Abstract
Doxorubicin (DOX) is a widely used and potent anticancer agent, but DOX dose-dependently induced cardiotoxicity greatly limits its use in clinic. Pterostilbene, a natural analog of resveratrol, is a known antioxidant and exerts myocardial protection. The present study explored the action and detailed mechanism of pterostilbene on DOX-treated cardiomyocytes. We investigated the effects of pterostilbene on established acute DOX-induced cardiotoxicity models in both H9c2 cells treated with 1 μM DOX and C57BL/6 mice with DOX (20 mg/kg cumulative dose) exposure. Pterostilbene markedly alleviated the DOX exposure-induced acute myocardial injury. Both in vitro and in vivo studies revealed that pterostilbene inhibited the acute DOX exposure-caused oxidative stress and mitochondrial morphological disorder via the PGC1α upregulation through activating AMPK and via PGC1α deacetylation through enhancing SIRT1. However, these effects were partially reversed by knockdown of AMPK or SIRT1 in vitro and treatment of Compound C (AMPK inhibitor) or EX527 (SIRT1 inhibitor) in vivo. Our results indicate that pterostilbene protects cardiomyocytes from acute DOX exposure-induced oxidative stress and mitochondrial damage via PGC1α upregulation and deacetylation through activating AMPK and SIRT1 cascades.
Highlights
Doxorubicin (DOX), a member of the anthracyclines, provided the oncologist with highly effective therapeutic regimen to treat tumors, but the unanticipated side-effects associated with acute or chronic cardiotoxicity greatly limits its clinical use [1]
Resveratrol could exert protection against DOX-induced cardiotoxicity via activating SIRT1 and AMPK signaling cascades mitigating oxidative stress, mitochondrial injury, cardiomyocyte apoptosis and cardiac fibrosis induced by DOX exposure [19, 26,27,28,29]
Our present study found that pterostilbene treatment could reverse the SIRT1 reduction and enhanced PGC1α acetylation induced by DOX-exposure both in vitro and in vivo
Summary
Doxorubicin (DOX), a member of the anthracyclines, provided the oncologist with highly effective therapeutic regimen to treat tumors, but the unanticipated side-effects associated with acute or chronic cardiotoxicity greatly limits its clinical use [1]. A dozen of basic studies reveal that pterostilbene is a potent myocardial protective agent against various cardiac diseases, including hypertrophy, diabetic cardiomyopathy, myocardial infarction and ischemia reperfusion injury [7,8,9,10]. These favorable effects of pterostilbene application are largely attributed to the free radical scavenging and anti-inflammatory actions [11, 12]. Whether pterostilbene could protect myocardium against DOX-induced acute cardiotoxicity still remains unknown
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