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 (2–10 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 (IC50 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.
Highlights
Modern advances in anticancer chemotherapies markedly optimize survival and outlook of cancer patients
Sunitinib (SU) is a tyrosine kinase inhibitor antineoplastic agent clinically used for the treatment of cancers including renal cell carcinoma and gastrointestinal stromal tumors, but its clinical application is hampered by potential cardiotoxicity (Reichardt et al 2015)
We sought to determine the potential effects of TMZ in SU-induced cardiotoxicity. Using both the mouse model of sunitinib cardiotoxicity and the in vitro H9c2 cardiomyocyte model of SU toxicity and SU-TMZ co-administration, we show that TMZ reverses SU-induced hypertension and left ventricular dysfunction (LVD) in mice, and alleviates SU-induced H9c2 cardiomyocyte viability loss via the AMPK/mTOR/autophagy pathway
Summary
Modern advances in anticancer chemotherapies markedly optimize survival and outlook of cancer patients. In a recent multicenter study of SU in 71 thyroid carcinoma patients, the incidence of cardiac events, including cardiac insufficiency, cardiac infarction and left ventricular ejection fraction (LVEF) decrease, mitral insufficiency, pericardial effusion and tachycardia was 14.1% (Ravaud et al 2017). This calls for developing strategies for the prevention and treatment of SU-induced cardiotoxicity that act cardiovascular-wise and do not compromise its tumourkilling potency. TMZ efficacy in anticancer drug-induced cardiotoxicity has mainly focused on anthracycline-induced cardiotoxicity. SU injures the myocardium via mechanisms different from anthracyclines, and potential effects of TMZ in SU-induced cardiotoxicity have not been investigated
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