New developments in anthracycline-induced cardiotoxicity.

  • Mordente A
  • Meucci E
  • Silvestrini A
 et al. 
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Abstract

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.

Author-supplied keywords

  • Anthracyclines
  • Anthracyclines: toxicity
  • Cytosol
  • Cytosol: metabolism
  • Heart
  • Heart: drug effects
  • Humans
  • NADP
  • NADP: metabolism
  • Polymorphism, Genetic
  • Reactive Oxygen Species
  • Reactive Oxygen Species: metabolism

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Authors

  • A Mordente

  • E Meucci

  • A Silvestrini

  • G E Martorana

  • B Giardina

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