Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou, Zhejiang, China; Zhejiang Academy of Medical Sciences, Hangzhou Medical College, Hangzhou, Zhejiang, China.
Zhejiang Academy of Medical Sciences, Hangzhou Medical College, Hangzhou, Zhejiang, China.
Life Sci. 2020 May 15;249:117498. doi: 10.1016/j.lfs.2020.117498. Epub 2020 Mar 3.
Doxorubicin (DOX) is an effective anthracycline anticancer drug. However, the clinical usage of it is limited due to its severe cardiotoxicity side effects. Metformin (Met) is a kind of first-line antihyperglycemic drug which has a potential protective effect on the heart，it is often used for oral treatment of type 2 diabetes. In this study, we explored whether Met could attenuate cardiotoxicity induced by DOX.
For the sake of exploring the Met protective effect and mechanism, we established the DOX-induced cardiotoxicity models both in H9C2 cells incubated with 5 μM DOX in vitro and Sprague-Dawley rats treated with 20 mg/kg cumulative dose of DOX.
Met is able to inhibit growth inhibition and apoptosis of H9C2 cells induced by DOX. The heart indexes of rats were examined to evaluate the Met cardiotoxicity protection. Met improved the abnormal indexes, serum markers of cardiac heart injury, echocardiography, electrocardiogram, cardiac pathology, cardiomyocyte apoptosis, and oxidative stress markers induced by DOX. Furthermore, in vivo and in vitro studies demonstrated that Met protected against DOX-induced increasing cleaved caspase-3 and Bax. Met also prevented the downregulation of Bcl-2, activated the AMPK pathway, and inhibited the MAPK pathway.
Met showed protective effects on DOX-induced cardiotoxicity by reducing oxidative stress and apoptosis, as well as regulating AMPK and MAPK signaling pathways.
多柔比星（DOX）是一种有效的蒽环类抗癌药物。然而，由于其严重的心脏毒性副作用，其临床应用受到限制。二甲双胍（Met）是一种一线抗高血糖药物，对心脏有潜在的保护作用，常用于治疗 2 型糖尿病的口服治疗。在这项研究中，我们探讨了二甲双胍是否可以减轻 DOX 引起的心脏毒性。
为了探讨二甲双胍的保护作用及其机制，我们在体外培养的 H9C2 细胞中用 5 μM DOX 建立 DOX 诱导的心脏毒性模型，并在给予 20 mg/kg 累积剂量 DOX 的 Sprague-Dawley 大鼠中建立心脏毒性模型。
二甲双胍可抑制 DOX 诱导的 H9C2 细胞生长抑制和凋亡。通过检测大鼠心脏指数来评估二甲双胍的心脏毒性保护作用。二甲双胍改善了 DOX 引起的异常指标、血清心肌损伤标志物、超声心动图、心电图、心脏病理、心肌细胞凋亡和氧化应激标志物。此外，体内和体外研究表明，二甲双胍通过减少氧化应激和细胞凋亡来保护 DOX 诱导的 caspase-3 和 Bax 的切割增加。二甲双胍还可以防止 Bcl-2 的下调，激活 AMPK 通路，并抑制 MAPK 通路。
二甲双胍通过减少氧化应激和细胞凋亡，以及调节 AMPK 和 MAPK 信号通路，对 DOX 诱导的心脏毒性表现出保护作用。
