Singh Manrose, Nicol Akito T, DelPozzo Jaclyn, Wei Jia, Singh Mandeep, Nguyen Tony, Kobayashi Satoru, Liang Qiangrong
Department of Biomedical Sciences, College of Osteopathic Medicine, New York Institute of Technology, Old Westbury, NY, United States.
Department of Cardiology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xian, China.
Front Cardiovasc Med. 2022 Jan 24;9:839644. doi: 10.3389/fcvm.2022.839644. eCollection 2022.
Doxorubicin (DOX) is an extremely effective and wide-spectrum anticancer drug, but its long-term use can lead to heart failure, which presents a serious problem to millions of cancer survivors who have been treated with DOX. Thus, identifying agents that can reduce DOX cardiotoxicity and concurrently enhance its antitumor efficacy would be of great clinical value. In this respect, the classical antidiabetic drug metformin (MET) has stood out, appearing to have both antitumor and cardioprotective properties. MET is proposed to achieve these beneficial effects through the activation of AMP-activated protein kinase (AMPK), an essential regulator of mitochondrial homeostasis and energy metabolism. AMPK itself has been shown to protect the heart and modulate tumor growth under certain conditions. However, the role and mechanism of the hypothesized MET-AMPK axis in DOX cardiotoxicity and antitumor efficacy remain to be firmly established by studies using tumor-bearing animal models and large-scale prospective clinical trials. This review summarizes currently available literature for or against a role of AMPK in MET-mediated protection against DOX cardiotoxicity. It also highlights the emerging evidence suggesting distinct roles of the AMPK subunit isoforms in mediating the functions of unique AMPK holoenzymes composed of different combinations of isoforms. Moreover, the review provides a perspective regarding future studies that may help fully elucidate the relationship between MET, AMPK and DOX cardiotoxicity.
阿霉素（DOX）是一种极其有效且广谱的抗癌药物，但其长期使用会导致心力衰竭，这给数百万接受过DOX治疗的癌症幸存者带来了严重问题。因此，鉴定出能够降低DOX心脏毒性并同时增强其抗肿瘤疗效的药物具有重大临床价值。在这方面，经典抗糖尿病药物二甲双胍（MET）脱颖而出，似乎具有抗肿瘤和心脏保护特性。有人提出MET通过激活AMP激活的蛋白激酶（AMPK）来实现这些有益效果，AMPK是线粒体稳态和能量代谢的重要调节因子。AMPK本身已被证明在某些情况下可保护心脏并调节肿瘤生长。然而，在荷瘤动物模型研究和大规模前瞻性临床试验中，MET-AMPK轴在DOX心脏毒性和抗肿瘤疗效中的作用及机制仍有待明确确立。本综述总结了目前关于AMPK在MET介导的DOX心脏毒性保护作用中是否起作用的现有文献。它还强调了新出现的证据，表明AMPK亚基异构体在介导由不同异构体组合构成的独特AMPK全酶功能中具有不同作用。此外，本综述提供了关于未来研究的观点，这些研究可能有助于充分阐明MET、AMPK与DOX心脏毒性之间的关系。
