Resveratrol-induced autophagy promotes survival and attenuates doxorubicin-induced cardiotoxicity
Resveratrol-induced autophagy promotes survival and attenuates doxorubicin-induced cardiotoxicity
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DOI：
10.1016/j.intimp.2016.01.002
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发表时间：
2016-03-01
影响因子：
5.6
通讯作者：
Wang, Chang-qian
中科院分区：
文献类型：
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作者：
Gu, Jun;Hu, Wei;Wang, Chang-qian
白藜芦醇 (RSV) 具有许多生物学作用，包括抗肿瘤和抗病毒活性以及血管保护。最近的研究表明，RSV 通过未知机制诱导自噬发挥抗肿瘤作用。阿霉素（DOX）是一种广谱抗肿瘤药物，但其心脏毒性限制了其临床应用。本研究评估了操纵自噬是否可以在体外以及在 DOX 诱导的心脏毒性大鼠模型中减弱 DOX 的心脏毒性作用。我们发现DOX通过抑制AMPK激活并通过p38MAPK/p53信号传导促进促凋亡蛋白表达来诱导H9C2细胞凋亡。 RSV 处理的 H9C2 细胞通过 AMPK/mTOR/U1k1 途径显示出自噬增加。当 DOX 和 RSV 联合使用时，尽管自噬比率略有增加，但细胞凋亡减少。在 DOX 诱导的心脏毒性大鼠模型中观察到相同的结果。单独或联合注射 DOX 或 RSV 一周，与单独 DOX 组相比，联合组的细胞凋亡率降低。我们的结果强烈表明，这种与 RSV 的联合治疗策略可以减弱 DOX 的心脏毒性作用。我们的发现可能具有重要的临床意义。 (C) 2016 Elsevier B.V. 保留所有权利。
Resveratrol (RSV) has many biological effects, including antitumor and antiviral activities, and vascular protection. Recent studies have suggested that RSV exerts its antitumor effects through induction of autophagy by an unknown mechanism. Doxorubicin (DOX) is a wide spectrum antitumor drug, but its clinical application is limited by its cardiotoxicity. This study evaluated whether the manipulation of autophagy could attenuate the cardiotoxic effects of DOX in vitro as well as in a rat model of DOX-induced cardiotoxicity. We found that DOX induced H9C2 cell apoptosis by inhibiting AMPK activation and promoting pro-apoptotic protein expression through p38MAPK/p53 signaling. RSV-treated H9C2 cells showed increased autophagy through the AMPK/mTOR/U1k1 pathway. When DOX and RSV were combined, apoptosis was decreased, despite a slight increase in the autophagy ratio. The same result was observed in the rat model of DOX-induced cardiotoxicity. Injection with DOX or RSV alone, or in combination, for a week, resulted in a reduced apoptotic ratio in the combination group compared with the DOX alone group. Our results strongly indicate that this co-treatment strategy with RSV can attenuate the cardiotoxic effects of DOX. Our findings may have important clinical implications. (C) 2016 Elsevier B.V. All rights reserved.