January 1, 2019SHILAP Revista de lepidopterologíaOpen Access

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

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Why the study?

Sunitinib clinical use is often limited by cardiovascular complications, but the potential cardioprotective effects of trimetazidine in sunitinib-induced cardiotoxicity had not been investigated.

Does trimetazidine prevent sunitinib-induced cardiotoxicity in mice and H9c2 cardiomyocytes?

Structured PICO

Does trimetazidine prevent sunitinib-induced cardiotoxicity in mice and H9c2 cardiomyocytes?

Population

Male 129S1/SvImJ mice and H9c2 cardiomyocytes

Intervention

Trimetazidine (20 mg/kg/d via oral gavage for 28 days in vivo; 40-120 μM for 48 h in vitro) co-administered with sunitinib

Comparator

Vehicle and sunitinib alone (40 mg/kg/d in vivo; 2-10 μM in vitro)

Outcome

Cardiovascular functions (systolic blood pressure, left ventricular ejection fraction) and cardiac protein expressions in vivo; cell viability, apoptosis, autophagy, and protein expression in vitrosurrogate

Trimetazidine protects against sunitinib-induced cardiotoxicity in preclinical models via activation of the AMPK/mTOR/autophagy pathway, suggesting a potential therapeutic strategy for cardio-oncology.

Implication

May offer cardioprotection with sunitinib; hypothesis-generating from animal data and requires clinical trials.

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.