Overcoming prostate cancer drug resistance with a novel organosilicon small molecule

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...

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Autores principales:	Rui Zhao, Xiaowei Ma, Lijuan Bai, Xin Li, Kenza Mamouni, Yang Yang, HongYan Liu, Alira Danaher, Nicholas Cook, Omer Kucuk, Robert S. Hodges, Lajos Gera, Daqing Wu
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	Prostate cancer Castration-resistance Chemoresistance Small-molecule therapy Silicon-containing compounds Preclinical studies Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/1f6b060eb516456db0aa542c6160f224
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spelling	oai:doaj.org-article:1f6b060eb516456db0aa542c6160f2242021-11-30T04:14:41ZOvercoming prostate cancer drug resistance with a novel organosilicon small molecule1476-558610.1016/j.neo.2021.11.006https://doaj.org/article/1f6b060eb516456db0aa542c6160f2242021-12-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S1476558621000968https://doaj.org/toc/1476-5586A 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.Rui ZhaoXiaowei MaLijuan BaiXin LiKenza MamouniYang YangHongYan LiuAlira DanaherNicholas CookOmer KucukRobert S. HodgesLajos GeraDaqing WuElsevierarticleProstate cancerCastration-resistanceChemoresistanceSmall-molecule therapySilicon-containing compoundsPreclinical studiesNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENNeoplasia: An International Journal for Oncology Research, Vol 23, Iss 12, Pp 1261-1274 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Prostate cancer Castration-resistance Chemoresistance Small-molecule therapy Silicon-containing compounds Preclinical studies Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	Prostate cancer Castration-resistance Chemoresistance Small-molecule therapy Silicon-containing compounds Preclinical studies Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Rui Zhao Xiaowei Ma Lijuan Bai Xin Li Kenza Mamouni Yang Yang HongYan Liu Alira Danaher Nicholas Cook Omer Kucuk Robert S. Hodges Lajos Gera Daqing Wu Overcoming prostate cancer drug resistance with a novel organosilicon small molecule
description	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.
format	article
author	Rui Zhao Xiaowei Ma Lijuan Bai Xin Li Kenza Mamouni Yang Yang HongYan Liu Alira Danaher Nicholas Cook Omer Kucuk Robert S. Hodges Lajos Gera Daqing Wu
author_facet	Rui Zhao Xiaowei Ma Lijuan Bai Xin Li Kenza Mamouni Yang Yang HongYan Liu Alira Danaher Nicholas Cook Omer Kucuk Robert S. Hodges Lajos Gera Daqing Wu
author_sort	Rui Zhao
title	Overcoming prostate cancer drug resistance with a novel organosilicon small molecule
title_short	Overcoming prostate cancer drug resistance with a novel organosilicon small molecule
title_full	Overcoming prostate cancer drug resistance with a novel organosilicon small molecule
title_fullStr	Overcoming prostate cancer drug resistance with a novel organosilicon small molecule
title_full_unstemmed	Overcoming prostate cancer drug resistance with a novel organosilicon small molecule
title_sort	overcoming prostate cancer drug resistance with a novel organosilicon small molecule
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/1f6b060eb516456db0aa542c6160f224
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Overcoming prostate cancer drug resistance with a novel organosilicon small molecule

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