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.

中文翻译：

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5α-还原酶抑制剂不能预防尿路上皮癌的发展和进展：体外证据

背景：雄激素受体（AR）激活与尿路上皮癌的发病有关。但是，是否存在已知的5α-还原酶抑制剂（5α-RIs）能够阻止睾丸激素向更强效的雄激素二氢睾丸激素的转化，并且通常被指定用于治疗例如良性前列腺增生，是否仍存在争议。膀胱癌的发展。目的：利用细胞系模型确定5α-RI疗法在尿路上皮肿瘤发生和进展中的作用。方法：在稳定表达全长野生型人AR（SVHUC-AR），致癌物/ MCA攻击和人膀胱癌的人非肿瘤尿路上皮SVHUC亚系中，我们评估了3种5α-RIs，度他雄胺（最高100 nM），非那雄胺（最高500 nM），和epristeride（最高5μM），分别针对肿瘤/恶性转化和细胞生长。结果：在AR阳性膀胱癌UMUC3和5637-AR细胞中，AR拮抗剂比卡鲁胺明显抑制了它们的增殖，而三个5α-RI则不能。同样，这些5α-RIs并没有显着抑制由睾丸激素治疗诱导的膀胱癌细胞迁移，睾丸激素可以在培养基中代谢成二氢睾丸激素。在MCA-SVHUC-AR细胞中，已确认比卡鲁胺可阻止睾丸激素诱导的肿瘤转化。然而，没有观察到5α-RIs对用或不用睾丸激素处理的AR阳性尿道上皮细胞的肿瘤转化有明显的抑制作用。结论：使用尿路上皮癌的体外模型，