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SYNERGISTIC ENHANCEMENT OF RESISTANCE TO CISPLATIN IN HUMAN BLADDER CANCER CELLS BY OVEREXPRESSION OF MUTANT-TYPE p53 AND Bcl-2

1999; Lippincott Williams & Wilkins; Volume: 162; Issue: 6 Linguagem: Inglês

10.1016/s0022-5347(05)68155-4

1527-3792

Hideaki Miyake, Isao Hara, Kazuki Yamanaka, Soichi Arakawa, Sadao Kamidono,

Cancer Research and Treatments

No AccessJournal of UrologyINVESTIGATIVE UROLOGY1 Dec 1999SYNERGISTIC ENHANCEMENT OF RESISTANCE TO CISPLATIN IN HUMAN BLADDER CANCER CELLS BY OVEREXPRESSION OF MUTANT-TYPE p53 AND Bcl-2 HIDEAKI MIYAKE, ISAO HARA, KAZUKI YAMANAKA, SOICHI ARAKAWA, and SADAO KAMIDONO HIDEAKI MIYAKEHIDEAKI MIYAKE More articles by this author , ISAO HARAISAO HARA More articles by this author , KAZUKI YAMANAKAKAZUKI YAMANAKA More articles by this author , SOICHI ARAKAWASOICHI ARAKAWA More articles by this author , and SADAO KAMIDONOSADAO KAMIDONO More articles by this author View All Author Informationhttps://doi.org/10.1016/S0022-5347(05)68155-4AboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract Purpose: The objective of this study was to characterize the effect of mutant-type p53 and Bcl-2 expression on the sensitivity to cisplatin in a human bladder cancer cell line both in vitro and in vivo. Materials and Methods: We transfected mutant-type p53 cDNA, Bcl-2 cDNA, or both cDNAs into KoTCC-1, a human bladder cancer cell line that does not express mutant-type p53 or Bcl-2 protein. The effects of the overexpression of mutant-type p53, Bcl-2, or both on the sensitivity to cisplatin and the apoptotic features in vitro were evaluated by the MTT assay, staining with Hoechst 33258 and a DNA fragmentation assay. We then examined the in vivo effects of cisplatin treatment on the transfectants by subcutaneous and intraperitoneal tumor cell injection models in athymic nude mice. Results: The introduction of mutant-type p53 or Bcl-2 conferred resistance to cisplatin on KoTCC-1 cells through the inhibition of apoptosis. This phenotype was more remarkable in the cell line transfected with both mutant-type p53 and Bcl-2 than in the cell lines transfected with either mutant-type p53 or Bcl-2 alone. Furthermore, the KoTCC-1 cells transfected with both mutant-type p53 and Bcl-2 exhibited significantly higher resistance to cisplatin treatment than cells transfected with mutant-type p53 or Bcl-2 alone in experimental models in vivo. Conclusions: These findings suggest that the overexpression of both mutant-type p53 and Bcl-2 in bladder cancer cells synergistically interferes with the therapeutic effect of cisplatin through the inhibition of the apoptotic pathway. References 1 : Current management of invasive and metastatic transitional cell carcinoma of the bladder. J. Urol.1993; 149: 957. Google Scholar 2 : Cellular response to cisplatin. J. Biol. Chem.1994; 269: 787. Google Scholar 3 : Long-term results of neoadjuvant M-VAC (methotrexate, vinblastine, doxorubicin, and cisplatin) for locally invasive transitional cell carcinoma of the urothelium. Int. J. Clin. Oncol.1999; 4: 32. Google Scholar 4 : The control of apoptosis and drug resistance in ovarian cancer: influence of p53 and Bcl-2. Oncogene1995; 11: 1217. Google Scholar 5 : Mutations in the p53 gene occur in diverse human tumor types. Nature1989; 342: 705. Google Scholar 6 : Expression of the mutated p53 tumor suppressor protein and its molecular and biochemical characterization in multidrug resistant MCF-7/Adr human breast cancer cells. Oncogene1997; 14: 499. Google Scholar 7 : Bcl-2 and the regulation of programmed cell death. J. Cell Biol.1994; 124: 1. Google Scholar 8 : Overexpression of Bcl-2 in bladder cancer cells inhibits apoptosis induced by cisplatin and adenoviral-mediated p53 gene transfer. Oncogene1998; 16: 933. Google Scholar 9 : Absence of p53 overexpression and favorable response to cisplatin-based neoadjuvant chemotherapy in urothelial carcinomas. Jpn. J. Cancer Res.1998; 89: 214. Google Scholar 10 : Enhancement of chemosensitivity in human bladder cancer cells by adenoviral-mediated p53 gene transfer. Anticancer Res.1998; 18: 3087. Google Scholar 11 : Abrogation of apoptosis induced by DNA-damaging agents in human bladder cancer cell lines with p21/WAF1/CIP1 and/or p53 gene alterations. Int. J. Cancer1996; 68: 501. Google Scholar 12 : Basic fibroblast growth factor regulates matrix metalloproteinases production and in vitro invasiveness in human bladder cancer cell lines. J. Urol.1997; 157: 2351. Link, Google Scholar 13 : p53 modulation of Fas/Apo-1 mediated apoptosis in a human renal cell carcinoma cell line. Int. J. Oncol.1998; 12: 469. Google Scholar 14 : Expression of basic fibroblast growth factor is associated with resistance to cisplatin in a human bladder cancer cell line. Cancer Lett.1998; 123: 121. Google Scholar 15 : Accumulation of nuclear p53 and tumor progression in bladder cancer. N. Engl. J. Med.1994; 331: 1259. Google Scholar 16 : Incidence of apoptosis, cell proliferation and bcl-2 expression in transitional cell carcinoma of the bladder: association with tumor progression. J. Urol.1996; 155: 316. Link, Google Scholar 17 : p53-dependent apoptosis modulates the cytotoxicity of anticancer agents. Cell1993; 74: 957. Google Scholar 18 : Drug-induced apoptosis in B-cell chronic lymphocytic leukemia: relationship between p53 gene mutation and bcl- 2/bax proteins in drug resistance. Oncogene1996; 12: 1055. Google Scholar 19 : Inactivation of p53 enhances sensitivity to multiple chemotherapeutic agents. Cancer Res.1996; 56: 892. Google Scholar From the Department of Urology, Kobe University School of Medicine, Kobe, Japan© 1999 by American Urological Association, Inc.FiguresReferencesRelatedDetailsCited ByMCKNIGHT J, GRAY S, O’KANE H, JOHNSTON S and WILLIAMSON K (2018) APOPTOSIS AND CHEMOTHERAPY FOR BLADDER CANCERJournal of Urology, VOL. 173, NO. 3, (683-690), Online publication date: 1-Mar-2005.CHANG F and LAI M (2018) VARIOUS FORMS OF MUTANT p53 CONFER SENSITIVITY TO CISPLATIN AND DOXORUBICIN IN BLADDER CANCER CELLSJournal of Urology, VOL. 166, NO. 1, (304-310), Online publication date: 1-Jul-2001. Volume 162Issue 6December 1999Page: 2176-2181 Advertisement Copyright & Permissions© 1999 by American Urological Association, Inc.Keywordsbladder cancerBcl-2chemoresistancemutant-type p53MetricsAuthor Information HIDEAKI MIYAKE More articles by this author ISAO HARA More articles by this author KAZUKI YAMANAKA More articles by this author SOICHI ARAKAWA More articles by this author SADAO KAMIDONO More articles by this author Expand All Advertisement PDF DownloadLoading ...