Abstract

Doxorubicin (DOX) acts as the cornerstone in multiple tumour chemotherapy regimens, however, its clinical application is often impeded due to the induction of a severe cardiotoxicity that eventually provokes left ventricular dysfunction and congestive heart failure. Coumestrol (CMT) is a common dietary phytoestrogen with pleiotropic pharmacological effects. The present study aims to investigate the role and mechanism of CMT on DOX-induced cardiotoxicity. Mice were intragastrically administrated with CMT (5 mg/kg/day) for consecutive 2 weeks and then received a single intraperitoneal injection of DOX (15 mg/kg) to mimic the clinical toxic effects after 8-day additional feeding. To verify the role of 5′ AMP-activated protein kinase alpha (AMPKα), AMPKα2 global knockout mice were used. H9C2 cells were cultured to further validate the beneficial role of CMT in vitro. CMT administration notably ameliorated oxidative damage, cell apoptosis and cardiac dysfunction in DOX-treated mice. Besides, we observed that DOX-induced reactive oxygen species overproduction and cardiomyocyte apoptosis were also reduced by CMT incubation in H9C2 cells. Mechanistically, CMT activated AMPKα and Ampkα deficiency abolished the beneficial effects of CMT in vivo and in vitro. Finally, we proved that protein kinase A (PKA) was required for CMT-mediated AMPKα activation and cardioprotective effects. CMT activated PKA/AMPKα pathway to alleviate DOX-induced oxidative damage, cell apoptosis and cardiac dysfunction. Our findings provide a promising therapeutic agent for cancer patients receiving anthracycline chemotherapy.

摘要

多柔比星（DOX）作为多种肿瘤化疗方案的基石，然而，由于诱导严重的心脏毒性，最终引起左心室功能障碍和充血性心力衰竭，其临床应用经常受到阻碍。Coumestrol (CMT) 是一种常见的膳食植物雌激素，具有多效药理作用。本研究旨在探讨 CMT 在 DOX 诱导的心脏毒性中的作用和机制。连续 2 周给小鼠灌胃 CMT（5 毫克/千克/天），然后接受单次腹腔注射 DOX（15 毫克/千克）以模拟额外喂养 8 天后的临床毒性作用。为了验证 5' AMP 活化蛋白激酶 α (AMPKα) 的作用，使用了 AMPKα2 全局敲除小鼠。体外。CMT 给药显着改善了 DOX 治疗小鼠的氧化损伤、细胞凋亡和心脏功能障碍。此外，我们观察到 CMT 在 H9C2 细胞中孵育也减少了 DOX 诱导的活性氧过量产生和心肌细胞凋亡。从机制上讲，CMT 激活 AMPKα 和Ampkα缺乏消除了 CMT在体内和体外的有益作用。最后，我们证明了 CMT 介导的 AMPKα 激活和心脏保护作用需要蛋白激酶 A (PKA)。CMT 激活 PKA/AMPKα 通路以减轻 DOX 诱导的氧化损伤、细胞凋亡和心脏功能障碍。我们的研究结果为接受蒽环类化疗的癌症患者提供了一种有前途的治疗剂。