5α-Reductase Inhibitors Do Not Prevent the Development and Progression of Urothelial Cancer: In Vitro Evidence

Abstract

BACKGROUND: Androgen receptor (AR) activation has been implicated in the pathogenesis of urothelial cancer. However, it remains controversial whether 5α-reductase inhibitors (5α-RIs), which are known for blocking the conversion of testosterone to the more potent androgen dihydrotestosterone and often prescribed for the treatment of, for instance, benign prostatic hyperplasia, contribute to preventing the development of bladder cancer. OBJECTIVE: To determine the role of 5α-RI therapy in urothelial tumorigenesis and tumor progression, using cell line models. METHODS: In a human non-neoplastic urothelial SVHUC subline stably expressing a full-length wild-type human AR (SVHUC-AR) with carcinogen/MCA challenge and human bladder cancer lines, we assessed the effects of three 5α-RIs, dutasteride (up to 100 nM), finasteride (up to 500 nM), and epristeride (up to 5μM), on neoplastic/malignant transformation and cell growth, respectively. RESULTS: In AR-positive bladder cancer UMUC3 and 5637-AR cells, an AR antagonist bicalutamide significantly inhibited their proliferation, whereas three 5α-RIs failed to do. Similarly, these 5α-RIs did not significantly inhibit the migration of bladder cancer cells induced by the treatment of testosterone which could be metabolized into dihydrotestosterone in culture medium. In MCA-SVHUC-AR cells, induction of their neoplastic transformation by testosterone, which was prevented by bicalutamide, was confirmed. However, no significant inhibitory effects of 5α-RIs on the neoplastic transformation of AR-positive urothelial cells treated with or without testosterone were observed. CONCLUSIONS: Using in vitro models for urothelial cancer, 5α-RI treatment even at supra-pharmacological doses was thus found to have no significant impact on the prevention of both tumorigenesis and tumor progression.