安普克
褪黑素
心脏毒性
氧化应激
药理学
阿霉素
细胞凋亡
氧化磷酸化
TFAM公司
尼泊尔卢比1
线粒体
化学
活性氧
癌症研究
医学
线粒体ROS
内分泌学
内科学
蛋白激酶A
线粒体生物发生
磷酸化
毒性
生物化学
化疗
作者
Dong Liu,Zhiqiang Ma,Shouyin Di,Yang Yang,Jingang Yang,Liqun Xu,Russel J. Reiter,Shubin Qiao,Jiansong Yuan
标识
DOI:10.1016/j.freeradbiomed.2018.08.032
摘要
Doxorubicin (DOX) is a highly effective anticancer anthracycline drug, but its side effects at the level of the heart has limited its widespread clinical application. Melatonin is a documented potent antioxidant, nontoxic and cardioprotective agent, and it is involved in maintaining mitochondrial homeostasis and function. The present study established acute DOX-induced cardiotoxicity models in both H9c2 cells incubated with 1 μM DOX and C57BL/6 mice treated with DOX (20 mg/kg cumulative dose). Melatonin markedly alleviated the DOX-induced acute cardiac dysfunction and myocardial injury. Both in vivo and in vitro studies verified that melatonin inhibited DOX-induced mitochondrial dysfunction and morphological disorders, apoptosis, and oxidative stress via the activation of AMPK and upregulation of PGC1α with its downstream signaling (NRF1, TFAM and UCP2). These effects were reversed by the use of AMPK siRNA or PGC1α siRNA in H9c2 cells, and were also negated by the cotreatment with AMPK inhibitor Compound C in vivo. Moreover, PGC1α knockdown was without effect on the AMPK phosphorylation induced by melatonin in the DOX treated H9c2 cells. Therefore, AMPK/PGC1α pathway activation may represent a new mechanism for melatonin exerted protection against acute DOX cardiotoxicity through preservation of mitochondrial homeostasis and alleviation of oxidative stress and apoptosis.
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