PDF(Pubmed)
Abstract：
Doxorubicin (DOX), one of the most effective and widely used anticancer drugs, has the major limitation of cancer treatment-related cardiotoxicity (CTRTOX) in the clinic. Reactive oxygen species (ROS) generation and mitochondrial dysfunction are well-known consequences of DOX-induced injury to cardiomyocytes. This study aimed to explore the mitochondrial functional consequences and associated mechanisms of pretreatment with carvedilol, a ß-blocking agent known to exert protection against DOX toxicity. When disease modeling was performed using cultured rat cardiac muscle cells (H9c2 cells) and human iPSC-derived cardiomyocytes (iPSC-CMs), we found that prophylactic carvedilol mitigated not only the DOX-induced suppression of mitochondrial function but that the mitochondrial functional readout of carvedilol-pretreated cells mimicked the readout of cells overexpressing the major regulator of mitochondrial biogenesis, PGC-1α. Carvedilol pretreatment reduces mitochondrial oxidants, decreases cell death in both H9c2 cells and human iPSC-CM and maintains the cellular \'redox poise\' as determined by sustained expression of the redox sensor Keap1 and prevention of DOX-induced Nrf2 nuclear translocation. These results indicate that, in addition to the already known ROS-scavenging effects, carvedilol has a hitherto unrecognized pro-reducing property against the oxidizing conditions induced by DOX treatment, the sequalae of DOX-induced mitochondrial dysfunction and compromised cell viability. The novel findings of our preclinical studies suggest future trial design of carvedilol prophylaxis, such as prescreening for redox state, might be an alternative strategy for preventing oxidative stress writ large in lieu of the current lack of clinical evidence for ROS-scavenging agents.
摘要：
阿霉素（DOX），最有效和广泛使用的抗癌药物之一，在临床上具有癌症治疗相关的心脏毒性（CTRTOX）的主要局限性。活性氧（ROS）的产生和线粒体功能障碍是DOX诱导的心肌细胞损伤的众所周知的后果。本研究旨在探讨卡维地洛预处理对线粒体功能的影响及相关机制,已知对DOX毒性具有保护作用的β-阻断剂。当使用培养的大鼠心肌细胞（H9c2细胞）和人iPSC来源的心肌细胞（iPSC-CM）进行疾病建模时，我们发现预防性卡维地洛不仅减轻了DOX诱导的线粒体功能抑制，而且卡维地洛预处理细胞的线粒体功能读数模拟了过表达线粒体生物发生主要调节因子的细胞的读数，PGC-1α。卡维地洛预处理减少线粒体氧化剂，减少H9c2细胞和人iPSC-CM中的细胞死亡，并通过持续表达氧化还原传感器Keap1和预防DOX诱导的Nrf2核易位来维持细胞氧化还原平衡。这些结果表明,除了已知的清除ROS的作用，卡维地洛对DOX处理诱导的氧化条件具有迄今未被认可的促还原性能，DOX诱导的线粒体功能障碍和细胞活力受损的后遗症。我们的临床前研究的新发现表明卡维地洛预防的未来试验设计，如氧化还原状态的预筛选，可能是预防氧化应激的替代策略，而不是目前缺乏ROS清除剂的临床证据。
