New developments in anthracycline-induced cardiotoxicity.
Anthracyclines are among the most effective anticancer drugs ever developed. Unfortunately, their clinical use is severely limited by the development of a progressive dose-dependent cardiomyopathy that irreversibly evolves toward congestive heart failure, usually refractory to conventional therapy. The pathophysiology of anthracycline-induced cardiomyopathy remains controversial and incompletely understood. The current thinking is that anthracyclines are toxic per se but gain further cardiotoxicity after one-electron reduction with ROS overproduction or two-electron reduction with conversion to C-13 alcohol metabolites. ROS overproduction can probably be held responsible for anthracycline acute cardiotoxicity, but not for all the aspects of progressive cardiomyopathy. Intramyocardial formation of secondary alcohol metabolites might play a key role in promoting the progression of cardiotoxicity toward end-stage cardiomyopathy and congestive heart failure. In this review we also discuss recent developments in: a) the molecular mechanisms underlying anthracycline-induced cardiotoxicity; b) the role of cytosolic NADPH-dependent reductases in anthracycline metabolism; c) the influence of genetic polymorphisms on cardiotoxicity outcome; d) the perspectives on the most promising strategies for limiting or preventing anthracycline-induced cardiotoxicity, focusing on controversial aspects and on recent data regarding analogues of the natural compounds, tumor-targeted formulations and cardioprotective agents.
Institute of Biochemistry and Clinical Biochemistry, Catholic University School of Medicine, 00168 Roma, Italy. alvaro.mordente@rm.unicatt.it
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A
Mordente
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Meucci
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Silvestrini
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GE
Martorana
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Giardina
D018943:Anthracyclines / Q000633:toxicity*; D003600:Cytosol / Q000378:metabolism; D006321:Heart / Q000187:drug effects*; D006801:Humans; D009249:NADP / Q000378:metabolism; D011110:Polymorphism, Genetic; D017382:Reactive Oxygen Species / Q000378:metabolism
D018943:Anthracyclines; D017382:Reactive Oxygen Species; D009249:NADP