title: Statins in anthracycline-induced cardiotoxicity: Rac and Rho, and the heartbreakers.
abstract: Cancer patients receiving anthracycline-based chemotherapy are at risk to develop life-threatening chronic cardiotoxicity with the pathophysiological mechanism of action not fully understood. Besides the most common hypothesis that anthracycline-induced congestive heart failure (CHF) is mainly caused by generation of reactive oxygen species, recent data point to a critical role of topoisomerase II beta (TOP2B), which is a primary target of anthracycline poisoning, in the pathophysiology of CHF. As the use of the only clinically approved cardioprotectant dexrazoxane has been limited by the FDA in 2011, there is an urgent need for alternative cardioprotective measures. Statins are anti-inflammatory and anti-oxidative drugs that are clinically well established for the prevention of cardiovascular diseases. They exhibit pleiotropic beneficial properties beyond cholesterol-lowering effects that most likely rest on the indirect inhibition of small Ras homologous (Rho) GTPases. The Rho GTPase Rac1 has been shown to be a major factor in the regulation of the pro-oxidative NADPH oxidase as well as in the regulation of type II topoisomerase. Both are discussed to play an important role in the pathophysiology of anthracycline-induced CHF. Therefore, off-label use of statins or novel Rac1 inhibitors might represent a promising pharmacological approach to gain control over chronic cardiotoxicity by interfering with key mechanisms of anthracycline-induced cardiomyocyte cell death.
authors.affiliation: Department of Toxicology, Medical Faculty, Heinrich Heine University Düsseldorf, Moorenstrasse 5, D-40225 Düsseldorf, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Henninger
authors.affiliation: Department of Toxicology, Medical Faculty, Heinrich Heine University Düsseldorf, Moorenstrasse 5, D-40225 Düsseldorf, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Fritz
mesh_terms: D018943:Anthracyclines / Q000009:adverse effects / Q000627:therapeutic use; D016923:Cell Death / Q000187:drug effects; D004250:DNA Topoisomerases, Type II / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D006333:Heart Failure / Q000139:chemically induced / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology; D019255:NADPH Oxidases / Q000235:genetics; D009369:Neoplasms / Q000150:complications* / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D000075223:Poly-ADP-Ribose Binding Proteins; D017382:Reactive Oxygen Species / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000235:genetics*
chemical_list: D018943:Anthracyclines; D004268:DNA-Binding Proteins; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000075223:Poly-ADP-Ribose Binding Proteins; C107953:RAC1 protein, human; D017382:Reactive Oxygen Species; D019255:NADPH Oxidases; D020830:rac1 GTP-Binding Protein; D004250:DNA Topoisomerases, Type II; C000618814:TOP2B protein, human