Inhibition of Rac1 signaling by lovastatin protects against anthracycline-induced cardiac toxicity

J Huelsenbeck,C Henninger,K J Lackner,G Fritz,B Kaina,A Schad

doi:10.1038/cddis.2011.65

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.

Highlights

It is under debate whether dexrazoxane has negative effects on the antitumor efficacy of anthracyclines.[10,11]
Doxorubicin influx and efflux were not affected by lovastatin (Figure 1b)
The antiapoptotic statin effect is likely not related to changes in cell-cycle progression because lovastatin did not impact the number of cells arrested in G2/M phase after doxorubicin exposure and, did not influence the level of Chk-1 phosphorylation stimulated by the anthracycline (Supplementary Figure S1)

Summary

Introduction

It is under debate whether dexrazoxane has negative effects on the antitumor efficacy of anthracyclines.[10,11]. HMG-CoA reductase inhibitors (statins), which are clinically established for lipid-lowering purposes, are known to have pleiotropic biological effects.[17] These pleiotropic effects are mainly based on the inhibition of the prenylation of Received 17.2.11; revised 16.6.11; accepted 17.6.11; Edited by A Stephanou low-molecular weight GTPases that are having key roles in the regulation of numerous cellular processes.[17,18,19] High doses of statins enhance the tumor cell kill of anticancer drugs[20,21] by impairing G1–S transition[22] and triggering apoptosis.[23,24] statins promote TNFa-triggered apoptosis[25] and reverse chemoresistance by inhibition of NF-kB.[26] Apart from increasing the antitumor activity of numerous anticancer drugs in vitro and in vivo,[19] low doses of statins reduce cell death of primary human endothelial cells (HUVECs) provoked by doxorubicin and ionizing radiation in vitro.[27,28] statins protect the intestine from the side effects of radiotherapy in vivo.[29,30,31] These reports point to a dual beneficial function of statins in anticancer therapy, that is, the promotion of anticancer drug-induced killing of malignant cells and concomitant protection of normal cells Based on these reports and the well-documented cardioprotective function of statins,[32] we hypothesized that statins might be clinically useful for alleviating adverse effects of anthracyclines, in particular anthracycline-induced cardiotoxicity. We show that the HMG-CoA reductase inhibitor lovastatin significantly protects against doxorubicin-induced cardiac toxicity and, at the same time, augments the anticancer effect of doxorubicin

Methods

Results

Conclusion