Cardiomyocyte death in doxorubicin-induced cardiotoxicity.
Doxorubicin (DOX) is one of the most widely used and successful antitumor drugs, but its cumulative and dose-dependent cardiac toxicity has been a major concern of oncologists in cancer therapeutic practice for decades. With the increasing population of cancer survivors, there is a growing need to develop preventive strategies and effective therapies against DOX-induced cardiotoxicity, in particular late-onset cardiomyopathy. Although intensive investigations on DOX-induced cardiotoxicity have continued for decades, the underlying mechanisms responsible for DOX-induced cardiotoxicity have not been completely elucidated. A rapidly expanding body of evidence supports the notion that cardiomyocyte death by apoptosis and necrosis is a primary mechanism of DOX-induced cardiomyopathy and that other types of cell death, such as autophagy and senescence/aging, may participate in this process. This review focuses on the current understanding of the molecular mechanisms underlying DOX-induced cardiomyocyte death, including the major primary mechanism of excess production of reactive oxygen species (ROS) and other recently discovered ROS-independent mechanisms. The different sensitivities to DOX-induced cell death signals between adult and young cardiomyocytes will also be discussed.
Zhang
Yi-Wei
YW
Riley Heart Research Center, Wells Center for Pediatric Research, Indiana University, School of Medicine, Indianapolis, IN 46202-5225, USA.
Shi
Jianjian
J
Li
Yuan-Jian
YJ
Wei
Lei
L
D000818:Animals; D009202:Cardiomyopathies / Q000139:chemically induced* / Q000517:prevention & control; D054715:Cardiotoxins / Q000009:adverse effects* / Q000627:therapeutic use; D016923:Cell Death / Q000187:drug effects; D016922:Cellular Senescence; D004317:Doxorubicin / Q000009:adverse effects* / Q000627:therapeutic use; D006801:Humans; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology; D009369:Neoplasms / Q000188:drug therapy*; D017382:Reactive Oxygen Species
D054715:Cardiotoxins; D017382:Reactive Oxygen Species; D004317:Doxorubicin