Inhibition of checkpoint kinase 1 potentiates anticancer activity of gemcitabine in bladder cancer cells

Abstract Checkpoint kinases (CHKs) are involved in the DNA damage response in many cancer cells. CHK inhibitors have been used in clinical trials in combination with chemotherapeutics; however, their effect against bladder cancer remains unclear. Here, we investigated the efficacy of combining gemci...

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Autores principales:	Makoto Isono, Kazuki Okubo, Takako Asano, Akinori Sato
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/961e795ec7d4455493f964a2d9a8fa35
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spelling	oai:doaj.org-article:961e795ec7d4455493f964a2d9a8fa352021-12-02T17:15:28ZInhibition of checkpoint kinase 1 potentiates anticancer activity of gemcitabine in bladder cancer cells10.1038/s41598-021-89684-52045-2322https://doaj.org/article/961e795ec7d4455493f964a2d9a8fa352021-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-89684-5https://doaj.org/toc/2045-2322Abstract Checkpoint kinases (CHKs) are involved in the DNA damage response in many cancer cells. CHK inhibitors have been used in clinical trials in combination with chemotherapeutics; however, their effect against bladder cancer remains unclear. Here, we investigated the efficacy of combining gemcitabine with MK-8776, a novel CHK1 inhibitor, in four bladder cancer cell lines. The effects of gemcitabine and MK-8776 on cell viability, clonogenicity, cell cycle, and apoptosis were examined alongside in vivo efficacy using murine xenograft tumor models. Combined treatment inhibited the viability and colony formation of bladder cancer cells compared to either single treatment. Although gemcitabine (10 nM) alone increased the cell number in S-phase, it increased the cell number in sub-G1 phase when combined with MK-8776 (0.5 µM). Combined treatment enhanced cleaved poly[ADP-ribose]-polymerase expression alongside the number of annexin-V-positive cells, indicating the induction of apoptosis. In vivo, administration of gemcitabine and MK-8776 was well tolerated and suppressed tumor growth. Mechanistically, the combined treatment elevated γH2A.X and suppressed Rad51 expression. Our study demonstrates that MK-8776 and gemcitabine combined induces apoptosis and suppresses proliferation in bladder cancer cells by inhibiting CHKs and DNA repair. Therefore, CHK1 inhibition combined with gemcitabine may be a potential treatment for bladder cancer.Makoto IsonoKazuki OkuboTakako AsanoAkinori SatoNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-8 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Makoto Isono Kazuki Okubo Takako Asano Akinori Sato Inhibition of checkpoint kinase 1 potentiates anticancer activity of gemcitabine in bladder cancer cells
description	Abstract Checkpoint kinases (CHKs) are involved in the DNA damage response in many cancer cells. CHK inhibitors have been used in clinical trials in combination with chemotherapeutics; however, their effect against bladder cancer remains unclear. Here, we investigated the efficacy of combining gemcitabine with MK-8776, a novel CHK1 inhibitor, in four bladder cancer cell lines. The effects of gemcitabine and MK-8776 on cell viability, clonogenicity, cell cycle, and apoptosis were examined alongside in vivo efficacy using murine xenograft tumor models. Combined treatment inhibited the viability and colony formation of bladder cancer cells compared to either single treatment. Although gemcitabine (10 nM) alone increased the cell number in S-phase, it increased the cell number in sub-G1 phase when combined with MK-8776 (0.5 µM). Combined treatment enhanced cleaved poly[ADP-ribose]-polymerase expression alongside the number of annexin-V-positive cells, indicating the induction of apoptosis. In vivo, administration of gemcitabine and MK-8776 was well tolerated and suppressed tumor growth. Mechanistically, the combined treatment elevated γH2A.X and suppressed Rad51 expression. Our study demonstrates that MK-8776 and gemcitabine combined induces apoptosis and suppresses proliferation in bladder cancer cells by inhibiting CHKs and DNA repair. Therefore, CHK1 inhibition combined with gemcitabine may be a potential treatment for bladder cancer.
format	article
author	Makoto Isono Kazuki Okubo Takako Asano Akinori Sato
author_facet	Makoto Isono Kazuki Okubo Takako Asano Akinori Sato
author_sort	Makoto Isono
title	Inhibition of checkpoint kinase 1 potentiates anticancer activity of gemcitabine in bladder cancer cells
title_short	Inhibition of checkpoint kinase 1 potentiates anticancer activity of gemcitabine in bladder cancer cells
title_full	Inhibition of checkpoint kinase 1 potentiates anticancer activity of gemcitabine in bladder cancer cells
title_fullStr	Inhibition of checkpoint kinase 1 potentiates anticancer activity of gemcitabine in bladder cancer cells
title_full_unstemmed	Inhibition of checkpoint kinase 1 potentiates anticancer activity of gemcitabine in bladder cancer cells
title_sort	inhibition of checkpoint kinase 1 potentiates anticancer activity of gemcitabine in bladder cancer cells
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/961e795ec7d4455493f964a2d9a8fa35
work_keys_str_mv	AT makotoisono inhibitionofcheckpointkinase1potentiatesanticanceractivityofgemcitabineinbladdercancercells AT kazukiokubo inhibitionofcheckpointkinase1potentiatesanticanceractivityofgemcitabineinbladdercancercells AT takakoasano inhibitionofcheckpointkinase1potentiatesanticanceractivityofgemcitabineinbladdercancercells AT akinorisato inhibitionofcheckpointkinase1potentiatesanticanceractivityofgemcitabineinbladdercancercells
_version_	1718381273772195840

Inhibition of checkpoint kinase 1 potentiates anticancer activity of gemcitabine in bladder cancer cells

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