title: Inhibition of Rac1 signaling by lovastatin protects against anthracycline-induced cardiac toxicity.
abstract: Normal tissue damage limits the efficacy of anticancer therapy. For anthracyclines, the clinically most relevant adverse effect is cardiotoxicity. The mechanisms involved are poorly understood and putative cardioprotectants are controversially discussed. Here, we show that the lipid-lowering drug lovastatin protects rat H9c2 cardiomyoblasts from doxorubicin in vitro. Protection by lovastatin is related to inhibition of the Ras-homologous GTPase Rac1. It rests on a reduced formation of DNA double-strand breaks, resulting from the inhibition of topoisomerase II by doxorubicin. Doxorubicin transport and reactive oxygen species are not involved. Protection by lovastatin was confirmed in vivo. In mice, lovastatin mitigated acute doxorubicin-induced heart and liver damage as indicated by reduced mRNA levels of the pro-fibrotic cytokine connective tissue growth factor (CTGF) and pro-inflammatory cytokines, respectively. Lovastatin also protected from doxorubicin-provoked subacute cardiac damage as shown by lowered mRNA levels of CTGF and atrial natriuretic peptide. Increase in the serum concentration of troponin I and cardiac fibrosis following doxorubicin treatment were also reduced by lovastatin. Whereas protecting the heart from harmful doxorubicin effects, lovastatin augmented its anticancer efficacy in a mouse xenograft model with human sarcoma cells. These data show that statins lower the incidence of cardiac tissue injury after anthracycline treatment in a Rac1-dependent manner, without impairing the therapeutic efficacy.
authors.affiliation: Institute of Toxicology, University Medical Center of the Johannes Gutenberg University Mainz, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Huelsenbeck
authors.forename: C
authors.initials: C
authors.lastname: Henninger
authors.forename: A
authors.initials: A
authors.lastname: Schad
authors.forename: K J
authors.initials: KJ
authors.lastname: Lackner
authors.forename: B
authors.initials: B
authors.lastname: Kaina
authors.forename: G
authors.initials: G
authors.lastname: Fritz
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity; D009320:Atrial Natriuretic Factor / Q000235:genetics / Q000378:metabolism; D055513:Connective Tissue Growth Factor / Q000235:genetics / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded; D004250:DNA Topoisomerases, Type II / Q000737:chemistry / Q000378:metabolism; D004317:Doxorubicin / Q000633:toxicity; D008148:Lovastatin / Q000494:pharmacology*; D051379:Mice; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D019210:Troponin I / Q000097:blood; D020830:rac1 GTP-Binding Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; C526318:CCN2 protein, mouse; D019210:Troponin I; D055513:Connective Tissue Growth Factor; D004317:Doxorubicin; D009320:Atrial Natriuretic Factor; D008148:Lovastatin; D020830:rac1 GTP-Binding Protein; D004250:DNA Topoisomerases, Type II