%0 Journal Article
%T Trimetazidine ameliorates sunitinib-induced cardiotoxicity in mice via the AMPK/mTOR/autophagy pathway
%A Chunmei Zhang
%A Lingxin Liu
%A Na Li
%A Peili Bu
%A Tongshuai Chen
%A Yan Qi
%A Yi Yang
%J Pharmaceutical Biology
%D 2019
%R https://doi.org/10.1080/13880209.2019.1657905
%X Abstract 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¨C10£¿¦ÌM) or SU and TMZ (40¨C120£¿¦ÌM) for 48£¿h, and cell viability, apoptosis, autophagy, and protein expression was tested. Results: SU induces hypertension (systolic blood pressure [SBP]£¿+£¿28.33£¿¡À£¿5.00£¿mmHg) and left ventricular dysfunction (left ventricular ejection fraction [LVEF]£¿£¿£¿11.16£¿¡À£¿2.53%) in mice. In H9c2 cardiomyocytes, SU reduces cell viability (IC50 4.07£¿¦ÌM) and inhibits the AMPK/mTOR/autophagy pathway (p£¿<£¿0.05). TMZ co-administration with SU reverses SU-induced cardiotoxicity in mice (SBP £¿ 23.75£¿¡À£¿4.69£¿mmHg, LVEF + 10.95£¿¡À£¿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
%U https://www.tandfonline.com/doi/full/10.1080/13880209.2019.1657905