title: A demethylating agent enhances chemosensitivity to vinblastine in a xenograft model of renal cell carcinoma.
abstract: Renal cell carcinoma (RCC) is resistant to chemo-therapy partly due to the overexpression of the P-glycoprotein. Several tumor suppressor genes have been reported to be silenced by hypermethylation of the promoter region in RCC. We recently reported that the in vitro cytotoxicity of vinblastine (VBL) was enhanced by pre-treatment with the demethylating agent, 5-aza-2'-deoxycytidine (Aza), in the RCC cell line, Caki-1. In this study, we investigated the combined effect of Aza and VBL in a Caki-1 xenograft model and in other RCC cell lines in vitro. In the xenograft model, tumor volume and weight were significantly suppressed in the co-treatment group, compared to the control, and the expressions of P-glycoprotein, Bcl-2 and cyclin B1 were reduced. Thus, this combined effect could be mediated by the accumulation of intracellular VBL and the enhancement of apoptosis and cell cycle arrest. More-over, the cytotoxicity of VBL was enhanced in vitro in three RCC cell lines by Aza treatment. These findings suggest that the combination treatment with Aza and VBL is effective against RCC.
authors.affiliation: Department of Geriatric Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan. hirokiiwata@graduate.chiba-u.jp
authors.forename: Hiroki
authors.initials: H
authors.lastname: Iwata
authors.forename: Hiromi
authors.initials: H
authors.lastname: Sato
authors.forename: Rina
authors.initials: R
authors.lastname: Suzuki
authors.forename: Ryota
authors.initials: R
authors.lastname: Yamada
authors.forename: Saki
authors.initials: S
authors.lastname: Ichinomiya
authors.forename: Midori
authors.initials: M
authors.lastname: Yanagihara
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Okabe
authors.forename: Yuko
authors.initials: Y
authors.lastname: Sekine
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Yano
authors.forename: Koichi
authors.initials: K
authors.lastname: Ueno
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D002292:Carcinoma, Renal Cell / Q000188:drug therapy; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation / Q000235:genetics; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors*; D000077209:Decitabine; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D011401:Promoter Regions, Genetic; D040901:Proteomics; D014747:Vinblastine / Q000494:pharmacology* / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004791:Enzyme Inhibitors; D014747:Vinblastine; D000077209:Decitabine; D015254:DNA Modification Methylases; D001374:Azacitidine