title: Anthracycline-induced cardiotoxicity: overview of studies examining the roles of oxidative stress and free cellular iron.
abstract: The risk of cardiotoxicity is the most serious drawback to the clinical usefulness of anthracycline antineoplastic antibiotics, which include doxorubicin (adriamycin), daunorubicin or epirubicin. Nevertheless, these compounds remain among the most widely used anticancer drugs. The molecular pathogenesis of anthracycline cardiotoxicity remains highly controversial, although the oxidative stress-based hypothesis involving intramyocardial production of reactive oxygen species (ROS) has gained the widest acceptance. Anthracyclines may promote the formation of ROS through redox cycling of their aglycones as well as their anthracycline-iron complexes. This proposed mechanism has become particularly popular in light of the high cardioprotective efficacy of dexrazoxane (ICRF-187). The mechanism of action of this drug has been attributed to its hydrolytic transformation into the iron-chelating metabolite ADR-925, which may act by displacing iron from anthracycline-iron complexes or by chelating free or loosely bound cellular iron, thus preventing site-specific iron-catalyzed ROS damage. However, during the last decade, calls for the critical reassessment of this "ROS and iron" hypothesis have emerged. Numerous antioxidants, although efficient in cellular or acute animal experiments, have failed to alleviate anthracycline cardiotoxicity in clinically relevant chronic animal models or clinical trials. In addition, studies with chelators that are stronger and more selective for iron than ADR-925 have also yielded negative or, at best, mixed outcomes. Hence, several lines of evidence suggest that mechanisms other than the traditionally emphasized "ROS and iron" hypothesis are involved in anthracycline-induced cardiotoxicity and that these alternative mechanisms may be better bases for designing approaches to achieve efficient and safe cardioprotection.
authors.affiliation: Charles University in Prague, Faculty of Pharmacy in Hradec Králové, Hradec Králové, Czech Republic. Tomas.Simunek@faf.cuni.cz
authors.forename: Tomás
authors.initials: T
authors.lastname: Simůnek
authors.forename: Martin
authors.initials: M
authors.lastname: Stérba
authors.forename: Olga
authors.initials: O
authors.lastname: Popelová
authors.forename: Michaela
authors.initials: M
authors.lastname: Adamcová
authors.forename: Radomír
authors.initials: R
authors.lastname: Hrdina
authors.forename: Vladimír
authors.initials: V
authors.lastname: Gersl
mesh_terms: D000818:Animals; D018943:Anthracyclines / Q000009:adverse effects* / Q000494:pharmacology; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects* / Q000494:pharmacology; D002986:Clinical Trials as Topic; D006331:Heart Diseases / Q000139:chemically induced* / Q000503:physiopathology; D006801:Humans; D007501:Iron / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D012307:Risk Factors
chemical_list: D018943:Anthracyclines; D000903:Antibiotics, Antineoplastic; D017382:Reactive Oxygen Species; D007501:Iron