Anti-HER2 monoclonal antibodies intensify the susceptibility of human gastric cancer cells to etoposide by promoting apoptosis, but not autophagy.

<h4>Background</h4>Gastric cancer (GC) is a multifactorial disease with high mortality. Anti-HER2 therapy is a promising strategy in GC treatment and trastuzumab was approved by FDA (Food and Drug Administration) as the first and the second line of treatment of the disease.<h4>Purp...

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Autores principales:	Agnieszka Gornowicz, Wojciech Szymanowski, Robert Czarnomysy, Krzysztof Bielawski, Anna Bielawska
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/e3fb1a28599f41c8bab125cc710e68f0
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spelling	oai:doaj.org-article:e3fb1a28599f41c8bab125cc710e68f02021-12-02T20:17:33ZAnti-HER2 monoclonal antibodies intensify the susceptibility of human gastric cancer cells to etoposide by promoting apoptosis, but not autophagy.1932-620310.1371/journal.pone.0255585https://doaj.org/article/e3fb1a28599f41c8bab125cc710e68f02021-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0255585https://doaj.org/toc/1932-6203<h4>Background</h4>Gastric cancer (GC) is a multifactorial disease with high mortality. Anti-HER2 therapy is a promising strategy in GC treatment and trastuzumab was approved by FDA (Food and Drug Administration) as the first and the second line of treatment of the disease.<h4>Purpose</h4>The aim of the study was to examine the effectiveness of a combination of etoposide with trastuzumab or pertuzumab in AGS gastric cancer cells and breast cancer cells such as MCF-7, MDA-MB-231 and HCC1954.<h4>Methods and findings</h4>The cytotoxic effects of the tested compounds against gastric and breast cancer cells were checked by MTT (3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide) assay. The anti-proliferative potential was analyzed by the incorporation of [3H]-thymidine into DNA. Fluorescent microscopy and flow cytometry was used to demonstrate the effect of the compounds on apoptosis. The mitochondrial membrane potential, and the activity of caspase-8 and caspase-9 were assessed. Autophagosomes and autolysosomes formation was checked by flow cytometry. The concentrations of Beclin-1, LC3A and LC3B were performed using ELISA. The expression of LC3A/B was also determined. The results from our study proved that the combination of etoposide with anti-HER2 antibodies was not cytotoxic against breast cancer cells, whereas the combination of etoposide with anti-HER2 antibodies decreased viability and DNA biosynthesis in gastric cancer cells. The interaction of etoposide with pertuzumab or trastuzumab induced programmed cell death via extrinsic and intrinsic apoptotic pathways in AGS gastric cancer cells, but did not affect autophagy, where a decrease of Beclin-1, LC3A and LC3B was observed in comparison with the untreated control.<h4>Conclusions</h4>The study demonstrated that etoposide (12.5 μM) with pertuzumab represent a promising strategy in gastric cancer treatment, but further in vivo examinations are also required.Agnieszka GornowiczWojciech SzymanowskiRobert CzarnomysyKrzysztof BielawskiAnna BielawskaPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 16, Iss 8, p e0255585 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Agnieszka Gornowicz Wojciech Szymanowski Robert Czarnomysy Krzysztof Bielawski Anna Bielawska Anti-HER2 monoclonal antibodies intensify the susceptibility of human gastric cancer cells to etoposide by promoting apoptosis, but not autophagy.
description	<h4>Background</h4>Gastric cancer (GC) is a multifactorial disease with high mortality. Anti-HER2 therapy is a promising strategy in GC treatment and trastuzumab was approved by FDA (Food and Drug Administration) as the first and the second line of treatment of the disease.<h4>Purpose</h4>The aim of the study was to examine the effectiveness of a combination of etoposide with trastuzumab or pertuzumab in AGS gastric cancer cells and breast cancer cells such as MCF-7, MDA-MB-231 and HCC1954.<h4>Methods and findings</h4>The cytotoxic effects of the tested compounds against gastric and breast cancer cells were checked by MTT (3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide) assay. The anti-proliferative potential was analyzed by the incorporation of [3H]-thymidine into DNA. Fluorescent microscopy and flow cytometry was used to demonstrate the effect of the compounds on apoptosis. The mitochondrial membrane potential, and the activity of caspase-8 and caspase-9 were assessed. Autophagosomes and autolysosomes formation was checked by flow cytometry. The concentrations of Beclin-1, LC3A and LC3B were performed using ELISA. The expression of LC3A/B was also determined. The results from our study proved that the combination of etoposide with anti-HER2 antibodies was not cytotoxic against breast cancer cells, whereas the combination of etoposide with anti-HER2 antibodies decreased viability and DNA biosynthesis in gastric cancer cells. The interaction of etoposide with pertuzumab or trastuzumab induced programmed cell death via extrinsic and intrinsic apoptotic pathways in AGS gastric cancer cells, but did not affect autophagy, where a decrease of Beclin-1, LC3A and LC3B was observed in comparison with the untreated control.<h4>Conclusions</h4>The study demonstrated that etoposide (12.5 μM) with pertuzumab represent a promising strategy in gastric cancer treatment, but further in vivo examinations are also required.
format	article
author	Agnieszka Gornowicz Wojciech Szymanowski Robert Czarnomysy Krzysztof Bielawski Anna Bielawska
author_facet	Agnieszka Gornowicz Wojciech Szymanowski Robert Czarnomysy Krzysztof Bielawski Anna Bielawska
author_sort	Agnieszka Gornowicz
title	Anti-HER2 monoclonal antibodies intensify the susceptibility of human gastric cancer cells to etoposide by promoting apoptosis, but not autophagy.
title_short	Anti-HER2 monoclonal antibodies intensify the susceptibility of human gastric cancer cells to etoposide by promoting apoptosis, but not autophagy.
title_full	Anti-HER2 monoclonal antibodies intensify the susceptibility of human gastric cancer cells to etoposide by promoting apoptosis, but not autophagy.
title_fullStr	Anti-HER2 monoclonal antibodies intensify the susceptibility of human gastric cancer cells to etoposide by promoting apoptosis, but not autophagy.
title_full_unstemmed	Anti-HER2 monoclonal antibodies intensify the susceptibility of human gastric cancer cells to etoposide by promoting apoptosis, but not autophagy.
title_sort	anti-her2 monoclonal antibodies intensify the susceptibility of human gastric cancer cells to etoposide by promoting apoptosis, but not autophagy.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/e3fb1a28599f41c8bab125cc710e68f0
work_keys_str_mv	AT agnieszkagornowicz antiher2monoclonalantibodiesintensifythesusceptibilityofhumangastriccancercellstoetoposidebypromotingapoptosisbutnotautophagy AT wojciechszymanowski antiher2monoclonalantibodiesintensifythesusceptibilityofhumangastriccancercellstoetoposidebypromotingapoptosisbutnotautophagy AT robertczarnomysy antiher2monoclonalantibodiesintensifythesusceptibilityofhumangastriccancercellstoetoposidebypromotingapoptosisbutnotautophagy AT krzysztofbielawski antiher2monoclonalantibodiesintensifythesusceptibilityofhumangastriccancercellstoetoposidebypromotingapoptosisbutnotautophagy AT annabielawska antiher2monoclonalantibodiesintensifythesusceptibilityofhumangastriccancercellstoetoposidebypromotingapoptosisbutnotautophagy
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Anti-HER2 monoclonal antibodies intensify the susceptibility of human gastric cancer cells to etoposide by promoting apoptosis, but not autophagy.

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