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Trimetazidine ameliorates sunitinib-induced cardiotoxicity in mice via the AMPK/mTOR/autophagy pathway

Context: Sunitinib (SU) is a multi-targeted tyrosine kinase inhibitor anticancer agent whose clinical use is often limited by cardiovascular complications. Trimetazidine (TMZ) is an anti-angina agent that has been demonstrated cardioprotective effects in numerous cardiovascular conditions, but its p...

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Autores principales: Yang, Yi, Li, Na, Chen, Tongshuai, Zhang, Chunmei, Liu, Lingxin, Qi, Yan, Bu, Peili
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Taylor & Francis 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6764339/
https://www.ncbi.nlm.nih.gov/pubmed/31545912
http://dx.doi.org/10.1080/13880209.2019.1657905
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author Yang, Yi
Li, Na
Chen, Tongshuai
Zhang, Chunmei
Liu, Lingxin
Qi, Yan
Bu, Peili
author_facet Yang, Yi
Li, Na
Chen, Tongshuai
Zhang, Chunmei
Liu, Lingxin
Qi, Yan
Bu, Peili
author_sort Yang, Yi
collection PubMed
description Context: Sunitinib (SU) is a multi-targeted tyrosine kinase inhibitor anticancer agent whose clinical use is often limited by cardiovascular complications. Trimetazidine (TMZ) is an anti-angina agent that has been demonstrated cardioprotective effects in numerous cardiovascular conditions, but its potential effects in SU-induced cardiotoxicity have not been investigated. Objective: This study investigates the effect of TMZ in sunitinib-induced cardiotoxicity in vivo and in vitro and molecular mechanisms. Materials and methods: Male 129S1/SvImJ mice were treated with vehicle, SU (40 mg/kg/d) or SU and TMZ (20 mg/kg/d) via oral gavage for 28 days, and cardiovascular functions and cardiac protein expressions were examined. H9c2 cardiomyocytes were treated with vehicle, SU (2–10 μM) or SU and TMZ (40–120 μM) for 48 h, and cell viability, apoptosis, autophagy, and protein expression was tested. Results: SU induces hypertension (systolic blood pressure [SBP] + 28.33 ± 5.00 mmHg) and left ventricular dysfunction (left ventricular ejection fraction [LVEF] − 11.16 ± 2.53%) in mice. In H9c2 cardiomyocytes, SU reduces cell viability (IC(50) 4.07 μM) and inhibits the AMPK/mTOR/autophagy pathway (p < 0.05). TMZ co-administration with SU reverses SU-induced cardiotoxicity in mice (SBP − 23.75 ± 4.69 mmHg, LVEF + 10.95 ± 3.317%), alleviates cell viability loss in H9c2 cardiomyocytes (p < 0.01) and activates the AMPK/mTOR/autophagy pathway in vivo (p < 0.001) and in vitro (p < 0.05). Discussion and conclusions: Our results suggest TMZ as a potential cardioprotective approach for cardiovascular complications during SU regimen, and potentially for cardiotoxicity of other anticancer chemotherapies associated with cardiomyocyte autophagic pathways.
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spelling pubmed-67643392019-10-08 Trimetazidine ameliorates sunitinib-induced cardiotoxicity in mice via the AMPK/mTOR/autophagy pathway Yang, Yi Li, Na Chen, Tongshuai Zhang, Chunmei Liu, Lingxin Qi, Yan Bu, Peili Pharm Biol Research Article Context: Sunitinib (SU) is a multi-targeted tyrosine kinase inhibitor anticancer agent whose clinical use is often limited by cardiovascular complications. Trimetazidine (TMZ) is an anti-angina agent that has been demonstrated cardioprotective effects in numerous cardiovascular conditions, but its potential effects in SU-induced cardiotoxicity have not been investigated. Objective: This study investigates the effect of TMZ in sunitinib-induced cardiotoxicity in vivo and in vitro and molecular mechanisms. Materials and methods: Male 129S1/SvImJ mice were treated with vehicle, SU (40 mg/kg/d) or SU and TMZ (20 mg/kg/d) via oral gavage for 28 days, and cardiovascular functions and cardiac protein expressions were examined. H9c2 cardiomyocytes were treated with vehicle, SU (2–10 μM) or SU and TMZ (40–120 μM) for 48 h, and cell viability, apoptosis, autophagy, and protein expression was tested. Results: SU induces hypertension (systolic blood pressure [SBP] + 28.33 ± 5.00 mmHg) and left ventricular dysfunction (left ventricular ejection fraction [LVEF] − 11.16 ± 2.53%) in mice. In H9c2 cardiomyocytes, SU reduces cell viability (IC(50) 4.07 μM) and inhibits the AMPK/mTOR/autophagy pathway (p < 0.05). TMZ co-administration with SU reverses SU-induced cardiotoxicity in mice (SBP − 23.75 ± 4.69 mmHg, LVEF + 10.95 ± 3.317%), alleviates cell viability loss in H9c2 cardiomyocytes (p < 0.01) and activates the AMPK/mTOR/autophagy pathway in vivo (p < 0.001) and in vitro (p < 0.05). Discussion and conclusions: Our results suggest TMZ as a potential cardioprotective approach for cardiovascular complications during SU regimen, and potentially for cardiotoxicity of other anticancer chemotherapies associated with cardiomyocyte autophagic pathways. Taylor & Francis 2019-09-23 /pmc/articles/PMC6764339/ /pubmed/31545912 http://dx.doi.org/10.1080/13880209.2019.1657905 Text en © 2019 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. http://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Yang, Yi
Li, Na
Chen, Tongshuai
Zhang, Chunmei
Liu, Lingxin
Qi, Yan
Bu, Peili
Trimetazidine ameliorates sunitinib-induced cardiotoxicity in mice via the AMPK/mTOR/autophagy pathway
title Trimetazidine ameliorates sunitinib-induced cardiotoxicity in mice via the AMPK/mTOR/autophagy pathway
title_full Trimetazidine ameliorates sunitinib-induced cardiotoxicity in mice via the AMPK/mTOR/autophagy pathway
title_fullStr Trimetazidine ameliorates sunitinib-induced cardiotoxicity in mice via the AMPK/mTOR/autophagy pathway
title_full_unstemmed Trimetazidine ameliorates sunitinib-induced cardiotoxicity in mice via the AMPK/mTOR/autophagy pathway
title_short Trimetazidine ameliorates sunitinib-induced cardiotoxicity in mice via the AMPK/mTOR/autophagy pathway
title_sort trimetazidine ameliorates sunitinib-induced cardiotoxicity in mice via the ampk/mtor/autophagy pathway
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6764339/
https://www.ncbi.nlm.nih.gov/pubmed/31545912
http://dx.doi.org/10.1080/13880209.2019.1657905
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