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

Abstract

<b>Context:</b> 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. <b>Objective:</b> This study investigates the effect of TMZ in sunitinib-induced cardiotoxicity <i>in vivo</i> and <i>in vitro</i> and molecular mechanisms. <b>Materials and methods:</b> 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. <b>Results:</b> 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 (IC₅₀ 4.07 μM) and inhibits the AMPK/mTOR/autophagy pathway (<i>p</i> < 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 (<i>p</i> < 0.01) and activates the AMPK/mTOR/autophagy pathway <i>in vivo</i> (<i>p</i> < 0.001) and <i>in vitro</i> (<i>p</i> < 0.05). <b>Discussion and conclusions:</b> 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.