AKR1C3 inhibitor KV-37 exhibits antineoplastic effects and potentiates enzalutamide in combination therapy in prostate adenocarcinoma cells

Kshitij Verma, Nehal Gupta, Tianzhu Zang, Phumvadee Wangtrakluldee, Sanjay K. Srivastava, Trevor M. Penning, Paul C. Trippier

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

Aldo-keto reductase 1C3 (AKR1C3), also known as type 5 17 b-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 5a-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.

Original languageEnglish (US)
Pages (from-to)1833-1845
Number of pages13
JournalMolecular cancer therapeutics
Volume17
Issue number9
DOIs
StatePublished - Sep 2018

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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