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.

Inhibition of Androgen Signalling Improves the Outcomes of Therapies for Bladder Cancer: Results from a Systematic Review of Preclinical and Clinical Evidence and Meta-Analysis of Clinical Studies

“…Despite these findings, the differential impact of different subtypes of androgen suppression modalities on BCa behaviour in preclinical models remains controversial. Indeed, in their in vitro study, Nagata et al demonstrated that, unlike androgen receptor antagonists, 5-ARIs have no significant impact on the development and progression of urothelial cancer [ 27 ].…”

Finasteride Use and Risk of Bladder Cancer in a Multiethnic Population

“…Efforts to demonstrate an inhibitory effect on tumorigenesis by 5ARIs in vitro and in vivo have failed. 24,25…”

“…Efforts to demonstrate an inhibitory effect on tumorigenesis by 5ARIs in vitro and in vivo have failed. 24,25 Moschini et al performed a risk regression analysis of 196,914 patients with histologically confirmed localized prostate cancer identified in the Surveillance, Epidemiology, and End Results-Medicare insurance program linked database to examine whether patients who had received androgen deprivation therapy (34.7%) would have a lower incidence of BCa (1.3%). 13 The treated group and untreated group had similar risks of BCa incidence, leading the authors to conclude that ADT had no impact on BCa risk.…”

Mineralocorticoid receptor signaling inhibits bladder cancer progression

“…This was further confirmed by the promotion of the cell growth by MR knockdown. We then examined the potential downstream targets of MR that had been known to involve urothelial cancer outgrowth [20][21][22][23][24][25][26][27][28]. We found that the expression levels of MR in bladder cancer cells were positively and inversely associated with those of tumor suppressive E-cadherin and p53, and oncogenic molecules, including β-catenin, c-fos, and N-cadherin, respectively.…”

“…We next assessed the impact of MR signaling on the expression of several molecules known to involve urothelial cancer progression, including β-catenin [20,21], c-fos [22,23], E-cadherin [24,25], N-cadherin [25,26], and p53 [27,28]. Western blotting in control vs. MRknockdown sublines consistently demonstrated that the expression levels of MR was inversely or positively correlated with those of β-catenin/c-fos/N-cadherin or E-cadherin/p53, respectively (Figure 9).…”