title: The role of nitric oxide in anthracycline toxicity and prospects for pharmacologic prevention of cardiac damage.
abstract: Anthracycline antibiotics are potent antitumor agents whose activity is severely limited by a cumulative dose-dependent chronic cardiotoxicity that results from the summation of multiple biochemical pathways of cellular damage, which ultimately yields to disruption of myocardiocyte integrity and loss of cardiac function. Nitric oxide (NO) is a key molecule involved in the pathophysiology of heart; dysregulation of activity of NO synthases (NOSs) and of NO metabolism seems to be a common feature in various cardiac diseases. The contribution of NO to anthracycline cardiac damage is suggested by evidence demonstrating anthracycline-mediated induction of NOS expression and NO release in heart and the ability of NOSs to promote anthracycline redox cycling to produce reactive oxygen species (ROS), including O2-* and H2O2. Overproduction of ROS and NO yields to reactive nitrogen species, particularly the powerful oxidant molecule peroxynitrite (ONOO-), which may produce the marked reduction of cardiac contractility. This review focuses on the anthracycline-mediated deregulation of NO network and presents an unifying viewpoint of the main molecular mechanisms involved in the pathogenesis of anthracycline cardiotoxicity, including iron, free radicals, and novel mechanistic notions on cardiac ceramide signaling and apoptosis. The data presented in the literature encourage the development of strategies of pharmacological manipulation of NO metabolism to be used as a novel approach to the prevention of cardiotoxicity induced by anthracyclines.
authors.affiliation: Department of Psychiatry, Neurobiology, Pharmacology and Biotechnology, University of Pisa, Via Bonanno, 6, Pisa, PI 56126 Italy. s.fogli@do.med.unipi.it
authors.forename: Stefano
authors.initials: S
authors.lastname: Fogli
authors.forename: Paola
authors.initials: P
authors.lastname: Nieri
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Breschi
mesh_terms: D000818:Animals; D018943:Anthracyclines / Q000037:antagonists & inhibitors / Q000633:toxicity*; D000900:Anti-Bacterial Agents / Q000633:toxicity*; D009202:Cardiomyopathies / Q000139:chemically induced* / Q000473:pathology / Q000517:prevention & control; D008954:Models, Biological; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009569:Nitric Oxide / Q000502:physiology*
chemical_list: D018943:Anthracyclines; D000900:Anti-Bacterial Agents; D009569:Nitric Oxide