2014-06-01

This is the first report showing that an epitope-specific ex vivo modulation of an allogeneic hematopoietic stem cell graft by the anti-human CD4 antibody MAX.16H5 IgG1 simultaneously facilitates the anti-tumor capacity of the graft (Graft-versus-leukemia effect, GvL) and the long-term suppression of the deleterious side effect Graft-versus-host-disease (GvHD). To distinguish and consolidate GvL from GvHD, the anti-human CD4 antibody MAX16.H5 IgG1 was tested in murine GvHD and tumor models. The survival rate was significantly increased in recipients receiving a MAX.16H5 IgG1 short-term (2 h) pre-incubated graft even when tumor cells were co-transplanted or when recipient mice were treated by MAX.16H5 IgG1 before transplantation. After engraftment, regulatory T-cells are generated only supporting the GvL effect. It was also possible to transfer the immune tolerance from GvHD-free recipient chimeras into third party recipient mice without the need of reapplication of MAX.16H5 IgG1 anti-human CD4 antibodies. These findings are also benefical for patients with leukemia when no matched related or unrelated donor is available and provides a safer allogeneic HSCT, which is more effective against leukemia. It also facilitates allogeneic (stem) cell transplantations for other indications (e.g., autoimmune-disorders).

Antitumor Responses Stimulated by Dendritic Cells Are Improved by Triiodothyronine Binding to the Thyroid Hormone Receptor β.

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Alamino, Vanina A; Mascanfroni, Iván D; Montesinos, María M; Gigena, Nicolás; Donadio, Ana C; Blidner, Ada G; Milotich, Sonia I; Cheng, Sheue-Yann; Masini-Repiso, Ana M; Rabinovich, Gabriel A; Pellizas, Claudia G

2015-04-01

Bidirectional cross-talk between the neuroendocrine and immune systems orchestrates immune responses in both physiologic and pathologic settings. In this study, we provide in vivo evidence of a critical role for the thyroid hormone triiodothyronine (T3) in controlling the maturation and antitumor functions of dendritic cells (DC). We used a thyroid hormone receptor (TR) β mutant mouse (TRβPV) to establish the relevance of the T3-TRβ system in vivo. In this model, TRβ signaling endowed DCs with the ability to stimulate antigen-specific cytotoxic T-cell responses during tumor development. T3 binding to TRβ increased DC viability and augmented DC migration to lymph nodes. Moreover, T3 stimulated the ability of DCs to cross-present antigens and to stimulate cytotoxic T-cell responses. In a B16-OVA mouse model of melanoma, vaccination with T3-stimulated DCs inhibited tumor growth and prolonged host survival, in part by promoting the generation of IFNγ-producing CD8(+) T cells. Overall, our results establish an adjuvant effect of T3-TRβ signaling in DCs, suggesting an immediately translatable method to empower DC vaccination approaches for cancer immunotherapy. ©2015 American Association for Cancer Research.

Anti-angiogenesis and anti-tumor activity of recombinant anginex

International Nuclear Information System (INIS)

Brandwijk, Ricardo J.M.G.E.; Dings, Ruud P.M.; Linden, Edith van der; Mayo, Kevin H.; Thijssen, Victor L.J.L.; Griffioen, Arjan W.

2006-01-01

Anginex, a synthetic 33-mer angiostatic peptide, specifically inhibits vascular endothelial cell proliferation and migration along with induction of apoptosis in endothelial cells. Here we report on the in vivo characterization of recombinant anginex and use of the artificial anginex gene for gene therapy approaches. Tumor growth of human MA148 ovarian carcinoma in athymic mice was inhibited by 80% when treated with recombinant anginex. Histological analysis of the tumors showed an approximate 2.5-fold reduction of microvessel density, suggesting that angiogenesis inhibition is the cause of the anti-tumor effect. Furthermore, there was a significant correlation between the gene expression patterns of 16 angiogenesis-related factors after treatment with both recombinant and synthetic anginex. To validate the applicability of the anginex gene for gene therapy, stable transfectants of murine B16F10 melanoma cells expressing recombinant anginex were made. Supernatants of these cells inhibited endothelial cell proliferation in vitro. Furthermore, after subcutaneous injection of these cells in C57BL/6 mice, an extensive delay in tumor growth was observed. These data show that the artificial anginex gene can be used to produce a recombinant protein with similar activity as its synthetic counterpart and that the gene can be applied in gene therapy approaches for cancer treatment

Antitumor Active Protein-containing Glycans from the Body of Ganoderma tsugae

Institute of Scientific and Technical Information of China (English)

LIU Ying; LI Yue-fei; ZHENG Ke-yan; FEI Xiao-fang

2012-01-01

To explore the effects of traditional herbal medicine Ganoderma tsugae(G.tsugae) on immunomodulatory and antitumor activities,the crude polysaccharides ofG.tsugae were purified by filtration,diethylaminoethyl(DEAE)sepharose-fast flow chromatography and sephadex G-100 size-exclusion chromatography.Two main fractions,protein-containing glycans CSSLP-I and CSSLP-2,were obtained via the gradient elution.The protein content,molecular weight,and monosaccharide composition of the two fractions were analyzed.Furthermore,the influence of the protein-containing glycans from G.tsugae on the activation of human acute monocytic leukemia cell line(THP-1 ) and their antitumor activities to the human hepatocellular liver carcinoma cell(HepG-2) in vitro were evaluated.The results indicate that CSSLP-I and CSSLP-2 could increase the pinocytic activity of THP-1 cells and induce THP-1 cells to produce the cytokines of TNFa and IL-2,significantly.CSSLP-1 and CSSLP-2 also played an inhibiting effect on the cancer cell(NepG-2).Moreover,the anti-proliferation activity of CSSLP-1 and CSSLP-2 increased with the participation of TNFa and 1L-2 or other antitumor factors induced from THP-1 cclls by G.tsugae protein-containing glycan fractions.

Preliminary evaluation of in vitro cytotoxicity and in vivo antitumor activity of Xanthium strumarium in transplantable tumors in mice.

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Aranjani, Jesil Mathew; Manuel, Atulya; Mallikarjuna Rao, Chamallamudi; Udupa, Nayanabhirama; Rao, Josyula Venkata; Joy, Ann Mary; Gandhi, Prajay; Radhakrishnan, Ethiraj Kannat

2013-01-01

In the present study, active fractions of the methanolic extract of Xanthium strumarium (XS) showing potent cytotoxicity were determined using microculture tetrazolium (MTT) and sulforhodamine B (SRB) assays in selected cancer cell lines. The active fractions viz., chloroform soluble fraction of root (CEXSR), hexane soluble fraction of leaf (HEXSL), hexane soluble fraction of fruits (HEXSF) and chloroform soluble fraction of fruits (CEXSF) of XS were tested in transplantable animal tumor models for their antitumor potential. Dalton's ascitic lymphoma (DLA) cells were used to induce solid and liquid (ascites) tumor in mice. The tumor bearing animals were treated with active fractions at two dose levels (100 and 200 mg/kg). The antitumor activities of the active fractions in tumor bearing animals were monitored with parameters such as body weight and increase in life-span as well as biochemical and hematological modalities (in the case of liquid tumor). Tumor incidence and tumor volume were the parameters monitored in the case of the solid tumor model. The results were analyzed by one-way ANOVA followed by Tukey's post hoc test. The extracts were found to increase the life-span of tumor bearing animals and restore the altered hematological and biochemical parameters significantly.

Medicinal Plants and Other Living Organisms with Antitumor Potential against Lung Cancer

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Luara de Sousa Monteiro

2014-01-01

Full Text Available Lung cancer is a disease with high morbidity and mortality rates. As a result, it is often associated with a significant amount of suffering and a general decrease in the quality of life. Herbal medicines are recognized as an attractive approach to lung cancer therapy with little side effects and are a major source of new drugs. The aim of this work was to review the medicinal plants and other living organisms with antitumor potential against lung cancer. The assays were conducted with animals and humans, and Lewis lung carcinoma was the most used experimental model. China, Japan, South Korea, and Ethiopia were the countries that most published studies of species with antitumor activity. Of the 38 plants evaluated, 27 demonstrated antitumor activity. In addition, six other living organisms were cited for antitumor activity against lung cancer. Mechanisms of action, combination with chemotherapeutic drugs, and new technologies to increase activity and reduce the toxicity of the treatment are discussed. This review was based on the NAPRALERT databank, Web of Science, and Chemical Abstracts. This work shows that natural products from plants continue to be a rich source of herbal medicines or biologically active compounds against cancer.

Synergistic antitumor activity of histamine plus melphalan in isolated limb perfusion: preclinical studies.

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Brunstein, Flavia; Hoving, Saske; Seynhaeve, Ann L B; van Tiel, Sandra T; Guetens, Gunther; de Bruijn, Ernst A; Eggermont, Alexander M M; ten Hagen, Timo L M

2004-11-03

We have previously shown how tumor response of isolated limb perfusion (ILP) with melphalan was improved when tumor necrosis factor alpha (TNF-alpha) was added. Taking into account that other vasoactive drugs could also improve tumor response to ILP, we evaluated histamine (Hi) as an alternative to TNF-alpha. We used a rat ILP model to assess the combined effects of Hi and melphalan (n = 6) on tumor regression, melphalan uptake (n = 6), and tissue histology (n = 2) compared with Hi or melphalan alone. We also evaluated the growth of BN-175 tumor cells as well as apoptosis, necrosis, cell morphology, and paracellular permeability of human umbilical vein endothelial cells (HUVECs) after Hi treatment alone and in combination with melphalan. The antitumor effect of the combination of Hi and melphalan in vivo was synergistic, and Hi-dependent reduction in tumor volume was blocked by H1 and H2 receptor inhibitors. Tumor regression was observed in 66% of the animals treated with Hi and melphalan, compared with 17% after treatment with Hi or melphalan alone. Tumor melphalan uptake increased and vascular integrity in the surrounding tissue was reduced after ILP treatment with Hi and melphalan compared with melphalan alone. In vitro results paralleled in vivo results. BN-175 tumor cells were more sensitive to the cytotoxicity of combined treatment than HUVECs, and Hi treatment increased the permeability of HUVECs. Hi in combination with melphalan in ILP improved response to that of melphalan alone through direct and indirect mechanisms. These results warrant further evaluation in the clinical ILP setting and, importantly, in organ perfusion.

Anti-tumor activities of a novel chlorin derivative for photodynamic therapy in vitro and in vivo

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Li-Jun Zhang

2015-01-01

Full Text Available In this study, a novel photosensitizer meso-tetra (3-pyrrolidinomethyl-4-methoxyphenyl chlorin (TPMC was reported. It displays a characteristic long wavelength absorption peak at 656 nm and it shows a singlet oxygen quantum yield of 0.48. After light irradiation with 650 nm laser, it can kill Eca-109 and SMMC-7721 cells in vitro (25 mW/cm2, 1.2 to 3.6 J/cm2 and destroy Eca-109 tumor in nude mice (50 mW/cm2, 90 J/cm2. It has the perspective to be developed as a new anti-tumor drug in photodynamic therapy (PDT photodiagnosis, and deserves further investigation.

B7-2 expressed on EL4 lymphoma suppresses antitumor immunity by an interleukin 4-dependent mechanism.

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Stremmel, C; Greenfield, E A; Howard, E; Freeman, G J; Kuchroo, V K

1999-03-15

For T cells to become functionally activated they require at least two signals. The B7 costimulatory molecules B7-1 and B7-2 provide the "second signal" pivotal for T cell activation. In this report, we studied the relative roles of B7-1 and B7-2 molecules in the induction of antitumor immunity to the T cell thymoma, EL4. We generated EL4 tumor cells that expressed B7-1, B7-2, and B7-1+B7-2 by transfecting murine cDNAs. Our results demonstrate that EL4-B7-1 cells are completely rejected in syngeneic mice. Unlike EL4-B7-1 cells, we find that EL4-B7-2 cells are not rejected but progressively grow in the mice. A B7-1- and B7-2-EL4 double transfectant was generated by introducing B7-2 cDNA into the EL4-B7-1 tumor line that regressed in vivo. The EL4-B7-1+B7-2 double transfectant was not rejected when implanted into syngeneic mice but progressively grew to produce tumors. The double transfectant EL4 cells could costimulate T cell proliferation that could be blocked by anti-B7-1 antibodies, anti-B7-2 antibodies, or hCTLA4 immunoglobulin, showing that the B7-1 and B7-2 molecules expressed on the EL4 cells were functional. In vivo, treatment of mice implanted with double-transfected EL4 cells with anti-B7-2 monoclonal antibody resulted in tumor rejection. Furthermore, the EL4-B7-2 and EL4-B7-1+B7-2 cells, but not the wild-type EL4 cells, were rejected in interleukin 4 (IL-4) knockout mice. Our data suggests that B7-2 expressed on some T cell tumors inhibits development of antitumor immunity, and IL-4 appears to play a critical role in abrogation of the antitumor immune response.

Potential Antitumor Effects of Pomegranates and Its Ingredients.

Science.gov (United States)

Rahmani, Arshad H; Alsahli, Mohammed A; Almatroodi, Saleh A

2017-01-01

The treatment based on plant or plant derivatives is a promising strategy in the killing of cancers cells. Moreover, wide-ranging finding has established that medicinal plant and its ingredient modulate several cells signaling pathways or inhibiting the carcinogenesis process. In this vista, pomegranates fruits, seeds and peels illustrate cancer preventive role seems to be due to rich source of antioxidant and other valuable ingredients. Furthermore, anti-tumour activities of pomegranates have been evidences through the modulation of cell signaling pathways including transcription factor, apoptosis and angiogenesis. In this review article, anti-tumor activity of pomegranates and its components or its different type of extracts are described to understand the mechanism of action of pomegranates in cancer therapy.

The role of radiotherapy for the induction of antitumor immune responses

International Nuclear Information System (INIS)

Multhoff, G.; Helmholtz-Zentrum Muenchen; Gaipl, U.S.; Niedermann, G.

2012-01-01

Effective radiotherapy is aimed to control the growth of the primary carcinoma and to induce a long-term specific antitumor immune response against the primary tumor, recurrence and metastases. The contribution covers the following issues: T cells and tumor specific immune responses, dendritic cells (DCs) start adaptive immune responses, NK (natural killer) cells for HLA independent tumor control, abscopal effects of radiotherapy, combination of radiotherapy and immune therapy, radiotherapy contribution to the induction of immunogenic cell death, combinability of radiotherapy and DC activation, combinability of radiotherapy and NK cell therapy. It turns out that the combination of radio-chemotherapy and immune therapy can change the microenvironment initiating antitumor immune reactions that inhibit the recurrence risk and the development of metastases.

Synthesis of sulfadimethoxine based surfactants and their evaluation as antitumor agents

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Manal Mohmed Khowdiary

2016-01-01

Summary: The main goal of cancer therapy is to attain the maximum therapeutic damage of tumor cells in combination with a minimum concentration of the drug. This can be achieved in principle via selective antitumor preparations, the cytostatic effects of which would be restricted within tumor tissue. While 100% selectivity may be impractical, the achievement of reasonably high selectivity seems to be a feasible aim. Platinum and cobalt complex surfactants in our research affect tumor tissue at a very low concentration at values lower than their CMC values; this indicate that the sulfadimethoxine complexes merit further investigation as potential antitumor drugs.

Antitumor and immunomodulatory effects of the naphthoquinone 5-methoxy-3,4-dehydroxanthomegnin

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Rodrigo Rezende Kitagawa

2011-12-01

Full Text Available Large number of quinones has been associated with antitumor, antibacterial, antimalarial and antifungal activities. In this work we describe the effect of the naphthoquinone, 5-methoxy-3,4-dehydroxanthomegnin, on murine tumor cells (LP07 and LM2 and its immunomodulatory effect on nitric oxide (NO production on LPS-stimulated macrophages. The results have shown that 5-methoxy-3,4-dehydroxanthomegnin was a significant inhibitor of LPS-stimulated NO generation from macrophage (inhibition percentage ranged from 97.4 to 98.9% and a strong cytotoxic agent against both tumor cells LP07 and LM2 (CI50 6.2±0.36 µM and 74.6±1.9 µM, respectively. These results indicate that the 5-methoxy-3,4-dehydroxanthomegnin may show promising activity in the treatment of murine breast and lung cancer by immunomodulatory and antiproliferative activities.

Antitumor and immunomodulatory effects of the naphthoquinone 5-methoxy-3,4-dehydroxanthomegnin

Directory of Open Access Journals (Sweden)

Rodrigo Rezende Kitagawa

2011-08-01

Full Text Available Large number of quinones has been associated with antitumor, antibacterial, antimalarial and antifungal activities. In this work we describe the effect of the naphthoquinone, 5-methoxy-3,4-dehydroxanthomegnin, on murine tumor cells (LP07 and LM2 and its immunomodulatory effect on nitric oxide (NO production on LPS-stimulated macrophages. The results have shown that 5-methoxy-3,4-dehydroxanthomegnin was a significant inhibitor of LPS-stimulated NO generation from macrophage (inhibition percentage ranged from 97.4 to 98.9% and a strong cytotoxic agent against both tumor cells LP07 and LM2 (CI50 6.2±0.36 µM and 74.6±1.9 µM, respectively. These results indicate that the 5-methoxy-3,4-dehydroxanthomegnin may show promising activity in the treatment of murine breast and lung cancer by immunomodulatory and antiproliferative activities.

Histone deacetylase inhibitor vorinostat suppresses the growth of uterine sarcomas in vitro and in vivo

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Petru Edgar

2010-03-01

Full Text Available Abstract Background Uterine sarcomas are very rare malignancies with no approved chemotherapy protocols. Histone deacetylase (HDAC inhibitors belong to the most promising groups of compounds for molecular targeting therapy. Here, we described the antitumor effects of suberoylanilide hydroxamic acid (SAHA; vorinostat on MES-SA uterine sarcoma cells in vitro and in vivo. We investigated effects of vorinostat on growth and colony forming ability by using uterine sarcoma MES-SA cells. We analyzed the influence of vorinostat on expression of different HDACs, p21WAF1 and activation of apoptosis. Finally, we examined the antitumor effects of vorinostat on uterine sarcoma in vivo. Results Vorinostat efficiently suppressed MES-SA cell growth at a low dosage (3 μM already after 24 hours treatment. Decrease of cell survival was even more pronounced after prolonged treatment and reached 9% and 2% after 48 and 72 hours of treatment, respectively. Colony forming capability of MES-SA cells treated with 3 μM vorinostat for 24 and 48 hours was significantly diminished and blocked after 72 hours. HDACs class I (HDAC2 and 3 as well as class II (HDAC7 were preferentially affected by this treatment. Vorinostat significantly increased p21WAF1 expression and apoptosis. Nude mice injected with 5 × 106 MES-SA cells were treated for 21 days with vorinostat (50 mg/kg/day and, in comparison to placebo group, a tumor growth reduction of more than 50% was observed. Results obtained by light- and electron-microscopy suggested pronounced activation of apoptosis in tumors isolated from vorinostat-treated mice. Conclusions Our data strongly indicate the high therapeutic potential of vorinostat in uterine sarcomas.

Evaluation of Anti-tumor and Chemoresistance-lowering Effects of ...

African Journals Online (AJOL)

formation in nude mice was used to test the effect of pectolinarigenin on tumorigenicity of breast cancer cells in vivo. ... women in 2008 [1]. However, survival rates are much poorer in developing countries compared with the western world. Recrudesce of breast cancer is still a great threat to the treatment of breast cancer [2].

Nimotuzumab enhances temozolomide-induced growth suppression of glioma cells expressing mutant EGFR in vivo

International Nuclear Information System (INIS)

Nitta, Yusuke; Shimizu, Saki; Shishido-Hara, Yukiko; Suzuki, Kaori; Shiokawa, Yoshiaki; Nagane, Motoo

2016-01-01

A mutant form of epidermal growth factor receptor (EGFR), EGFRvIII, is common in glioblastoma (GBM) and confers enhanced tumorigenic activity and drug resistance. Nimotuzumab, an anti-EGFR antibody, has shown preclinical and clinical activity to GBM, but its specific activity against EGFRvIII has not been fully investigated. Human glioma U87MG or LNZ308 cells overexpressing either wild-type (wt) EGFR or EGFRvIII were treated with nimotuzumab, temozolomide, or both. Expression and phosphorylation status of molecules were determined by Western blot analysis. Methylation status of promoter region of O 6 -methylguanine-DNA methyltransferase (MGMT) was detected by methylation-specific PCR. Antitumor activity was tested using nude mice bearing either subcutaneous or intracerebral xenografts along with analyses of EGFR phosphorylation status, proliferation, apoptosis, and vessel density. Nimotuzumab treatment resulted in reduction of EGFRvIII tyrosine phosphorylation with a decrease in Akt phosphorylation that was greater than that of wtEGFR. Correspondingly, antitumor effects, growth suppression and survival elongation, were more significant in mice bearing either subcutaneous or intracerebral tumor expressing EGFRvIII than in those expressing wtEGFR. These effects were markedly increased when temozolomide was combined with nimotuzumab. The post-treatment recurrent brain tumors exhibited a decrease in expression of the mismatch repair (MMR) proteins, MSH6 and MLH1, but their methylated MGMT status did not changed. Nimotuzumab has in vivo antitumor activity against GBM, especially those expressing EGFRvIII, when combined with temozolomide. This could provide a basis for preselection of patients with GBM by EGFR status who might benefit from the nimotuzumab and temozolomide combination therapy

A new anti-tumor strategy based on in vivo tumstatin overexpression after plasmid electrotransfer in muscle

Energy Technology Data Exchange (ETDEWEB)

Thevenard, Jessica, E-mail: jessica.thevenard@univ-reims.fr [FRE CNRS/URCA 3481, University of Reims Champagne-Ardenne, 51 rue Cognacq Jay, F-51095 Reims (France); Ramont, Laurent, E-mail: lramont@chu-reims.fr [FRE CNRS/URCA 3481, University of Reims Champagne-Ardenne, 51 rue Cognacq Jay, F-51095 Reims (France); CHU de Reims, Avenue du Général Koenig, F-51092 Reims (France); Mir, Lluis M., E-mail: luis.mir@igr.fr [CNRS, UMR 8203, Institut Gustave Roussy, 114, Rue Edouard Vaillant, F-94805 Villejuif Cedex (France); Université Paris-Sud, UMR 8203, Institut Gustave Roussy, 114, Rue Edouard Vaillant, F-94405 Orsay Cedex (France); Dupont-Deshorgue, Aurélie, E-mail: aurelie.dupont@univ-reims.fr [FRE CNRS/URCA 3481, University of Reims Champagne-Ardenne, 51 rue Cognacq Jay, F-51095 Reims (France); Maquart, François-Xavier, E-mail: fmaquart@chu-reims.fr [FRE CNRS/URCA 3481, University of Reims Champagne-Ardenne, 51 rue Cognacq Jay, F-51095 Reims (France); CHU de Reims, Avenue du Général Koenig, F-51092 Reims (France); Monboisse, Jean-Claude, E-mail: jc.monboisse@univ-reims.fr [FRE CNRS/URCA 3481, University of Reims Champagne-Ardenne, 51 rue Cognacq Jay, F-51095 Reims (France); CHU de Reims, Avenue du Général Koenig, F-51092 Reims (France); Brassart-Pasco, Sylvie, E-mail: sylvie.brassart-pasco@univ-reims.fr [FRE CNRS/URCA 3481, University of Reims Champagne-Ardenne, 51 rue Cognacq Jay, F-51095 Reims (France)

2013-03-22

Highlights: ► A new therapeutic strategy based on tumstatin in vivo overexpression is proposed. ► pVAX1©–tumstatin electrotransfer in muscle mediates protein expression in muscle. ► A substantial expression of tumstatin is detected in the serum of electrotransfected mice. ► Tumstatin overexpression decreases tumor growth and increases mouse survival. -- Abstract: The NC1 domains from the different α(IV) collagen chains were found to exert anti-tumorigenic and/or anti-angiogenic activities. A limitation to the therapeutic use of these matrikines is the large amount of purified recombinant proteins, in the milligram range in mice that should be administered daily throughout the experimental procedures. In the current study, we developed a new therapeutic approach based on tumstatin (NC1α3(IV)) overexpression in vivo in a mouse melanoma model. Gene electrotransfer of naked plasmid DNA (pDNA) is particularly attractive because of its simplicity, its lack of immune responsiveness and its safety. The pDNA electrotransfer in muscle mediates a substantial gene expression that lasts several months. A pVAX1© vector containing the tumstatin cDNA was injected into the legs of C57BL/6 mice and submitted to electrotranfer. Sera were collected at different times and tumstatin was quantified by ELISA. Tumstatin secretion reached a plateau at day 21 with an expression level of 12 μg/mL. For testing the effects of tumstatin expression on tumor growth in vivo, B16F1 melanoma cells were subcutaneously injected in mice 7 days after empty pVAX1© (Mock) or pVAX1©–tumstatin electrotransfer. Tumstatin expression triggered a large decrease in tumor growth and an increase in mouse survival. This new therapeutic approach seems promising to inhibit tumor progression in vivo.

A new anti-tumor strategy based on in vivo tumstatin overexpression after plasmid electrotransfer in muscle

International Nuclear Information System (INIS)

Thevenard, Jessica; Ramont, Laurent; Mir, Lluis M.; Dupont-Deshorgue, Aurélie; Maquart, François-Xavier; Monboisse, Jean-Claude; Brassart-Pasco, Sylvie

2013-01-01

Highlights: ► A new therapeutic strategy based on tumstatin in vivo overexpression is proposed. ► pVAX1©–tumstatin electrotransfer in muscle mediates protein expression in muscle. ► A substantial expression of tumstatin is detected in the serum of electrotransfected mice. ► Tumstatin overexpression decreases tumor growth and increases mouse survival. -- Abstract: The NC1 domains from the different α(IV) collagen chains were found to exert anti-tumorigenic and/or anti-angiogenic activities. A limitation to the therapeutic use of these matrikines is the large amount of purified recombinant proteins, in the milligram range in mice that should be administered daily throughout the experimental procedures. In the current study, we developed a new therapeutic approach based on tumstatin (NC1α3(IV)) overexpression in vivo in a mouse melanoma model. Gene electrotransfer of naked plasmid DNA (pDNA) is particularly attractive because of its simplicity, its lack of immune responsiveness and its safety. The pDNA electrotransfer in muscle mediates a substantial gene expression that lasts several months. A pVAX1© vector containing the tumstatin cDNA was injected into the legs of C57BL/6 mice and submitted to electrotranfer. Sera were collected at different times and tumstatin was quantified by ELISA. Tumstatin secretion reached a plateau at day 21 with an expression level of 12 μg/mL. For testing the effects of tumstatin expression on tumor growth in vivo, B16F1 melanoma cells were subcutaneously injected in mice 7 days after empty pVAX1© (Mock) or pVAX1©–tumstatin electrotransfer. Tumstatin expression triggered a large decrease in tumor growth and an increase in mouse survival. This new therapeutic approach seems promising to inhibit tumor progression in vivo

Potent anti-tumor effect generated by a novel human papillomavirus (HPV antagonist peptide reactivating the pRb/E2F pathway.

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Cai-ping Guo

Full Text Available Human papillomavirus type 16 (HPV16 E7 is a viral oncoprotein believed to play a major role in cervical cancer. In this study, an antagonist peptide against HPV16E7 protein was first identified from screening the c7c phage display peptide library. The binding specificity and affinity of the selected peptide to HPV16E7 were tested by competitive enzyme-linked immunosorbent assay (ELISA. The antagonist peptide showed obvious anti-tumor efficacy both in cell lines and animal tumor models. Significant cell proliferation inhibition with high specificity was noted when HPV16-positive cells were treated with the peptide. This anti-tumor efficacy was resulted from overriding the activities of HPV16E7 and reactivating the pRb/E2F pathway, as shown by a series of experiments. Flow cytometry analysis revealed that the selected peptide induced G1 arrest in a dose-dependent manner. Competitive ELISA, pull down, and Co-IP experiments indicated that the selected peptide disrupted the interaction between HPV16E7 and pRb proteins both in vitro and in vivo. Luciferase reporter assay verified that transcription activities of E2F were suppressed by the peptide through restoration of pRb. RT-PCR and Western blot revealed that it reduced cyclins A, D1, and E1 expression, and led to HPV16E7 protein degradation, but pRb protein stabilization. The current study suggests that this specific peptide may serve as a potential therapeutic agent for HPV16-positive cervical cancer.

Augmentation of Antitumor Immunity by Human and Mouse CAR T Cells Secreting IL-18

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Biliang Hu

2017-09-01

Full Text Available The effects of transgenically encoded human and mouse IL-18 on T cell proliferation and its application in boosting chimeric antigen receptor (CAR T cells are presented. Robust enhancement of proliferation of IL-18-secreting human T cells occurred in a xenograft model, and this was dependent on TCR and IL-18R signaling. IL-18 augmented IFN-γ secretion and proliferation of T cells activated by the endogenous TCR. TCR-deficient, human IL-18-expressing CD19 CAR T cells exhibited enhanced proliferation and antitumor activity in the xenograft model. Antigen-propelled activation of cytokine helper ensemble (APACHE CAR T cells displayed inducible expression of IL-18 and enhanced antitumor immunity. In an intact mouse tumor model, CD19-IL-18 CAR T cells induced deeper B cell aplasia, significantly enhanced CAR T cell proliferation, and effectively augmented antitumor effects in mice with B16F10 melanoma. These findings point to a strategy to develop universal CAR T cells for patients with solid tumors.

A flavonoid component from Docynia delavayi (Franch.) Schneid represses transplanted H22 hepatoma growth and exhibits low toxic effect on tumor-bearing mice.

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Zhao, Xiangpei; Shu, Guangwen; Chen, Lvyi; Mi, Xue; Mei, Zhinan; Deng, Xukun

2012-09-01

The fruit of Docynia delavayi (Franch.) Schneid is a kind of popular food in southwestern areas of China. Additionally, its rhizome has been long used as a folk medicine in the treatment of liver cancer by local people. Chrysin is a kind of flavonoid which induces cancer cell death in vitro. However, its anti-tumor activity in vivo and toxicological effects on the tumor-bearing animals still remain poorly understood. In this study, we obtained four flavonoids from this herb. Among them, chrysin showed the strongest cytotoxic effect on an array of cultured tumor cells. Further investigations revealed that it significantly repressed transplanted H22 ascitic hepatic tumor cell growth in vivo. Moreover, this compound displayed little toxic effects. Additionally, we demonstrated that in transplanted tumor tissues, chrysin not only activated caspase-3 and induced apoptosis, but also inhibited the production of vascular endothelial growth factor (VEGF) and suppressed angiogenesis. These data showed that chrysin exhibited prominent anti-tumor activities and low toxic effects in vivo. Copyright © 2012 Elsevier Ltd. All rights reserved.

Novel Antitumor Platinum(II) Conjugates Containing the Nonsteroidal Anti-inflammatory Agent Diclofenac: Synthesis and Dual Mechanisms of Antiproliferative Effects.

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Intini, Francesco Paolo; Zajac, Juraj; Novohradsky, Vojtech; Saltarella, Teresa; Pacifico, Concetta; Brabec, Viktor; Natile, Giovanni; Kasparkova, Jana

2017-02-06

One concept how to improve anticancer effects of conventional metallodrugs consists in conjugation of these compounds with other biologically (antitumor) active agents, acting by a different mechanism. Here, we present synthesis, biological effects, and mechanisms of action of new Pt(II) derivatives containing one or two nonsteroidal anti-inflammatory diclofenac (DCF) ligands also known for their antitumor effects. The antiproliferative properties of these metallic conjugates show that these compounds are potent and cancer cell selective cytotoxic agents exhibiting activity in cisplatin resistant and the COX-2 positive tumor cell lines. One of these compounds, compound 3, in which DCF molecules are coordinated to Pt(II) through their carboxylic group, is more potent than parental conventional Pt(II) drug cisplatin, free DCF and the congeners of 3 in which DCF ligands are conjugated to Pt(II) via a diamine. The potency of 3 is due to several factors including enhanced internalization that correlates with enhanced DNA binding and cytotoxicity. Mechanistic studies show that 3 combines multiple effects. After its accumulation in cells, it releases Pt(II) drug capable of binding/damaging DNA and DCF ligands, which affect distribution of cells in individual phases of the cell cycle, inhibit glycolysis and lactate transport, collapse mitochondrial membrane potential, and suppress the cellular properties characteristic of metastatic progression.

Potentiation of antitumor immunity in tumor-bearing mice by a degraded D-manno-D-glucan (DMG), a new antitumor polysaccharide.

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Nakajima, H; Kita, Y; Hashimoto, S; Tsukada, W; Abe, S; Mizuno, D

1983-12-01

DMG, a degraded D-manno-D-glucan from the culture fluid of Microellobosporia grisea, inhibited the growth of murine syngeneic MM46 mammary carcinoma. Mice in which the tumor had completely regressed by DMG treatment showed tumor-specific antitumor resistance. The antitumor action of DMG was studied by examining the influences of DMG on tumor-specific and non-specific immune responses in tumor-bearing hosts. The tumor-specific delayed hypersensitivity reaction appeared transiently on day 7 after tumor inoculation but had decreased by day 15 in untreated tumor-bearing mice. In contrast, the reaction was retained and augmented in DMG-treated tumor-bearing mice. The tumor-neutralizing activity of spleen cells from DMG-treated tumor-bearing mice, tested by a Winn assay, was tumor-specific and significantly higher than that of untreated tumor-bearing mice. The tumor-neutralizing activity of peritoneal cells and the in vitro cytostatic activity of peritoneal macrophages in response to lymphokine supernatants containing macrophage activation factor were also augmented by DMG treatment. In contrast, the level of antitumor antibody in the serum increased with time, irrespective of DMG administration. Thus, DMG potentiated cellular antitumor effector mechanisms.

B7-2 Expressed on EL4 Lymphoma Suppresses Antitumor Immunity by an Interleukin 4–dependent Mechanism

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Stremmel, C.; Greenfield, E.A.; Howard, E.; Freeman, G.J.; Kuchroo, V.K.

1999-01-01

For T cells to become functionally activated they require at least two signals. The B7 costimulatory molecules B7-1 and B7-2 provide the “second signal” pivotal for T cell activation. In this report, we studied the relative roles of B7-1 and B7-2 molecules in the induction of antitumor immunity to the T cell thymoma, EL4. We generated EL4 tumor cells that expressed B7-1, B7-2, and B7-1+B7-2 by transfecting murine cDNAs. Our results demonstrate that EL4–B7-1 cells are completely rejected in syngeneic mice. Unlike EL4–B7-1 cells, we find that EL4–B7-2 cells are not rejected but progressively grow in the mice. A B7-1– and B7-2–EL4 double transfectant was generated by introducing B7-2 cDNA into the EL4–B7-1 tumor line that regressed in vivo. The EL4–B7-1+B7-2 double transfectant was not rejected when implanted into syngeneic mice but progressively grew to produce tumors. The double transfectant EL4 cells could costimulate T cell proliferation that could be blocked by anti–B7-1 antibodies, anti–B7-2 antibodies, or hCTLA4 immunoglobulin, showing that the B7-1 and B7-2 molecules expressed on the EL4 cells were functional. In vivo, treatment of mice implanted with double-transfected EL4 cells with anti–B7-2 monoclonal antibody resulted in tumor rejection. Furthermore, the EL4–B7-2 and EL4–B7-1+B7-2 cells, but not the wild-type EL4 cells, were rejected in interleukin 4 (IL-4) knockout mice. Our data suggests that B7-2 expressed on some T cell tumors inhibits development of antitumor immunity, and IL-4 appears to play a critical role in abrogation of the antitumor immune response. PMID:10075975

Antitumor agent 25-epi Ritterostatin GN1N induces endoplasmic reticulum stress and autophagy mediated cell death in melanoma cells.

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Riaz Ahmed, Kausar Begam; Kanduluru, Ananda Kumar; Feng, Li; Fuchs, Philip L; Huang, Peng

2017-05-01

Metastatic melanoma is the most aggressive of all skin cancers and is associated with poor prognosis owing to lack of effective treatments. 25-epi Ritterostatin GN1N is a novel antitumor agent with yet undefined mechanisms of action. We sought to delineate the antitumor mechanisms of 25-epi Ritterostatin GN1N in melanoma cells to determine the potential of this compound as a treatment for melanoma. Activation of the endoplasmic reticulum (ER) stress protein glucose-regulated protein 78 (GRP78) has been associated with increased melanoma progression, oncogenic signaling, drug resistance, and suppression of cell death. We found that 25-epi Ritterostatin GN1N induced cell death in melanoma cells at nanomolar concentrations, and this cell death was characterized by inhibition of GRP78 expression, increased expression of the ER stress marker CHOP, loss of mitochondrial membrane potential, and lipidation of the autophagy marker protein LC3B. Importantly, normal melanocytes exhibited limited sensitivity to 25-epi Ritterostatin GN1N. Subsequent in vivo results demonstrated that 25-epi Ritterostatin GN1N reduced melanoma growth in mouse tumor xenografts and did not affect body weight, suggesting minimal toxicity. In summary, our findings indicate that 25-epi Ritterostatin GN1N causes ER stress and massive autophagy, leading to collapse of mitochondrial membrane potential and cell death in melanoma cells, with minimal effects in normal melanocytes. Thus, 25-epi Ritterostatin GN1N is a promising anticancer agent that warrants further investigation.

Efficacy of BIBF 1120 or BIBF 1120 plus chemotherapy on nasopharyngeal carcinoma in vitro and in vivo

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Xue C

2016-03-01

Full Text Available Cong Xue,1 Ying Tian,2 Jing Zhang,3 Yuanyuan Zhao,1 Jianhua Zhan,2 Wenfeng Fang,1 Li Zhang1 1Department of Medical Oncology, 2Department of Research, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, 3Department of Medical Oncology, The First Affiliated Hospital of Guangzhou Traditional Chinese Medicine University, Guangzhou, People’s Republic of China Purpose: BIBF 1120 is a potent triple angiokinase inhibitor now being evaluated in many types of tumors. We examine the antitumor effects of BIBF 1120 on nasopharyngeal carcinoma (NPC in vitro and in vivo. Materials and methods: The effect of BIBF 1120 on NPC cell proliferation was evaluated using the Cell Counting Kit 8 assay. The activities of BIBF 1120 as a single agent and in combination with cisplatin (DDP in NPC tumor xenografts were evaluated by measuring microvessel density and expression of vascular endothelial growth factor signaling. Results: BIBF 1120 exhibited limited inhibition of the growth of three NPC cell lines. Concurrent administration of BIBF 1120 and DDP provided greater antitumor effects compared to that observed with the use of either inhibitor as a single agent in the NPC xenograft model. Microvessel density and expression of vascular endothelial growth factor signaling were significantly reduced. Conclusion: BIBF 1120, either as a single agent or in combination with DDP, demonstrates significant antitumor and antiangiogenic effects in the NPC xenograft model. Our results indicate that BIBF 1120 administered in conjunction with chemotherapy might provide an effective treatment method for NPC. Keywords: BIBF 1120, nasopharyngeal carcinoma, antiangiogenesis, microvessel density

iNKT cell cytotoxic responses control T-lymphoma growth in vitro and in vivo

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Bassiri, Hamid; Das, Rupali; Guan, Peng; Barrett, David M.; Brennan, Patrick J.; Banerjee, Pinaki P.; Wiener, Susan J.; Orange, Jordan S.; Brenner, Michael B.; Grupp, Stephan A.; Nichols, Kim E.

2013-01-01

Invariant natural killer T (iNKT) cells comprise a lineage of CD1d-restricted glycolipid-reactive T lymphocytes with important roles in host immunity to cancer. iNKT cells indirectly participate in antitumor responses by inducing dendritic cell maturation and producing cytokines that promote tumor clearance by CD8+ T and NK cells. Although iNKT cells thereby act as potent cellular adjuvants, it is less clear whether they directly control the growth of tumors. To gain insights into the direct contribution of iNKT cells to tumor immune surveillance, we developed in vitro and in vivo systems to selectively examine the antitumor activity of iNKT cells in the absence of other cytolytic effectors. Using the EL4 T-lymphoma cell line as a model, we find that iNKT cells exert robust and specific lysis of tumor cells in vitro in a manner that is differentially-induced by iNKT cell agonists of varying TCR affinities, such as OCH, α-galactosyl ceramide and PBS44. In vitro blockade of CD1d-mediated lipid antigen presentation, disruption of T cell receptor (TCR) signaling, or loss of perforin expression significantly reduce iNKT cell killing. Consistent with these findings, iNKT cell reconstitution of T, B, and NK cell-deficient mice slows EL4 growth in vivo via TCR-CD1d and perforin-dependent mechanisms. Together, these observations establish that iNKT cells are sufficient to control the growth of T-lymphoma in vitro and in vivo. They also suggest that the induction of iNKT cell cytotoxic responses in situ might serve as a more effective strategy to prevent and/or treat CD1d+ cancers, such as T-lymphoma. PMID:24563871

iNKT cell cytotoxic responses control T-lymphoma growth in vitro and in vivo .

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Bassiri, Hamid; Das, Rupali; Guan, Peng; Barrett, David M; Brennan, Patrick J; Banerjee, Pinaki P; Wiener, Susan J; Orange, Jordan S; Brenner, Michael B; Grupp, Stephan A; Nichols, Kim E

2014-01-01

Invariant natural killer T (iNKT) cells comprise a lineage of CD1d-restricted glycolipid-reactive T lymphocytes with important roles in host immunity to cancer. iNKT cells indirectly participate in antitumor responses by inducing dendritic cell maturation and producing cytokines that promote tumor clearance by CD8+ T and NK cells. Although iNKT cells thereby act as potent cellular adjuvants, it is less clear whether they directly control the growth of tumors. To gain insights into the direct contribution of iNKT cells to tumor immune surveillance, we developed in vitro and in vivo systems to selectively examine the antitumor activity of iNKT cells in the absence of other cytolytic effectors. Using the EL4 T-lymphoma cell line as a model, we found that iNKT cells exert robust and specific lysis of tumor cells in vitro in a manner that is differentially induced by iNKT cell agonists of varying T-cell receptor (TCR) affinities, such as OCH, α-galactosyl ceramide, and PBS44. In vitro blockade of CD1d-mediated lipid antigen presentation, disruption of TCR signaling, or loss of perforin expression significantly reduce iNKT cell killing. Consistent with these findings, iNKT cell reconstitution of T, B, and NK cell–deficient mice slows EL4 growth in vivo via TCR-CD1d and perforin-dependent mechanisms. Together, these observations establish that iNKT cells are sufficient to control the growth of T lymphoma in vitro and in vivo. They also suggest that the induction of iNKT cell cytotoxic responses in situ might serve as a more effective strategy to prevent and/or treat CD1d+ cancers, such as T lymphoma. ©2013 AACR.

Piper betle extracts exhibit antitumor activity by augmenting antioxidant potential.

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Alam, Badrul; Majumder, Rajib; Akter, Shahina; Lee, Sang-Han

2015-02-01

The present study was conducted to evaluate the methanolic extract of Piper betle leaves (MPBL) and its organic fractions with regard to antitumor activity against Ehrlich ascites carcinoma (EAC) in Swiss albino mice and to confirm their antioxidant activities. At 24 h post-intraperitoneal inoculation of tumor cells into mice, extracts were administered at 25, 50 and 100 mg/kg body weight for nine consecutive days. The antitumor effects of the extracts were then assessed according to tumor volume, packed cell count, viable and non-viable tumor cell count, median survival time and increase in life span of EAC-bearing mice. Next, hematological profiles and serum biochemical parameters were calculated, and antioxidant properties were assessed by estimating lipid peroxidation, reduced glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) levels. MPBL and the ethylacetate fraction (EPBL) at a dose of 100 mg/kg induced a significant decrease in tumor volume, packed cell volume and viable cell count and increased the life span of the EAC-bearing mice (PPiper betle extracts exhibit significant antitumor activity, which may be attributed to the augmentation of endogenous antioxidant potential.

Metronomic Small Molecule Inhibitor of Bcl-2 (TW-37) Is Antiangiogenic and Potentiates the Antitumor Effect of Ionizing Radiation

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Zeitlin, Benjamin D.; Spalding, Aaron C.; Campos, Marcia S.; Ashimori, Naoki; Dong Zhihong; Wang Shaomeng; Lawrence, Theodore S.; Noer, Jacques E.

2010-01-01

Purpose: To investigate the effect of a metronomic (low-dose, high-frequency) small-molecule inhibitor of Bcl-2 (TW-37) in combination with radiotherapy on microvascular endothelial cells in vitro and in tumor angiogenesis in vivo. Methods and Materials: Primary human dermal microvascular endothelial cells were exposed to ionizing radiation and/or TW-37 and colony formation, as well as capillary sprouting in three-dimensional collagen matrices, was evaluated. Xenografts vascularized with human blood vessels were engineered by cotransplantation of human squamous cell carcinoma cells (OSCC3) and human dermal microvascular endothelial cells seeded in highly porous biodegradable scaffolds into the subcutaneous space of immunodeficient mice. Mice were treated with metronomic TW-37 and/or radiation, and tumor growth was evaluated. Results: Low-dose TW-37 sensitized primary endothelial cells to radiation-induced inhibition of colony formation. Low-dose TW-37 or radiation partially inhibited endothelial cell sprout formation, and in combination, these therapies abrogated new sprouting. Combination of metronomic TW-37 and low-dose radiation inhibited tumor growth and resulted in significant increase in time to failure compared with controls, whereas single agents did not. Notably, histopathologic analysis revealed that tumors treated with TW-37 (with or without radiation) are more differentiated and showed more cohesive invasive fronts, which is consistent with less aggressive phenotype. Conclusions: These results demonstrate that metronomic TW-37 potentiates the antitumor effects of radiotherapy and suggest that patients with head and neck cancer might benefit from the combination of small molecule inhibitor of Bcl-2 and radiation therapy.

Combined SEP and anti-PD-L1 antibody produces a synergistic antitumor effect in B16-F10 melanoma-bearing mice.

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Hu, Zhengping; Ye, Liang; Xing, Yingying; Hu, Jinhang; Xi, Tao

2018-01-09

The increased PD-L1 induces poorer prognosis in melanoma. The treatment with PD-1/PD-L1 antibodies have a low response rate. The combination immunotherapies are the encouraging drug development strategy to receive maximal therapeutic benefit. In this study, we investigated the enhanced antitumor and immunomodulatory activity of combined SEP and αPD-L1 in B16-F10 melanoma-bearing mice. The results shown that combined SEP and αPD-L1 presented significant synergistic antitumor effects, increased the frequency of CD8 + and CD4 + T cells in spleen and tumor, cytotoxic activity of CTL in spleen, and IL-2 and IFN-γ levels in splenocytes and tumor. The combination treatment also produced synergistic increase in P-ERK1/2 level in spleen. Immunohistochemistry shown that SEP induced the PD-L1 expression in melanoma tissue possibly by promoting IFN-γ excretion, which led to the synergistic anti-tumor effects of aPD-L1 and SEP. Furthermore, in the purified T lymphocyte from the naive mice, the combination of SEP and αPD-L1 had more potent than SEP or αPD-L1 in promoting T lymphocyte proliferation and cytokines secretion including IL-2 and IFN-γ, at least partially by activating MEK/ERK pathway. Our study provides the scientific basis for a clinical trial that would involve combination of anti-PD-L1 mAb and SEP for sustained melanoma control.

Comparative study of the antitumor effect of natural monoterpenes: relationship to cell cycle analysis

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Abdeslam Jaafari

2012-06-01

Full Text Available Monoterpenes have been identified as responsible of important therapeutic effects of plant-extracts. In this work, we try to compare the cytotoxic effect of six monoterpenes (carvacrol, thymol, carveol, carvone, eugenol and isopulegol as well as their molecular mechanisms. The in vitro antitumor activity of the tested products, evaluated against five tumor cell lines, show that the carvacrol is the most cytotoxic monoterpene. The investigation of an eventual synergistic effect of the six natural monoterpenes with two anticancer drugs revealed that there is a significant synergy between them (p<5%. On the other hand, the effect of the tested products on cell cycle progression was examined by flow cytometry after DNA staining in order to investigate the molecular mechanism of their cytotoxic activity. The results revealed that carvacrol and carveol stopped the cell cycle progression in S phase; however, thymol and isopulegol stopped it in G0/G1 phase. Regarding carvone and eugenol, no effect on cell cycle was observed.

Inhibition of eukaryotic translation elongation by the antitumor natural product Mycalamide B.

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Dang, Yongjun; Schneider-Poetsch, Tilman; Eyler, Daniel E; Jewett, John C; Bhat, Shridhar; Rawal, Viresh H; Green, Rachel; Liu, Jun O

2011-08-01

Mycalamide B (MycB) is a marine sponge-derived natural product with potent antitumor activity. Although it has been shown to inhibit protein synthesis, the molecular mechanism of action by MycB remains incompletely understood. We verified the inhibition of translation elongation by in vitro HCV IRES dual luciferase assays, ribosome assembly, and in vivo [(35)S]methinione labeling experiments. Similar to cycloheximide (CHX), MycB inhibits translation elongation through blockade of eEF2-mediated translocation without affecting the eEF1A-mediated loading of tRNA onto the ribosome, AUG recognition, or dipeptide synthesis. Using chemical footprinting, we identified the MycB binding site proximal to the C3993 28S rRNA residue on the large ribosomal subunit. However, there are also subtle, but significant differences in the detailed mechanisms of action of MycB and CHX. First, MycB arrests the ribosome on the mRNA one codon ahead of CHX. Second, MycB specifically blocked tRNA binding to the E-site of the large ribosomal subunit. Moreover, they display different polysome profiles in vivo. Together, these observations shed new light on the mechanism of inhibition of translation elongation by MycB.

Celecoxib enhances radiation response of secondary bone tumors of a human non-small cell lung cancer via antiangiogenesis in vivo

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Klenke, Frank Michael [Bern Univ. (Switzerland). Dept. of Orthopedic Surgery; Abdollahi, Amir [Deutsches Krebsforschungszentrum, Heidelberg (Germany). Dept. of Radiation Oncology; Tufts Univ. School of Medicine, Boston, MA (United States). Center of Cancer Systems Biology; Bischof, Marc; Huber, Peter E. [Deutsches Krebsforschungszentrum, Heidelberg (Germany). Dept. of Radiation Oncology; Gebhard, Martha-Maria [Heidelberg Univ. (Germany). Dept. of Experimental Surgery; Ewerbeck, Volker [Heidelberg Univ. (Germany). Dept. of Orthopedic Surgery; Sckell, Axel [Charite Univ. Medical Center, Berlin (Germany). Dept. of Orthopedic, Trauma and Reconstructive Surgery

2011-01-15

Purpose: Cyclooxygenase-2 (COX-2) inhibitors mediate a systemic antitumor activity via antiangiogenesis and seem to enhance the response of primary tumors to radiation. Radiosensitizing effects of COX-2 inhibition have not been reported for bone metastases. Therefore, the aim of this study was the investigation of the radiosensitizing effects of the selective COX-2 inhibitor celecoxib in secondary bone tumors of a non-small cell lung carcinoma in vivo. Materials and Methods: Human A549 lung carcinomas were implanted into a cranial window preparation in male SCID mice (n = 24). Animals were treated with either celecoxib or radiation (7 Gy single photon dose) alone or a combination of celecoxib and radiation, respectively. Untreated animals served as controls. The impact of radiation and COX-2 inhibition on angiogenesis, microcirculation, and tumor growth was analyzed over 28 days by means of intravital microscopy and histological methods. Results: Monotherapies with radiation as well as celecoxib had significant antitumor effects compared to untreated controls. Both therapies reduced tumor growth and vascularization to a similar extent. The simultaneous administration of celecoxib and radiation further enhanced the antitumor and antiangiogenic effects of single-beam radiation. With the combined treatment approach, tumor vascularization and tumor size were decreased by 57% and 51%, respectively, as compared to monotherapy with radiation. Conclusion: The combined application of radiation therapy and COX-2 inhibition showed synergistic effects concerning the inhibition of tumor growth and tumor angiogenesis. Therefore, the combination of radiation with COX-2 inhibitor therapy represents a promising approach to improve the therapeutic efficacy of radiotherapy of bone metastases. (orig.)

NKT cells as an ideal anti-tumor immunotherapeutic.

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Fujii, Shin-Ichiro; Shimizu, Kanako; Okamoto, Yoshitaka; Kunii, Naoki; Nakayama, Toshinori; Motohashi, Shinichiro; Taniguchi, Masaru

2013-12-02

Human natural killer T (NKT) cells are characterized by their expression of an invariant T cell antigen receptor α chain variable region encoded by a Vα24Jα18 rearrangement. These NKT cells recognize α-galactosylceramide (α-GalCer) in conjunction with the MHC class I-like CD1d molecule and bridge the innate and acquired immune systems to mediate efficient and augmented immune responses. A prime example of one such function is adjuvant activity: NKT cells augment anti-tumor responses because they can rapidly produce large amounts of IFN-γ, which acts on NK cells to eliminate MHC negative tumors and also on CD8 cytotoxic T cells to kill MHC positive tumors. Thus, upon administration of α-GalCer-pulsed DCs, both MHC negative and positive tumor cells can be effectively eliminated, resulting in complete tumor eradication without tumor recurrence. Clinical trials have been completed in a cohort of 17 patients with advanced non-small cell lung cancers and 10 cases of head and neck tumors. Sixty percent of advanced lung cancer patients with high IFN-γ production had significantly prolonged median survival times of 29.3 months with only the primary treatment. In the case of head and neck tumors, 10 patients who completed the trial all had stable disease or partial responses 5 weeks after the combination therapy of α-GalCer-DCs and activated NKT cells. We now focus on two potential powerful treatment options for the future. One is to establish artificial adjuvant vector cells containing tumor mRNA and α-GalCer/CD1d. This stimulates host NKT cells followed by DC maturation and NK cell activation but also induces tumor-specific long-term memory CD8 killer T cell responses, suppressing tumor metastasis even 1 year after the initial single injection. The other approach is to establish induced pluripotent stem (iPS) cells that can generate unlimited numbers of NKT cells with adjuvant activity. Such iPS-derived NKT cells produce IFN-γ in vitro and in vivo upon

L-Asparaginase Isolated from Phaseolus vulgaris Seeds Exhibited Potent Anti-Acute Lymphoblastic Leukemia Effects In-Vitro and Low Immunogenic Properties In-Vivo

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Saleh A. Mohamed

2016-10-01

Full Text Available Escherichia coli-derived L-asparaginases have been used in the treatment of acute lymphoblastic leukemia (ALL, however, clinical hypersensitivity reactions and silent inactivation due to antibodies against E. coli-asparaginase, lead to inactivation of these preparations in most cases.Therefore, this study was aimed to investigate the cytotoxicity and antitumor effects ofa novel L-asparaginaseenzyme, isolated from Phaseolus vulgaris seeds (P-Asp on the ALL cell line (Jurkat. The immunogenicity of the enzyme was also evaluated in-vivo and results were compared to commercially available enzymes of microbial sources. The data demonstrated that P-Asp has an enhanced anti-proliferative effect on ALL cells as detected by the WST-8 cell viability assay kit. Cells treated with P-Asp also exhibited a higher degree of early apoptosis compared with asparaginase from Escherichia coli (L-Asp or its pegylated form Pegasparagas (PEG-ASP that induced higher rates of late apoptosis and necrosis as detected by an Annexin V/Propidium iodide binding assay. In-vivo experiments indicated that mice treated with P-Asp had less distinct allergenic responses than other bacterial enzyme preparations as indicated by lower serum concentrations of IgG, IgE, IgM and mMCP-1 compared with other treated groups. In conclusion, P-Asp can be considered as a promising candidate for use in the treatment of ALL.

Risk of Lymphoma in Patients With Inflammatory Bowel Disease Treated With Anti-Tumor Necrosis Factor Alpha Agents: A Systematic Review and Meta-analysis.

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Yang, Chen; Huang, Junlin; Huang, Xiaowen; Huang, Shaozhuo; Cheng, Jiaxin; Liao, Weixin; Chen, Xuewen; Wang, Xueyi; Dai, Shixue

2018-05-12

The association between anti-tumor necrosis factor alpha agents and the risk of lymphoma in patients with inflammatory bowel disease has already been sufficiently reported. However, the results of these studies are inconsistent. Hence, this analysis was conducted to investigate whether anti-tumor necrosis factor alpha agents can increase the risk of lymphoma in inflammatory bowel disease patients. MEDLINE, EMBASE and the Cochrane Library were searched to identify relevant studies which evaluated the risk of lymphoma in inflammatory bowel disease patients treated with anti-tumor necrosis factor alpha agents. A random-effects meta-analysis was performed to calculate the pooled incidence rate ratios as well as risk ratios. Twelve studies comprising 285811 participants were included. The result showed that there was no significantly increased risk of lymphoma between anti-tumor necrosis factor alpha agents exposed and anti-tumor necrosis factor alpha agents unexposed groups (random effects: incidence rate ratio [IRR], 1.43 95%CI, 0.91-2.25, p= 0.116; random effects: risk ratio [RR], 0.83 95%CI, 0.47-1.48, p=0.534). However, monotherapy of anti-tumor necrosis factor alpha agents (random effects: IRR=1.65, 95%CI, 1.16-2.35; p=0.006; random effects: RR=1.00, 95%CI, 0.39-2.59; p=0.996) or combination therapy (random effects: IRR=3.36, 95%CI, 2.23-5.05; ptumor necrosis factor alpha agents in patients with inflammatory bowel disease is not associated with a higher risk of lymphoma. Combination therapy and anti-tumor necrosis factor alpha agents monotherapy can significantly increase the risk of lymphoma in patients with inflammatory bowel disease.

[Anti-tumor effects of DDP-PLLA-CNTs on human cholangiocarcinoma cell line in vitro].

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Li, Maolan; Lu, Wei; Zhang, Fei; Ding, Qichen; Wu, Xiangsong; Tan, Zhujun; Wu, Wenguang; Weng, Hao; Wang, Xuefeng; Shi, Weibin; Dong, Ping; Gu, Jun; Liu, Yingbin

2014-11-04

To explore the antitumor effects of DDP-PLLA-CNTs on human cholangiocarcinoma cell line. DDP-PLLA-CNTs were prepared with the method of ultrasound emulsification. The morphology of DDP-PLLA-CNTs was determined by scanning electron microscope (SEM). And its drug loading and drug release curve in vitro was detected by UV-Vis-NIR spectrophotometer. CCK8 was used to test the cytotoxic effects of DDP-PLLA-CNTs at different concentrations on QBC939 cell proliferation.Flow cytometry was employed to measure the changes of apoptotic rate. With excellent controlled-release characteristic of in vitro drug release, DDP-PLLA-CNTs inhibited the proliferation and significantly increased the apoptotic rate of QBC939 cell line. DDP-PLLA-CNTs have drug sustained-release characteristics and can significantly inhibit the proliferation of QBC939 cell line.

Antitumor effect and toxicity of free rhodium (II) citrate and rhodium (II) citrate-loaded maghemite nanoparticles in mice bearing breast cancer.

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Carneiro, Marcella Lemos Brettas; Peixoto, Raphael C A; Joanitti, Graziela A; Oliveira, Ricardo G S; Telles, Luis A M; Miranda-Vilela, Ana L; Bocca, Anamélia L; Vianna, Leonora M S; da Silva, Izabel C R; de Souza, Aparecido R; Lacava, Zulmira G M; Báo, Sônia N

2013-02-16

Magnetic fluids containing superparamagnetic iron oxide nanoparticles represent an attractive platform as nanocarriers in chemotherapy. Recently, we developed a formulation of maghemite nanoparticles coated with rhodium (II) citrate, which resulted in in vitro cytotoxicity enhanced up to 4.6 times when compared to free rhodium (II) citrate formulation on breast carcinoma cells. In this work, we evaluate the antitumor activity and toxicity induced by these formulations in Balb/c mice bearing orthotopic 4T1 breast carcinoma. Mice were evaluated with regard to the treatments' toxicity through analyses of hemogram, serum levels of alanine aminotransferase, iron, and creatinine; DNA fragmentation and cell cycle of bone marrow cells; and liver, kidney and lung histology. In addition, the antitumor activity of rhodium (II) citrate and maghemite nanoparticles coated with rhodium (II) citrate was verified by tumor volume reduction, histology and immunohistochemistry. Regarding the treatments' toxicity, no experimental groups had alterations in levels of serum ALT or creatinine, and this suggestion was corroborated by the histopathologic examination of liver and kidney of mice. Moreover, DNA fragmentation frequency of bone marrow cells was lower than 15% in all experimental groups. On the other hand, the complexes rhodium (II) citrate-functionalized maghemite and free rhodium (II) citrate led to a marked growth inhibition of tumor and decrease in CD31 and Ki-67 staining. In summary, we demonstrated that both rhodium (II) citrate and maghemite nanoparticles coated with rhodium (II) citrate formulations exhibited antitumor effects against 4T1 metastatic breast cancer cell line following intratumoral administration. This antitumor effect was followed by inhibition of both cell proliferation and microvascularization and by tumor tissue injury characterized as necrosis and fibrosis. Remarkably, this is the first published report demonstrating the therapeutic efficacy of maghemite

Extraction of a Novel Cold-Water-Soluble Polysaccharide from Astragalus membranaceus and Its Antitumor and Immunological Activities

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An-jun Liu

2017-12-01

Full Text Available The polysaccharides of Astragalus membranaceus have received extensive study and attention, but there have been few reports on the extraction of these polysaccharides using cold water (4 °C. In this study, we fractionated a novel cold-water-soluble polysaccharide (cAMPs-1A from Astragalus membranaceus with a 92.00% carbohydrate content using a DEAE-cellulose 52 anion exchange column and a Sephadex G-100 column. Our UV, Fourier-transform infrared spectroscopy (FTIR, high-performance gel permeation chromatography, and ion chromatography analysis results indicated the monosaccharide composition of cAMPs-1A with 1.23 × 104 Da molecular weight to be fucose, arabinose, galactose, glucose, and xylose, with molar ratios of 0.01:0.06:0.20:1.00:0.06, respectively. The UV spectroscopy detected no protein and nucleic acid in cAMPs-1A. We used FTIR analysis to characterize the α-d-pyranoid configuration in cAMPs-1A. In addition, we performed animal experiments in vivo to evaluate the antitumor and immunomodulatory effects of cAMPs-1A. The results suggested that cAMPs-1A oral administration could significantly inhibit tumor growth with the inhibitory rate of 20.53%, 36.50% and 44.49%, respectively, at the dosage of 75,150, and 300 mg/kg. Moreover, cAMPs-1A treatment could also effectively protect the immune organs, promote macrophage pinocytosis, and improve the percentages of lymphocyte subsets in the peripheral blood of tumor-bearing mice. These findings demonstrate that the polysaccharide cAMPs-1A has an underlying application as natural antitumor agents.

Enhancement of intrinsic antitumor activity in spore-endotoxin mixtures of Bacillus thuringiensis by exposure to ultraviolet radiation

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Zamola, B; Karminski-Zamola, G; Fuks, Z; Kubovic, M [Zagreb Univ. (Yugoslavia); Wrishcer, M [Institut Rudjer Boskovic, Zagreb (Yugoslavia)

1985-03-01

Irradiation of spore-endotoxin mixtures from Bacillus thuringiensis cultures at 254 nm (60 ..mu..W cm/sup -2/) enhances their intrinsic antitumor potency as well as that of either component. The extent of enhancement depends on the length of exposure (optimum: 35 min) and may thus be due to photochemical changes of the endotoxin protein or/and to photoproduction of additional compounds with antitumor activity. Antitumor effects, expressed as survival rates of C57BL/6 mice inoculated with Lewis' mouse lung carcinoma and subjected to treatments 24 h later, depended on the number of doses of preparations administered (mixture, separated components).

Fraction From Lycium barbarum Polysaccharides Reduces Immunotoxicity and Enhances Antitumor Activity of Doxorubicin in Mice.

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Deng, Xiangliang; Luo, Shuang; Luo, Xia; Hu, Minghua; Ma, Fangli; Wang, Yuanyuan; Zhou, Lian; Huang, Rongrong

2018-01-01

The aim of the present study was to investigate whether fraction from Lycium barbarum polysaccharide (LBP) could reduce immunotoxicity and enhance antitumor activity of doxorubicin (Dox) in mice. A water-soluble LBP fraction, designated LBP3, was isolated from edible Chinese herbal Lycium barbarum and used in this study. To investigate the effect of LBP3 on Dox-induced immunotoxicity, tumor-free mice were used and treated with either normal saline, Dox, or Dox plus LBP3. To investigate the effect of LBP3 on antitumor activity of Dox, H22 tumor-bearing mice were used and treated with either normal saline, Dox, LBP3, or Dox plus LBP3. The results showed that LBP3 did not protect against the body weight loss caused by Dox, but it promoted the recovery of body weight starting at day 5 after Dox treatment in tumor-free mice. LBP3 also improved peripheral blood lymphocyte counts, promoted cell cycle recovery in bone marrow cells, and restored the cytotoxicity of natural killer cells. Furthermore, in H22 tumor-bearing mice, LBP3 enhanced antitumor activity of Dox and improved peripheral blood lymphocyte counts and the cytotoxicity of splenocytes. In brief, our results demonstrated that LBP3 could reduce the immunotoxicity and enhance antitumor activity of Dox.

Antitumor effects of metformin via indirect inhibition of protein phosphatase 2A in patients with endometrial cancer.

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Shinsuke Hanawa

Full Text Available Metformin, an antidiabetic drug, inhibits the endometrial cancer cell growth in vivo by improving the insulin resistance; however, its mechanism of action is not completely understood. Protein phosphatase 2A (PP2A is a serine/threonine phosphatase associated with insulin resistance and type 2 diabetes, and its inhibition restores the insulin resistance. This study investigated the antitumor effect of metformin on endometrial cancer with a focus on PP2A.Metformin (1,500-2,250 mg/day was preoperatively administered to patients with endometrial cancer for 4 to 6 weeks. Expression of the PP2A regulatory subunits, 4 (PPP2R4 and B (PP2A-B, was evaluated using real-time polymerase chain reaction (RT-PCR and immunohistochemistry (IHC using paired specimens obtained before and after metformin treatment. The effect of PPP2R4 inhibition with small interfering RNA was evaluated in the endometrial cancer cell lines HEC265 and HEC1B. P values of < .05 were considered statistically significant.Preoperative metformin treatment significantly reduced the expression of PP2A-B, as determined using IHC, and the mRNA expression of PPP2R4, as determined using RT-PCR, in the patients with endometrial cancer. However, metformin could not directly alter the PPP2R4 mRNA levels in the endometrial cancer cell lines in vitro. PPP2R4 knockdown reduced the proliferation and induced the apoptosis by activating caspases 3/7 in HEC265 and HEC1B cells.Downregulation of the PP2A-B subunit, including PPP2R4, is an important indirect target of metformin. Inhibition of PP2A may be an option for the treatment of endometrial cancer patients with insulin resistance.This trial is registered with UMIN-CTR (number UMIN000004852.

Effects of a piperidine ligand on DNA modification by antitumor cisplatin analogues

Czech Academy of Sciences Publication Activity Database

Kašpárková, Jana; Nováková, Olga; Najajreh, Y.; Gibson, D.; Perez, J.M.; Brabec, Viktor

2003-01-01

Roč. 16, č. 11 (2003), s. 1424-1432 ISSN 0893-228X R&D Projects: GA ČR GA305/02/1552; GA AV ČR KJB5004301; GA AV ČR IBS5004009 Institutional research plan: CEZ:AV0Z5004920 Keywords : DNA * piperidine ligand * antitumor cisplatin analogues Subject RIV: BO - Biophysics Impact factor: 3.332, year: 2003

Enhanced anti-tumor effect of a gene gun-delivered DNA vaccine encoding the human papillomavirus type 16 oncoproteins genetically fused to the herpes simplex virus glycoprotein D

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M.O. Diniz

2011-05-01

Full Text Available Anti-cancer DNA vaccines have attracted growing interest as a simple and non-invasive method for both the treatment and prevention of tumors induced by human papillomaviruses. Nonetheless, the low immunogenicity of parenterally administered vaccines, particularly regarding the activation of cytotoxic CD8+ T cell responses, suggests that further improvements in both vaccine composition and administration routes are still required. In the present study, we report the immune responses and anti-tumor effects of a DNA vaccine (pgD-E7E6E5 expressing three proteins (E7, E6, and E5 of the human papillomavirus type 16 genetically fused to the glycoprotein D of the human herpes simplex virus type 1, which was administered to mice by the intradermal (id route using a gene gun. A single id dose of pgD-E7E6E5 (2 µg/dose induced a strong activation of E7-specific interferon-γ (INF-γ-producing CD8+ T cells and full prophylactic anti-tumor effects in the vaccinated mice. Three vaccine doses inhibited tumor growth in 70% of the mice with established tumors. In addition, a single vaccine dose consisting of the co-administration of pgD-E7E6E5 and the vector encoding interleukin-12 or granulocyte-macrophage colony-stimulating factor further enhanced the therapeutic anti-tumor effects and conferred protection to 60 and 50% of the vaccinated mice, respectively. In conclusion, id administration of pgD-E7E6E5 significantly enhanced the immunogenicity and anti-tumor effects of the DNA vaccine, representing a promising administration route for future clinical trials.

Cytotoxic and Antitumor Effects of Curzerene from Curcuma longa.

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Wang, Youdi; Li, Jiahong; Guo, Jiquan; Wang, Qiyou; Zhu, Shuguang; Gao, Siyuan; Yang, Chen; Wei, Min; Pan, Xuediao; Zhu, Wei; Ding, Dongmei; Gao, Ruiping; Zhang, Wei; Wang, Junye; Zang, Linquan

2017-01-01

Curzerene is a sesquiterpene and component used in oriental medicine. It was originally isolated from the traditional Chinese herbal medicine Curcuma rhizomes. In this study, anticancer activity of curzerene was examined in both in vitro and in vivo models. The result of the MTT assay showed that curzerene exhibited antiproliferative effects in SPC-A1 human lung adenocarcinoma cells in a time-dependent and dose-dependent manner. The anticancer IC 50 s were 403.8, 154.8, and 47.0 µM for 24, 48, and 72 hours, respectively. The flow cytometry analysis indicated curzerene arrested the cells in the G2/M cell cycle and promoted or induced apoptosis of SPC-A1 cells. The percentage of cells arrested in the G2/M phase increased from 9.26 % in the control group cells to 17.57 % in the cells treated with the highest dose (100 µM) of curzerene. Western blot and RT-PCR analysis demonstrated that curzerene induced the downregulation of GSTA1 protein and mRNA expressions in SPC-A1 cells. Tumor growth was significantly inhibited in SPC-A1 cell-bearing nude mice by using curzerene (135 mg/kg daily), meanwhile, curzerene did not significantly affect body mass and the organs of the mice, which may indicate that curzerene has limited toxicity and side effects in vivo . In conclusion, curzerene could inhibit the proliferation of SPC-A1 human lung adenocarcinoma cells line in both in vitro and in vivo models. Focusing on its relationship with GSTA1, curzerene could induce the downregulation of GSTA1 protein and mRNA expressions in SPC-A1 cells. Curzerene might be used as an anti-lung adenocarcinoma drug candidate compound for further development. Georg Thieme Verlag KG Stuttgart · New York.

Lenalidomide, an anti-tumor drug, regulates retinal endothelial cell function: Implication for treating ocular neovascular disorder

International Nuclear Information System (INIS)

Dong, Ling-Feng; Yao, Jin; Wang, Xiao-Qun; Shan, Kun; Yang, Hong; Yan, Biao; Jiang, Qin

2015-01-01

Ocular angiogenesis is an important pathologic character of several ocular diseases, such as retinopathy of prematurity, diabetic retinopathy and age-related macular degeneration (AMD). Inhibition of ocular angiogenesis has great therapeutic value for treating these dieses. Here we show that lenalidomide, an anti-tumor drug, has great anti-angiogenic potential in ocular diseases. Lenalidomide inhibits retinal endothelial cell viability in normal and pathological condition, and inhibits VEGF-induced endothelial cell migration and tube formation in vitro. Moreover, lenalidomide inhibits ocular angiogenesis in vivo through the reduction of angiogenesis- and inflammation-related protein expression. Collectively, lenalidomide is a promising drug for treating ocular angiogenesis through its anti-proliferative and anti-inflammatory property. - Highlights: • Lenalidomide inhibits retinal endothelial cell viability in vitro. • Lenalidomide inhibits retinal endothelial cell migration and tube formation. • Lenalidomide inhibits pathological ocular angiogenesis in vivo. • Lenalidomide inhibits angiogenesis- and inflammation-related protein expression.

Lenalidomide, an anti-tumor drug, regulates retinal endothelial cell function: Implication for treating ocular neovascular disorder

Energy Technology Data Exchange (ETDEWEB)

Dong, Ling-Feng; Yao, Jin; Wang, Xiao-Qun; Shan, Kun; Yang, Hong [Eye Hospital, Nanjing Medical University, Nanjing (China); The Fourth School of Clinical Medicine, Nanjing Medical University, Nanjing (China); Yan, Biao, E-mail: yanbiao1982@hotmail.com [Eye Hospital, Nanjing Medical University, Nanjing (China); The Fourth School of Clinical Medicine, Nanjing Medical University, Nanjing (China); Jiang, Qin, E-mail: jiangqin710@126.com [Eye Hospital, Nanjing Medical University, Nanjing (China); The Fourth School of Clinical Medicine, Nanjing Medical University, Nanjing (China)

2015-10-02

Ocular angiogenesis is an important pathologic character of several ocular diseases, such as retinopathy of prematurity, diabetic retinopathy and age-related macular degeneration (AMD). Inhibition of ocular angiogenesis has great therapeutic value for treating these dieses. Here we show that lenalidomide, an anti-tumor drug, has great anti-angiogenic potential in ocular diseases. Lenalidomide inhibits retinal endothelial cell viability in normal and pathological condition, and inhibits VEGF-induced endothelial cell migration and tube formation in vitro. Moreover, lenalidomide inhibits ocular angiogenesis in vivo through the reduction of angiogenesis- and inflammation-related protein expression. Collectively, lenalidomide is a promising drug for treating ocular angiogenesis through its anti-proliferative and anti-inflammatory property. - Highlights: • Lenalidomide inhibits retinal endothelial cell viability in vitro. • Lenalidomide inhibits retinal endothelial cell migration and tube formation. • Lenalidomide inhibits pathological ocular angiogenesis in vivo. • Lenalidomide inhibits angiogenesis- and inflammation-related protein expression.

Bovine lactoferrin binds oleic acid to form an anti-tumor complex similar to HAMLET.

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Fang, Bing; Zhang, Ming; Tian, Mai; Jiang, Lu; Guo, Hui Yuan; Ren, Fa Zheng

2014-04-04

α-Lactalbumin (α-LA) can bind oleic acid (OA) to form HAMLET-like complexes, which exhibited highly selective anti-tumor activity in vitro and in vivo. Considering the structural similarity to α-LA, we conjectured that lactoferrin (LF) could also bind OA to obtain a complex with anti-tumor activity. In this study, LF-OA was prepared and its activity and structural changes were compared with α-LA-OA. The anti-tumor activity was evaluated by methylene blue assay, while the apoptosis mechanism was analyzed using flow cytometry and Western blot. Structural changes of LF-OA were measured by fluorescence spectroscopy and circular dichroism. The interactions of OA with LF and α-LA were evaluated by isothermal titration calorimetry (ITC). LF-OA was obtained by heat-treatment at pH8.0 with LD50 of 4.88, 4.95 and 4.62μM for HepG2, HT29, and MCF-7 cells, respectively, all of which were 10 times higher than those of α-LA-OA. Similar to HAMLET, LF-OA induced apoptosis in tumor cells through both death receptor- and mitochondrial-mediated pathways. Exposure of tryptophan residues and the hydrophobic regions as well as the loss of tertiary structure were observed in LF-OA. Besides these similarities, LF showed different secondary structure changes when compared with α-LA, with a decrease of α-helix and β-turn and an increase of β-sheet and random coil. ITC results showed that there was a higher binding number of OA to LF than to α-LA, while both of the proteins interacted with OA through van der Waals forces and hydrogen bonds. This study provides a theoretical basis for further exploration of protein-OA complexes. Copyright © 2013 The Authors. Published by Elsevier B.V. All rights reserved.

Smart Mesoporous Nanomaterials for Antitumor Therapy

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Marina Martínez-Carmona

2015-11-01

Full Text Available The use of nanomaterials for the treatment of solid tumours is receiving increasing attention by the scientific community. Among them, mesoporous silica nanoparticles (MSNs exhibit unique features that make them suitable nanocarriers to host, transport and protect drug molecules until the target is reached. It is possible to incorporate different targeting ligands to the outermost surface of MSNs to selectively drive the drugs to the tumour tissues. To prevent the premature release of the cargo entrapped in the mesopores, it is feasible to cap the pore entrances using stimuli-responsive nanogates. Therefore, upon exposure to internal (pH, enzymes, glutathione, etc. or external (temperature, light, magnetic field, etc. stimuli, the pore opening takes place and the release of the entrapped cargo occurs. These smart MSNs are capable of selectively reaching and accumulating at the target tissue and releasing the entrapped drug in a specific and controlled fashion, constituting a promising alternative to conventional chemotherapy, which is typically associated with undesired side effects. In this review, we overview the recent advances reported by the scientific community in developing MSNs for antitumor therapy. We highlight the possibility to design multifunctional nanosystems using different therapeutic approaches aimed at increasing the efficacy of the antitumor treatment.

Enhanced antitumor effects of novel intracellular delivery of an active form of menaquinone-4, menahydroquinone-4, into hepatocellular carcinoma.

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Setoguchi, Shuichi; Watase, Daisuke; Matsunaga, Kazuhisa; Matsubara, Misa; Kubo, Yohei; Kusuda, Mariko; Nagata-Akaho, Nami; Enjoji, Munechika; Nakashima, Manabu; Takeshita, Morishige; Karube, Yoshiharu; Takata, Jiro

2015-02-01

Reduced cellular uptake of menaquinone-4 (MK-4), a vitamin K2 homolog, in human hepatocellular carcinoma (HCC) limits its usefulness as a safe long-term antitumor agent for recurrent HCC and produces des-γ-carboxy prothrombin (DCP). We hypothesized that effective delivery of menahydroquinone-4 (MKH), the active form of MK-4 for γ-glutamyl carboxylation, into HCC cells is critical for regulating HCC growth, and may enable it to be applied as a safe antitumor agent. In this study, we verified this hypothesis using menahydroquinone-4 1,4-bis-N,N-dimethylglycinate hydrochloride (MKH-DMG), a prodrug of MKH, and demonstrated its effectiveness. Intracellular delivery of MKH and subsequent growth inhibition of PLC/PRF/5 and Hep3B (DCP-positive) and SK-Hep-1 (DCP-negative) cells after MKH-DMG administration were determined and compared with MK-4. The activity of MKH-DMG against tumor progression in the liver alongside DCP formation was determined in a spleen-liver metastasis mouse model. MKH-DMG exhibited greater intracellular delivery of MKH in vitro (AUC0-72 hour of MKH) and increased growth-inhibitory activity against both DCP-positive and DCP-negative HCC cell lines. The phenomena of MKH delivery into cells in parallel with simultaneous growth inhibition suggested that MKH is the active form for growth inhibition of HCC cells. Cell-cycle arrest was determined to be involved in the growth inhibition mechanisms of MKH-DMG. Furthermore, MKH-DMG showed significant inhibition of tumor progression in the liver, and a substantial decrease in plasma DCP levels in the spleen-liver metastasis mouse model. Our results suggest that MKH-DMG is a promising new candidate antitumor agent for safe long-term treatment of HCC. ©2014 American Association for Cancer Research.

Spin-labeled 1-alkyl-1-nitrosourea synergists of antitumor antibiotics.

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Gadjeva, V; Koldamova, R

2001-01-01

A new method for synthesis of four spin-labeled structural analogues of the antitumor drug 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU), using ethyl nitrite for nitrosation of the intermediate spin-labeled ureas has been described. In vitro synergistic effects of 1-ethyl-3-[4-(2,2,6,6-tetramethylpiperidine-1-oxyl)]-1-nitrosourea (3b) on the cytotoxicity of bleomycin and farmorubicin were found in human lymphoid leukemia tumor cells. We measured the tissue distribution of 3b in organ homogenates of C57BL mice by an electron paramagnetic resonance method. The spin-labeled nitrosourea was mainly localized in the lungs. Our results strongly support the development and validation of a new approach for synthesis of less toxic nitrosourea derivatives as potential synergists of antitumor drugs.

Hypoxia-targeted suicidal gene therapy system enhances antitumor effects of radiotherapy

International Nuclear Information System (INIS)

Liu Junye; Guo Yao; Guo Guozhen

2006-01-01

Objective: To explore the effects of hypoxia-targeted suicidal gene therapy system combined with radiotherapy on pancreatic cancer. Methods: The recombinant adenovirus Ad-5HRE/hCMVmp-BCD was constructed by DNA recombinant technique. Western blot was used to detect hypoxia-induced expression of bacterial cytosine deaminase (BCD). Cell growth inhibition assay was used to determine the sensitivity of human pancreatic cancer cells MIA-PACA2 to 5-fluorocytosine (5-FC). Tumor xenograft growth delay assays was used to evaluate the effects of Ad-5HRE/hCMVmp-BCD/5-FC combined with radiotherapy on pancreatic cancer. Results: Western blot analysis demonstrated that hypoxia-induced BCD protein expression was achieved in MIA-PACA2 cells infected with Ad-5HRE/hCMVmp-BCD. With hypoxia treatment, the sensitivity of MIA-PACA2 cells infected with Ad-5HRE/hCMVmp-BCD to 5-FC significantly increased. Administration of either Ad-5HRE/hCMVmp-BCD/5-FC or radiotherapy could inhibit the growth of MIA-PACA2 xenografts in nude mice. Moreover, combination of Ad-5HRE/hCMVmp-BCD/5-FC could significantly enhance suppressing effects of radiotherapy on MIA-PACA2 xenografts. Conclusion: Hypoxia-targeted suicidal gene therapy system Ad-5HRE/hCMVmp-BCD/5-FC could enhance antitumor effects of radiotherapy on pancreatic cancer and can be used as a powerful adjunct to conventional radiotherapy. (authors)

Anti-tumor effect and mechanism of cyclooxygenase-2 inhibitor through matrix metalloproteinase 14 pathway in PANC-1 cells.

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Li, Siyuan; Gu, Zhuoyu; Xiao, Zhiwei; Zhou, Ting; Li, Jun; Sun, Kan

2015-01-01

To investigate whether celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, can attenuate proliferation, migration, invasion and MMP-14 expression in pancreatic cancer cells PANC-1 and the possible anti-tumor mechanism of celecoxib. Human pancreatic cancer cell line PANC-1 cells were treated with diverse concentrations of celecoxib (20, 60, 100 μmol/L). Cell proliferation, invasion and migration capabilities were measured by MTT colorimetry, transwell invasion assay, and scratch assay separately. At the same time, the protein expression of COX-2 and MMP-14 was assessed by ELISA. The capabilities of proliferation, invasion and migration in PANC-1 cells were attenuated in a concentration-dependent manner after treated with celecoxib, followed by the down-regulation of the protein expression of COX-2 and MMP-14. In addition, MMP-14 expression was significantly positively correlated with COX-2 expression. COX-2 inhibitor celecoxib can inhibit the proliferation, invasion and migration of PANC-1 cells via down-regulating the expression of MMP-14 in a concentration-dependent manner, thus contributing to its anti-tumor effect in pancreatic cancer.

Antitumor effects of cecropin B-LHRH’ on drug-resistant ovarian and endometrial cancer cells

International Nuclear Information System (INIS)

Li, Xiaoyong; Shen, Bo; Chen, Qi; Zhang, Xiaohui; Ye, Yiqing; Wang, Fengmei; Zhang, Xinmei

2016-01-01

Luteinizing hormone-releasing hormone receptor (LHRHr) represents a promising therapeutic target for treating sex hormone-dependent tumors. We coupled cecropin B, an antimicrobial peptide, to LHRH’, a form of LHRH modified at carboxyl-terminal residues 4–10, which binds to LHRHr without interfering with luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion. This study aimed to assess the antitumor effects of cecropin B-LHRH’ (CB-LHRH’) in drug-resistant ovarian and endometrial cancers. To evaluate the antitumor effects of CB-LHRH’, three drug resistant ovarian cancer cell lines (SKOV-3, ES-2, NIH:OVCAR-3) and an endometrial cancer cell line (HEC-1A) were treated with CB-LHRH’. Cell morphology changes were assessed using inverted and electron microscopes. In addition, cell growth and cell cytotoxicity were measured by MTT assay and LDH release, respectively. In addition, hemolysis was measured. Furthermore, radioligand receptor binding, hypersensitization and minimal inhibitory concentrations (against Staphylococcus aureus, Klebsiella pneumoniae, Escherichia coli, Enterobacter cloacae, Pseudomonas aeruginosa, and Acinetobacter baumannii) were determined. Finally, the impact on tumor growth in BALB/c-nu mice was assessed in an ES-2 xenograft model. CB-LHRH’ bound LHRHr with high-affinity (dissociation constant, Kd = 0.252 ± 0.061nM). Interestingly, CB-LHRH’ significantly inhibited the cell viability of SKOV-3, ES-2, NIH:OVCAR-3 and HEC-1A, but not that of normal eukaryotic cells. CB-LHRH’ was active against bacteria at micromolar concentrations, and caused no hypersensitivity in guinea pigs. Furthermore, CB-LHRH’ inhibited tumor growth with a 23.8 and 20.4 % reduction in tumor weight at 50 and 25 mg/kg.d, respectively. CB-LHRH’ is a candidate for targeted chemotherapy against ovarian and endometrial cancers

Antioxidative and antitumor properties of in vitro-cultivated broccoli (Brassica oleracea var. italica).

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Cakar, Jasmina; Parić, Adisa; Maksimović, Milka; Bajrović, Kasim

2012-02-01

Broccoli [Brassica oleracea L. var. italica Plenck. (Brassicaceae)] contains substantial quantities of bioactive compounds, which are good free radical scavengers and thus might have strong antitumor properties. Enhancing production of plant secondary metabolites could be obtained with phytohormones that have significant effects on the metabolism of secondary metabolites. In that manner, in vitro culture presents good model for manipulation with plant tissues in order to affect secondary metabolite production and thus enhance bioactive properties of plants. Estimation of the antioxidative and antitumor properties of broccoli cultivated in different in vitro conditions. In vitro germinated and cultivated broccoli seedlings, as well as spontaneously developed calli, were subjected to Soxhlet extraction. Antioxidative activity of the herbal extracts was determined using 1,1-diphenyl-2-picrylhydrazyl (DPPH(•)) radical method. Antitumor properties of the extracts were determined using crown-gall tumor inhibition (potato disc) assay. Three, 10, 20, and 30 days old broccoli seedlings, cultivated in vitro on three different Murashige-Skoog media, two types of callus, and seedlings from sterile filter paper were used for extraction. In total, 15 aqueous extracts were tested for antioxidative and antitumor potential. Three day-old seedlings showed the highest antioxidative activity. Eleven out of 15 aqueous extracts demonstrated above 50% of crown-gall tumor inhibition in comparison with the control. Tumor inhibition was in association with types and concentrations of phytohormones presented in growing media. It is demonstrated that phytohormones in plant-growing media could affect the bioactive properties of broccoli either through increasing or decreasing their antioxidative and antitumor potential.

In vivo gene transfer using pDNA/chitosan/chondroitin sulfate ternary complexes: influence of chondroitin sulfate on the stability of freeze-dried complexes and transgene expression in vivo.

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Hagiwara, Kenji; Kishimoto, Satoko; Ishihara, Masayuki; Koyama, Yoshiyuki; Mazda, Osam; Sato, Toshinori

2013-02-01

Chitosan has been investigated as a promising nonviral vector. However, several problems still remain, such as a relatively low transfection efficiency and instability under physiological conditions. We previously demonstrated that a chondroitin sulfate (CS) coating enhanced the transfection efficiency and physicochemical stability of plasmid DNA (pDNA)/chitosan complexes in vitro. In the present study, the effects of coating pDNA/chitosan complexes with CS on the stability in freeze-dry rehydration processes and gene expression in vivo were investigated. Freeze-drying storage at -20 °C, 4 °C, or room temperature, freezing storage at -20 °C, or liquid storage at 4 °C or room temperature, were examined for preservation conditions of pDNA/chitosan/CS ternary complexes by a gel retardation assay, measurements of sizes and zeta potentials, and a luciferase assay. Moreover, to determine the transfection efficiency of the ternary complexes in vivo, suicide gene therapy was carried out in Huh-7-implanted mice using herpes simplex virus thymidine kinase coding pDNA and ganciclovir. The freeze-dried pDNA/chitosan/CS ternary complexes showed sufficient cell transfection ability in vitro and in vivo. In addition, ternary complexes were associated with a significant suppression of tumor growth and a histopathologically high anti-tumor effect by intratumoral injection to tumor-bearing mice. The CS coating enhanced the preservation stability of the pDNA/chitosan complexes after freeze-drying-rehydration and their transgene expression in vivo. Copyright © 2013 John Wiley & Sons, Ltd.

ATN-224 enhances antitumor efficacy of oncolytic herpes virus against both local and metastatic head and neck squamous cell carcinoma

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Ji Young Yoo

Full Text Available Head and neck squamous cell carcinoma (HNSCC is the sixth most frequent cancer worldwide, and the 5-year survival rates are among the worst of the major cancers. Oncolytic herpes simplex viruses (oHSV have the potential to make a significant impact in the targeted treatment of these patients. Here, we tested antitumor efficacy of RAMBO, an oHSV armed with the antiangiogenic Vstat120, alone and in conjunction with ATN-224, a copper chelator against HNSCC in vitro and in vivo animal models. We found that all tested HNSCC cells responded well to virus treatment and were sensitive to RAMBO-mediated oncolytic destruction. In vivo, RAMBO had a significant antiangiogenic and antitumorigenic effect. Physiologic levels of copper inhibited viral replication and HNSCC cell killing. Chelation of copper using ATN-224 treatment significantly improved serum stability of RAMBO and permitted systemic delivery in HNSCC tumor xenografts models. Furthermore, our results show that the combination of ATN-224 and RAMBO strongly inhibits lung metastases in a mouse model of HNSCC. These findings suggest that combining ATN-224 with RAMBO has potential for clinical trials in both early and advanced HNSCC patients.

Inhibition of protein kinase CK2 reduces CYP24A1 expression and enhances 1,25-dihydroxyvitamin D3 anti-tumor activity in human prostate cancer cells

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Luo, Wei; Yu, Wei-Dong; Ma, Yingyu; Chernov, Mikhail; Trump, Donald L.; Johnson, Candace S.

2013-01-01

Vitamin D has broad range of physiological functions and anti-tumor effects. 24-hydroxylase, encoded by the CYP24A1 gene, is the key enzyme for degrading many forms of vitamin D including the most active form, 1,25D3. Inhibition of CYP24A1 enhances 1,25D3 anti-tumor activity. In order to isolate regulators of CYP24A1 expression in prostate cancer cells, we established a stable prostate cancer cell line PC3 with CYP24A1 promoter driving luciferase expression to screen a small molecular library for compounds that inhibit CYP24A1 promoter activity. From this screening, we identified, 4,5,6,7-tetrabromobenzimidazole (TBBz), a protein kinase CK2 selective inhibitor as a disruptor of CYP24A1 promoter activity. We show that TBBz inhibits CYP24A1 promoter activity induced by 1,25D3 in prostate cancer cells. In addition, TBBz downregulates endogenous CYP24A1 mRNA level in TBBz treated PC3 cells. Furthermore, siRNA-mediated CK2 knockdown reduces 1,25D3 induced CYP24A1 mRNA expression in PC3 cells. These results suggest that CK2 contributes to 1,25D3 mediated target gene expression. Lastly, inhibition of CK2 by TBBz or CK2 siRNA significantly enhanced 1,25D3 mediated anti-proliferative effect in vitro and in vivo in a xenograft model. In summary, our findings reveal that protein kinase CK2 is involved in the regulation of CYP24A1 expression by 1,25D3 and CK2 inhibitor enhances 1,25D3 mediated anti-tumor effect. PMID:23358686

Chimeric peptide containing both B and T cells epitope of tumor-associated antigen L6 enhances anti-tumor effects in HLA-A2 transgenic mice.

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Lin, Su-I; Huang, Ming-Hsi; Chang, Yu-Wen; Chen, I-Hua; Roffler, Steve; Chen, Bing-Mae; Sher, Yuh-Pyng; Liu, Shih-Jen

2016-07-28

Synthetic peptides are attractive for cancer immunotherapy because of their safety and flexibility. In this report, we identified a new B cell epitope of tumor-associated antigen L6 (TAL6) that could induce antibody-dependent cellular cytotoxicity (ADCC) in vivo. We incorporated the B cell epitope with a cytotoxic T lymphocyte (CTL) and a helper T (Th) epitope to form a chimeric long peptide. We formulated the chimeric peptide with different adjuvants to immunize HLA-A2 transgenic mice and evaluate their immunogenicity. The chimeric peptide formulated with an emulsion type nanoparticle (PELC) adjuvant and a toll-like receptor 9 agonist (CpG ODN) (PELC/CpG) induced the greatest ADCC and CTL responses. The induced anti-tumor immunity inhibited the growth of TAL6-positive cancer cells. Moreover, we observed that immunization with the chimeric peptide inhibited cancer cell migration in vitro and metastasis in vivo. These data suggest that a chimeric peptide containing both B and T cell epitopes of TAL6 formulated with PELC/CpG adjuvant is feasible for cancer immunotherapy. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Potent anti-inflammatory effects of systemically-administered curcumin modulates periodontal disease in vivo

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Guimarães, Morgana R.; Coimbra, Leila S.; de Aquino, Sabrina Garcia; Spolidorio, Luis C.; Kirkwood, Keith L.; Junior, Carlos Rossa

2011-01-01

Background Curcumin is a plant-derived dietary spice with various biological activities, including anti-tumoral and anti-inflammatory. Its therapeutic applications have been studied in a variety of conditions, including rheumatoid arthritis, colon cancer and depression; but no studies evaluated the effects of curcumin on periodontal disease in vivo. Methods Experimental periodontal disease was induced in rats by placing cotton ligatures around both lower first molars. Curcumin was given to the rats intragastrically daily in two doses (30 and 100 mg/Kg) during 15 days. Control animals received ligatures but only the corn oil vehicle by gavage and no treatment negative control animals were included. Bone resorption was assessed by microcomputer tomography and the inflammatory status was evaluated by stereometric analysis. RT-qPCR and ELISA were used to determine the expression of interleukin (IL)-6, tumor necrosis factor (TNF)-alpha and prostaglandin E2 (PGE2) synthase on the gingival tissues. Modulation of p38 mitogen-activated protein kinase (MAPK) and NK-kB activation was assessed by western blot. Results Bone resorption was effectively induced in the experimental period, but it was not affected by either dose of curcumin. Curcumin effectively inhibited cytokine gene expression at mRNA and protein levels and dose-dependently inhibited activation of NF-kB in the gingival tissues. p38 MAPK activation was not inhibited by curcumin. Curcumin-treated animals also presented a marked reduction on the inflammatory cell infiltrate and increased collagen content and fibroblastic cell numbers. Conclusions Curcumin did not prevent alveolar bone resorption, but its potent anti-inflammatory effect suggests it may have a therapeutic potential in periodontal diseases. PMID:21306385

Enhanced anti-tumor activity of a new curcumin-related compound against melanoma and neuroblastoma cells

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Pastorino Fabio

2010-06-01

Full Text Available Abstract Background Sharing the common neuroectodermal origin, melanoma and neuroblastoma are tumors widely diffused among adult and children, respectively. Clinical prognosis of aggressive neuroectodermal cancers remains dismal, therefore the search for novel therapies against such tumors is warranted. Curcumin is a phytochemical compound widely studied for its antioxidant, anti-inflammatory and anti-cancer properties. Recently, we have synthesized and tested in vitro various curcumin-related compounds in order to select new anti-tumor agents displaying stronger and selective growth inhibition activity on neuroectodermal tumors. Results In this work, we have demonstrated that the new α,β-unsaturated ketone D6 was more effective in inhibiting tumor cells growth when compared to curcumin. Normal fibroblasts proliferation was not affected by this treatment. Clonogenic assay showed a significant dose-dependent reduction in both melanoma and neuroblastoma colony formation only after D6 treatment. TUNEL assay, Annexin-V staining, caspases activation and PARP cleavage unveiled the ability of D6 to cause tumor cell death by triggering apoptosis, similarly to curcumin, but with a stronger and quicker extent. These apoptotic features appear to be associated with loss of mitochondrial membrane potential and cytochrome c release. In vivo anti-tumor activity of curcumin and D6 was surveyed using sub-cutaneous melanoma and orthotopic neuroblastoma xenograft models. D6 treated mice exhibited significantly reduced tumor growth compared to both control and curcumin treated ones (Melanoma: D6 vs control: P and D6 vs curcumin P Neuroblastoma: D6 vs both control and curcumin: P . Conclusions Our data indicate D6 as a good candidate to develop new therapies against neural crest-derived tumors.

The Role of Bystander Effects in the Antitumor Activity of the Hypoxia-Activated Prodrug PR-104

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Foehrenbacher, Annika; Patel, Kashyap; Abbattista, Maria R.; Guise, Chris P.; Secomb, Timothy W.; Wilson, William R.; Hicks, Kevin O.

2013-01-01

Activation of prodrugs in tumors (e.g., by bioreduction in hypoxic zones) has the potential to generate active metabolites that can diffuse within the tumor microenvironment. Such “bystander effects” may offset spatial heterogeneity in prodrug activation but the relative importance of this effect is not understood. Here, we quantify the contribution of bystander effects to antitumor activity for the first time, by developing a spatially resolved pharmacokinetic/pharmacodynamic (SR-PK/PD) model for PR-104, a phosphate ester pre-prodrug that is converted systemically to the hypoxia-activated prodrug PR-104A. Using Green’s function methods we calculated concentrations of oxygen, PR-104A and its active metabolites, and resultant cell killing, at each point of a mapped three-dimensional tumor microregion. Model parameters were determined in vitro, using single cell suspensions to determine relationships between PR-104A metabolism and clonogenic cell killing, and multicellular layer (MCL) cultures to measure tissue diffusion coefficients. LC-MS/MS detection of active metabolites in the extracellular medium following exposure of anoxic single cell suspensions and MCLs to PR-104A confirmed that metabolites can diffuse out of cells and through a tissue-like environment. The SR-PK/PD model estimated that bystander effects contribute 30 and 50% of PR-104 activity in SiHa and HCT116 tumors, respectively. Testing the model by modulating PR-104A-activating reductases and hypoxia in tumor xenografts showed overall clonogenic killing broadly consistent with model predictions. Overall, our data suggest that bystander effects are important in PR-104 antitumor activity, although their reach may be limited by macroregional heterogeneity in hypoxia and reductase expression in tumors. The reported computational and experimental techniques are broadly applicable to all targeted anticancer prodrugs and could be used to identify strategies for rational prodrug optimization. PMID

Oncolytic Immunotherapy: Dying the Right Way is a Key to Eliciting Potent Antitumor Immunity

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Zong Sheng eGuo

2014-04-01

Full Text Available Oncolytic viruses (OVs are novel immunotherapeutic agents whose anticancer effects come from both oncolysis and elicited antitumor immunity. OVs induce mostly immunogenic cancer cell death (ICD, including immunogenic apoptosis, necrosis/necroptosis, pyroptosis and autophagic cell death, leading to exposure of calreticulin and heat-shock proteins to the cell surface, and/or released ATP, high mobility group box-1 [HMGB1], uric acid, and other DAMPs as well as PAMPs as danger signals, along with tumor-associated antigens, to activate dendritic cells (DCs and elicit adaptive antitumor immunity. Dying the right way may greatly potentiate adaptive antitumor immunity. The mode of cancer cell death may be modulated by individual OVs and cancer cells as they often encode and express genes that inhibit/promote apoptosis, necroptosis or autophagic cell death. We can genetically engineer OVs with death-pathway-modulating genes and thus skew the infected cancer cells towards certain death pathways for the enhanced immunogenicity. Strategies combining with some standard therapeutic regimens may also change the immunological consequence of cancer cell death. In this review, we discuss recent advances in our understanding of danger signals, modes of cancer cell death induced by OVs, the induced danger signals and functions in eliciting subsequent antitumor immunity. We also discuss potential combination strategies to target cells into specific modes of ICD and enhance cancer immunogenicity, including blockade of immune checkpoints, in order to break immune tolerance, improve antitumor immunity and thus the overall therapeutic efficacy.

Design, Synthesis and Biological Evaluation of C(6-Modified Celastrol Derivatives as Potential Antitumor Agents

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Kaiyong Tang

2014-07-01

Full Text Available New six C6-celastrol derivatives were designed, synthesized, and evaluated for their in vitro cytotoxic activities against nine human cancer cell lines (BGC-823, H4, Bel7402, H522, Colo 205, HepG2 and MDA-MB-468. The results showed that most of the compounds displayed potent inhibition against BGC823, H4, and Bel7402, with IC50s of 1.84–0.39 μM. The best compound NST001A was tested in an in vivo antitumor assay on nude mice bearing Colo 205 xenografts, and showed significant inhibition of tumor growth at low concentrations. Therefore, celastrol C-6 derivatives are potential drug candidates for treating cancer.

Promotion of Tumor Invasion by Cooperation of Granulocytes and Macrophages Activated by Anti-tumor Antibodies

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Emilio Barbera-Guillem

1999-11-01

Full Text Available We investigated the potential role of anti-tumor antibodies and tumor antigens in the formation of immune complexes which promote matrix degradation and angiogenesis. B-cell deficient or B-cell depleted mice showed a reduction in tumor invasion and metastasis. In vitro invasion assays and in vivo models of metastasis showed that anti-sTn antibodies and sTn tumor antigens form complexes which induce granulocytes and macrophages together to mediate tumor invasion and metastasis by processes including extracellular matrix degradation and angiogenesis. These results suggest the existence of a tumor promoting role of a B-cell immune response induced by shed tumor associated antigens of solid, nonlymphoid tumors.

Labeling of BCNU with 11C and 13N and its in vivo pharmacokinetics study with PET

International Nuclear Information System (INIS)

Diksic, M.; Farrokhzad, S.; Yamamoto, L.; Feindel, W.

1982-01-01

1,3-bis(2-chloroethyl)-1-nitrosourea(BCNU) is an antitumor drug. 13 N and 11 C labeled BCNU were synthesized and made suitable for in vivo studies with positron emission tomography (PET). The optimization of the labeling procedures were discussed with an emphasis on the radiochemical yield and specific activity of the final product

A Potent In Vivo Antitumor Efficacy of Novel Recombinant Type I Interferon.

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Zhang, Kang-Jian; Yin, Xiao-Fei; Yang, Yuan-Qin; Li, Hui-Ling; Xu, Yan-Ni; Chen, Lie-Yang; Liu, Xi-Jun; Yuan, Su-Jing; Fang, Xian-Long; Xiao, Jing; Wu, Shuai; Xu, Hai-Neng; Chu, Liang; Katlinski, Kanstantsin V; Katlinskaya, Yuliya V; Guo, Rong-Bing; Wei, Guang-Wen; Wang, Da-Cheng; Liu, Xin-Yuan; Fuchs, Serge Y

2017-04-15

Purpose: Antiproliferative, antiviral, and immunomodulatory activities of endogenous type I IFNs (IFN1) prompt the design of recombinant IFN1 for therapeutic purposes. However, most of the designed IFNs exhibited suboptimal therapeutic efficacies against solid tumors. Here, we report evaluation of the in vitro and in vivo antitumorigenic activities of a novel recombinant IFN termed sIFN-I. Experimental Design: We compared primary and tertiary structures of sIFN-I with its parental human IFNα-2b, as well as affinities of these ligands for IFN1 receptor chains and pharmacokinetics. These IFN1 species were also compared for their ability to induce JAK-STAT signaling and expression of the IFN1-stimulated genes and to elicit antitumorigenic effects. Effects of sIFN-I on tumor angiogenesis and immune infiltration were also tested in transplanted and genetically engineered immunocompetent mouse models. Results: sIFN-I displayed greater affinity for IFNAR1 (over IFNAR2) chain of the IFN1 receptor and elicited a greater extent of IFN1 signaling and expression of IFN-inducible genes in human cells. Unlike IFNα-2b, sIFN-I induced JAK-STAT signaling in mouse cells and exhibited an extended half-life in mice. Treatment with sIFN-I inhibited intratumoral angiogenesis, increased CD8 + T-cell infiltration, and robustly suppressed growth of transplantable and genetically engineered tumors in immunodeficient and immunocompetent mice. Conclusions: These findings define sIFN-I as a novel recombinant IFN1 with potent preclinical antitumorigenic effects against solid tumor, thereby prompting the assessment of sIFN-I clinical efficacy in humans. Clin Cancer Res; 23(8); 2038-49. ©2016 AACR . ©2016 American Association for Cancer Research.

Evaluation of a novel photosensitizing drug having antitumor effect for advanced prostate cancer

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Saito, Sachiko; Inai, Mizuho; Honda, Norihiro; Hazama, Hisanao; Kaneda, Yasufumi; Awazu, Kunio