Aldo-keto reductase 1C3 (AKR1C3), also known as type 5 17 β-hydroxysteroid dehydrogenase, is responsible for intratumoral androgen biosynthesis, contributing to the development of castration-resistant prostate cancer (CRPC) and eventual chemotherapeutic failure. Significant upregulation of AKR1C3 is observed in CRPC patient samples and derived CRPC cell lines. As AKR1C3 is a downstream steroidogenic enzyme synthesizing intratumoral testosterone (T) and 5α-dihydrotestosterone (DHT), the enzyme represents a promising therapeutic target to manage CRPC and combat the emergence of resistance to clinically employed androgen deprivation therapy. Herein, we demonstrate the antineoplastic activity of a potent, isoform-selective and hydrolytically stable AKR1C3 inhibitor (E)-3-(4-(3-methylbut-2-en-1-yl)-3-(3-phenylpropanamido)phenyl)acrylic acid (KV-37), which reduces prostate cancer cell growth in vitro and in vivo and sensitizes CRPC cell lines (22Rv1 and LNCaP1C3) toward the antitumor effects of enzalutamide. Crucially, KV-37 does not induce toxicity in nonmalignant WPMY-1 prostate cells nor does it induce weight loss in mouse xenografts. Moreover, KV-37 reduces androgen receptor (AR) transactivation and prostate-specific antigen expression levels in CRPC cell lines indicative of a therapeutic effect in prostate cancer. Combination studies of KV-37 with enzalutamide reveal a very high degree of synergistic drug interaction that induces significant reduction in prostate cancer cell viability via apoptosis, resulting in >200-fold potentiation of enzalutamide action in drug-resistant 22Rv1 cells. These results demonstrate a promising therapeutic strategy for the treatment of drug-resistant CRPC that invariably develops in prostate cancer patients following initial treatment with AR antagonists such as enzalutamide. Mol Cancer Ther; 17(9); 1833–45. ©2018 AACR.

中文翻译：

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AKR1C3 抑制剂 KV-37 在前列腺腺癌细胞的联合治疗中表现出抗肿瘤作用并增强 Enzalutamide

醛酮还原酶 1C3 (AKR1C3)，也称为 5 型 17 β-羟基类固醇脱氢酶，负责肿瘤内雄激素的生物合成，促进去势抵抗性前列腺癌 (CRPC) 的发展和最终的化疗失败。在 CRPC 患者样本和衍生的 CRPC 细胞系中观察到 AKR1C3 的显着上调。由于 AKR1C3 是一种合成瘤内睾酮 (T) 和 5α-二氢睾酮 (DHT) 的下游类固醇生成酶，该酶代表了一个有希望的治疗靶点，可用于管理 CRPC 和对抗对临床使用的雄激素剥夺疗法产生的耐药性。在此，我们证明了一种有效的、异构体选择性和水解稳定的 AKR1C3 抑制剂 (E)-3-(4-(3-methylbut-2-en-1-yl)-3-(3-phenylpropanamido)phenyl 的抗肿瘤活性)丙烯酸（KV-37），在体外和体内减少前列腺癌细胞的生长并使 CRPC 细胞系（22Rv1 和 LNCaP1C3）对恩杂鲁胺的抗肿瘤作用敏感。至关重要的是，KV-37 不会在非恶性 WPMY-1 前列腺细胞中诱导毒性，也不会在小鼠异种移植物中诱导体重减轻。此外，KV-37 降低了 CRPC 细胞系中的雄激素受体 (AR) 反式激活和前列腺特异性抗原表达水平，表明在前列腺癌中具有治疗效果。KV-37 与 enzalutamide 的联合研究揭示了一种非常高程度的协同药物相互作用，通过细胞凋亡诱导前列腺癌细胞活力显着降低，导致 enzalutamide 在耐药 22Rv1 细胞中的作用增强 200 倍以上。这些结果证明了治疗耐药性 CRPC 的有希望的治疗策略，在使用 AR 拮抗剂（如恩杂鲁胺）进行初始治疗后，前列腺癌患者总是会出现这种治疗策略。摩尔癌症治疗; 17(9); 1833-45 年。©2018 AACR。