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) towards the anti-tumor effects of enzalutamide. Crucially, KV-37 does not induce toxicity in non-malignant 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 (PSA) expression levels in CRPC cells 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.
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