Topoisomerase II alpha inhibition can overcome taxane-resistant prostate cancer through DNA repair pathways

Abstract Cabazitaxel (CBZ) is approved for the treatment of docetaxel-resistant castration-resistant prostate cancer (CRPC). However, its efficacy against CRPC is limited, and there are no effective treatments for CBZ-resistant CRPC. This study explored the optimal treatment for CRPC in the post-cab...

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Autores principales:	Hiroshi Hongo, Takeo Kosaka, Yoko Suzuki, Shuji Mikami, Junichi Fukada, Mototsugu Oya
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/56f8f480566741bda2848c462abb3516
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spelling	oai:doaj.org-article:56f8f480566741bda2848c462abb35162021-11-21T12:23:35ZTopoisomerase II alpha inhibition can overcome taxane-resistant prostate cancer through DNA repair pathways10.1038/s41598-021-01697-22045-2322https://doaj.org/article/56f8f480566741bda2848c462abb35162021-11-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-01697-2https://doaj.org/toc/2045-2322Abstract Cabazitaxel (CBZ) is approved for the treatment of docetaxel-resistant castration-resistant prostate cancer (CRPC). However, its efficacy against CRPC is limited, and there are no effective treatments for CBZ-resistant CRPC. This study explored the optimal treatment for CRPC in the post-cabazitaxel setting. PC3 (CBZ-sensitive) and PC3CR cells (CBZ-resistant) were used in this study. We performed in silico drug screening for candidate drugs that could reprogram the gene expression signature of PC3CR cells. The in vivo effect of the drug combination was tested in xenograft mice models. We identified etoposide (VP16) as a promising treatment candidate for CBZ-resistant CRPC. The WST assay revealed that VP16 had a significant antitumor effect on PC3CR cells. PC3CR cells exhibited significantly higher topoisomerase II alpha (TOP2A) expression than PC3 cells. Higher TOP2A expression was a poor prognostic factor in The Cancer Genome Atlas prostate cancer cohort. In the Fred Hutchinson Cancer Research Center dataset, docetaxel-exposed tissues and metastatic tumors had higher TOP2A expression. In addition, VP16 significantly inhibited the growth of tumors generated from both cell lines. Based on these findings, VP16-based chemotherapy may be an optimal treatment for CPRC in the post-CBZ setting.Hiroshi HongoTakeo KosakaYoko SuzukiShuji MikamiJunichi FukadaMototsugu OyaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Hiroshi Hongo Takeo Kosaka Yoko Suzuki Shuji Mikami Junichi Fukada Mototsugu Oya Topoisomerase II alpha inhibition can overcome taxane-resistant prostate cancer through DNA repair pathways
description	Abstract Cabazitaxel (CBZ) is approved for the treatment of docetaxel-resistant castration-resistant prostate cancer (CRPC). However, its efficacy against CRPC is limited, and there are no effective treatments for CBZ-resistant CRPC. This study explored the optimal treatment for CRPC in the post-cabazitaxel setting. PC3 (CBZ-sensitive) and PC3CR cells (CBZ-resistant) were used in this study. We performed in silico drug screening for candidate drugs that could reprogram the gene expression signature of PC3CR cells. The in vivo effect of the drug combination was tested in xenograft mice models. We identified etoposide (VP16) as a promising treatment candidate for CBZ-resistant CRPC. The WST assay revealed that VP16 had a significant antitumor effect on PC3CR cells. PC3CR cells exhibited significantly higher topoisomerase II alpha (TOP2A) expression than PC3 cells. Higher TOP2A expression was a poor prognostic factor in The Cancer Genome Atlas prostate cancer cohort. In the Fred Hutchinson Cancer Research Center dataset, docetaxel-exposed tissues and metastatic tumors had higher TOP2A expression. In addition, VP16 significantly inhibited the growth of tumors generated from both cell lines. Based on these findings, VP16-based chemotherapy may be an optimal treatment for CPRC in the post-CBZ setting.
format	article
author	Hiroshi Hongo Takeo Kosaka Yoko Suzuki Shuji Mikami Junichi Fukada Mototsugu Oya
author_facet	Hiroshi Hongo Takeo Kosaka Yoko Suzuki Shuji Mikami Junichi Fukada Mototsugu Oya
author_sort	Hiroshi Hongo
title	Topoisomerase II alpha inhibition can overcome taxane-resistant prostate cancer through DNA repair pathways
title_short	Topoisomerase II alpha inhibition can overcome taxane-resistant prostate cancer through DNA repair pathways
title_full	Topoisomerase II alpha inhibition can overcome taxane-resistant prostate cancer through DNA repair pathways
title_fullStr	Topoisomerase II alpha inhibition can overcome taxane-resistant prostate cancer through DNA repair pathways
title_full_unstemmed	Topoisomerase II alpha inhibition can overcome taxane-resistant prostate cancer through DNA repair pathways
title_sort	topoisomerase ii alpha inhibition can overcome taxane-resistant prostate cancer through dna repair pathways
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/56f8f480566741bda2848c462abb3516
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Topoisomerase II alpha inhibition can overcome taxane-resistant prostate cancer through DNA repair pathways

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