MP49-16 ENZALUTAMIDE INHIBITS ANDROGEN RECEPTOR-POSITIVE BLADDER CANCER CELL GROWTH

Abstract

You have accessJournal of UrologyBladder Cancer: Basic Research III1 Apr 2015MP49-16 ENZALUTAMIDE INHIBITS ANDROGEN RECEPTOR-POSITIVE BLADDER CANCER CELL GROWTH Takashi Kawahara, Hiroki Ide, Eiji Kashiwagi, Leonardo Reis, 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 , Leonardo ReisLeonardo Reis 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.2015.02.2811AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Emerging preclinical evidence suggests the involvement of androgen-mediated androgen receptor (AR) signals in bladder cancer progression. 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 the growth of bladder cancer cells. In this study, we compared the effects of enzalutamide and 2 other anti-androgens, flutamide and bicalutamide, on androgen-induced bladder cancer cell proliferation, migration, and invasion. METHODS MTT assay, colony formation assay, scratch wound healing assay, transwell invasion assay, real-time polymerase chain reaction, and reporter gene assay were performed in AR-positive (e.g. UMUC3, TCCSUP, 5637-AR, 647V-AR) and AR-negative (e.g. UMUC3-AR-shRNA, TCCSUP-AR-shRNA, 5637, 647V) bladder cancer lines treated with dihydrotestosterone and/or each anti-androgen. We also used a mouse xenograft model for bladder cancer. RESULTS Dihydrotestosterone increased cell viability, colony formation, cell migration, and cell invasion, indicating that endogenous or exogenous AR was functional. Enzalutamide, hydroxyflutamide, and bicalutamide showed similar inhibitory effects, without significant agonist activity, on androgen-induced cell proliferation/migration/invasion in AR-positive lines. No significant effects of dihydrotestosterone as well as anti-androgens on the growth were seen in AR-negative cells. Correspondingly, in UMUC3 cells, these anti-androgens down-regulated androgen-induced expression of MMP-2 and IL-6. Androgen-enhanced AR-mediated transcriptional activity was also blocked by each anti-androgen exhibiting marginal agonist activity. In UMUC3 xenograft-bearing mice, oral gavage treatment with each anti-androgen retarded tumor growth, and enzalutamide showed more significant suppressive effects, compared with flutamide or bicalutamide treatment. CONCLUSIONS These findings support recent findings indicating that androgens promote bladder cancer progression via the AR pathway and further suggest that anti-androgens, including enzalutamide, are of therapeutic benefit in AR-positive bladder cancer. © 2015 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 193Issue 4SApril 2015Page: e608-e609 Advertisement Copyright & Permissions© 2015 by American Urological Association Education and Research, Inc.MetricsAuthor Information Takashi Kawahara More articles by this author Hiroki Ide More articles by this author Eiji Kashiwagi More articles by this author Leonardo Reis 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 ...