Overcoming prostate cancer drug resistance with a novel organosilicon small molecule

Rui Zhao, Xiaowei Ma, Lijuan Bai, Xin Li, Kenza Mamouni, Yang Yang, Hong Yan Liu, Alira Danaher, Nicholas Cook, Omer Kucuk, Robert S. Hodges, Lajos Gera, Daqing Wu

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)1261-1274
Number of pages14
JournalNeoplasia (United States)
Volume23
Issue number12
DOIs
StatePublished - Dec 2021
Externally publishedYes

Keywords

  • Castration-resistance
  • Chemoresistance
  • Preclinical studies
  • Prostate cancer
  • Silicon-containing compounds
  • Small-molecule therapy

ASJC Scopus subject areas

  • Cancer Research

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