Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center, School of Pharmacy, Amarillo, Texas.
Center of Excellence in Environmental Toxicology, Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
Mol Cancer Ther. 2018 Sep;17(9):1833-1845. doi: 10.1158/1535-7163.MCT-17-1023. Epub 2018 Jun 11.
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 ()-3-(4-(3-methylbut-2-en-1-yl)-3-(3-phenylpropanamido)phenyl)acrylic acid (), which reduces prostate cancer cell growth and and sensitizes CRPC cell lines (22Rv1 and LNCaP1C3) toward the antitumor effects of enzalutamide. Crucially, does not induce toxicity in nonmalignant WPMY-1 prostate cells nor does it induce weight loss in mouse xenografts. Moreover, 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 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. .
醛酮还原酶 1C3（AKR1C3），也称为 5 型 17β-羟甾脱氢酶，负责肿瘤内雄激素的生物合成，导致去势抵抗性前列腺癌（CRPC）的发展和最终化疗失败。在 CRPC 患者样本和衍生的 CRPC 细胞系中观察到 AKR1C3 的显著上调。由于 AKR1C3 是一种合成肿瘤内睾酮（T）和 5α-二氢睾酮（DHT）的下游甾体生成酶，该酶代表了一种有前途的治疗靶点，可用于管理 CRPC 并对抗临床应用的雄激素剥夺疗法的耐药性出现。本文证明了一种强效、同工型选择性和水解稳定的 AKR1C3 抑制剂 ()-3-(4-(3-甲基-2-丁烯-1-基)-3-(3-苯丙酰胺基)苯基)丙烯酸（）的抗肿瘤活性，该抑制剂可降低前列腺癌细胞生长和，并使 CRPC 细胞系（22Rv1 和 LNCaP1C3）对恩扎卢胺的抗肿瘤作用敏感。至关重要的是，在非恶性 WPMY-1 前列腺细胞中不会诱导毒性，也不会在小鼠异种移植中引起体重减轻。此外，在 CRPC 细胞系中，降低了雄激素受体（AR）的反式激活和前列腺特异性抗原的表达水平，表明在前列腺癌中具有治疗作用。与恩扎卢胺的联合研究表明，药物相互作用具有非常高的协同作用，通过凋亡诱导显著降低前列腺癌细胞活力，导致耐药性 22Rv1 细胞中恩扎卢胺作用增强 200 多倍。这些结果表明，对于治疗去势抵抗性 CRPC 是一种很有前途的治疗策略，在前列腺癌患者初始接受 AR 拮抗剂（如恩扎卢胺）治疗后，这种 CRPC 不可避免地会发展。
