MP83-20 ENZALUTAMIDE AS AN ANDROGEN RECEPTOR INHIBITOR PREVENTS UROTHELIAL TUMORIGENESIS

Abstract

You have accessJournal of UrologyBladder Cancer: Basic Research & Pathophysiology IV1 Apr 2016MP83-20 ENZALUTAMIDE AS AN ANDROGEN RECEPTOR INHIBITOR PREVENTS UROTHELIAL TUMORIGENESIS Takashi Kawahara, Hiroki Ide, Eiji Kashiwagi, Yi Li, Satoshi Inoue, Yichun Zheng, and Hiroshi Miyamoto Takashi KawaharaTakashi Kawahara More articles by this author , Hiroki IdeHiroki Ide More articles by this author , Eiji KashiwagiEiji Kashiwagi More articles by this author , Yi LiYi Li More articles by this author , Satoshi InoueSatoshi Inoue More articles by this author , Yichun ZhengYichun Zheng More articles by this author , and Hiroshi MiyamotoHiroshi Miyamoto More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2016.02.2202AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Emerging preclinical evidence suggests the critical role of androgen-mediated androgen receptor (AR) signals in the development of bladder cancer. However, little is known about the efficacy of enzalutamide, an AR signaling inhibitor that not only blocks androgen binding to AR but also prevents AR nuclear translocation, DNA binding, and coactivator recruitment, in urothelial tumorigenesis. In the current study, we aimed to assess the effects of enzalutamide as well as other anti-androgens, such as flutamide and bicalutamide, on androgen-induced neoplastic transformation of urothelial cells. METHODS An immortalized normal urothelial cell line SVHUC stably expressing wild-type AR (SVHUC-AR) was exposed to a chemical carcinogen 3-methylcholanthrene (MCA) 3 times, to induce neoplastic transformation, and subsequently cultured for 6 weeks in the presence or absence of anti-androgens. Tumorigenesis was then monitored, using plate and soft agar colony formation assays as well as mouse xenograft models. In the SVHUC-AR cells with the carcinogen challenge, quantitative real-time polymerase chain reaction analysis was also performed to determine the expression levels of tumor suppressor genes and oncogenes. RESULTS In SVHUC-AR cells, each anti-androgen was found to inhibit AR-mediated transcriptional activity. In vitro transformation showed that treatment with each anti-androgen during the process of neoplastic transformation similarly reduced the efficiency of colony formation in vitro. Compared with mock treatment, culture with enzalutamide (P = 0.028), hydroxyflutamide (P = 0.033), or bicalutamide (P = 0.038) also resulted in prevention/retardation of tumor formation in male NOD-SCID mice. Additionally, anti-androgens up-regulated the expression of several molecules that play a protective role in bladder tumorigenesis, including p53, p21, p27, and PTEN, and down-regulated that of several oncogenic genes, such as c-myc, cyclin D1, cyclin D3, and cyclin E, in MCA-exposed SVHUC-AR cells. However, significant effects of anti-androgens on the expression of these genes were not observed in SVHUC-AR cells without the carcinogen challenge. CONCLUSIONS Enzalutamide, flutamide, and bicalutamide similarly prevent neoplastic transformation of urothelial cells. These findings offer a potential chemopreventive approach for urothelial tumors using AR antagonists. © 2016FiguresReferencesRelatedDetails Volume 195Issue 4SApril 2016Page: e1088-e1089 Advertisement Copyright & Permissions© 2016MetricsAuthor Information Takashi Kawahara More articles by this author Hiroki Ide More articles by this author Eiji Kashiwagi More articles by this author Yi Li More articles by this author Satoshi Inoue More articles by this author Yichun Zheng More articles by this author Hiroshi Miyamoto More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...