Overcoming prostate cancer drug resistance with a novel organosilicon small molecule

• Type of Material: Article
• Authors: Rui Zhao, Jilin University; Xiaowei Ma, Augusta University; Lijuan Bai, Augusta University; Xin Li, Augusta University; Kenza Mamouni, Augusta University; Yang Yang, Augusta University; Hongyan Liu, University of Washington; Alira Danaher, Clark Atlanta University; Nicholas Cook, Clark Atlanta University; Omer Kucuk, Emory University; Robert S Hodges, University of Colorado Anschutz Medical Campus; Lajos Gera, University of Colorado Anschutz Medical Campus; Daqing Wu, Emory University
• Language: English
• Date: 2021-11-12
• Publisher: ELSEVIER SCIENCE INC
• Publication Version: Final Published Version
• Copyright Statement: © 2021 The Authors. Published by Elsevier Inc.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.neo.2021.11.006
• Title of Journal or Parent Work: NEOPLASIA
• Volume: 23
• Issue: 12
• Start Page: 1261
• End Page: 1274
• Keywords: THERAPY; Science & Technology; ANDROGEN RECEPTOR; PROGRESSION; CELLS; DOCETAXEL RESISTANCE; Life Sciences & Biomedicine; AR-V7; Silicon-containing compounds; Prostate cancer; DEGRADATION; Oncology; Chemoresistance; Castration-resistance; Small-molecule therapy; MULTIDRUG-RESISTANCE; EXPRESSION; MECHANISMS; Preclinical studies
• Research Categories: Chemistry, Biochemistry; Health Sciences, Oncology

Abstract

A major challenge to the treatment of advanced prostate cancer (PCa) is the development of resistance to androgen-deprivation therapy (ADT) and chemotherapy. It is imperative to discover effective therapies to overcome drug resistance and improve clinical outcomes. We have developed a novel class of silicon-containing compounds and evaluated the anticancer activities and mechanism of action using cellular and animal models of drug-resistant PCa. Five organosilicon compounds were evaluated for their anticancer activities in the NCI-60 panel and established drug-resistant PCa cell lines. GH1504 exhibited potent in vitro cytotoxicity in a broad spectrum of human cancer cells, including PCa cells refractory to ADT and chemotherapy. Molecular studies identified several potential targets of GH1504, most notably androgen receptor (AR), AR variant 7 (AR-v7) and survivin. Mechanistically, GH1504 may promote the protein turnover of AR, AR-v7 and survivin, thereby inducing apoptosis in ADT-resistant and chemoresistant PCa cells. Animal studies demonstrated that GH1504 effectively inhibited the in vivo growth of ADT-resistant CWR22Rv1 and chemoresistant C4-2B-TaxR xenografts in subcutaneous and intraosseous models. These preclinical results indicated that GH1504 is a promising lead that can be further developed as a novel therapy for drug-resistant PCa.