gms | German Medical Science

After more than fifty years of anthracycline-based chemotherapy the molecular mechanisms of its dose limiting cardiotoxic side effects are still elusive. Anthracycline-induced cardiotoxicity (AIC) is thought to involve multiple mechanisms including reactive oxygen species (ROS), inhibition of topoisomerase II (topII) isoforms, generation of toxic metabolites and autophagic cell death. Identification of candidates for preventive strategies is delicate as the pathophysiology of acute and chronic cardiotoxicity seems to be different. Furthermore, the contribution of different cardiovascular cell types to AIC is unclear.

For years the iron/ROS-hypothesis was favoured because dexrazoxane (DRZ) – the only approved cardioprotectant in anthracycline-based therapy – complexes iron which is required for anthracycline-induced generation of hydroxyl radicals. Yet, since neither N acetylcysteine nor EDTA-derivatives are cardioprotective, its mechanism of action is still enigmatic. DRZ itself is a topII inhibitor with cytostatic potential. In contrast to anthracyclines, topoII inhibition by DRZ does not cause DNA double-strand breaks (DSBs). Inhibition of topIIb might be particularly relevant for AIC since high expression promotes doxorubicin-induced toxicity and topoIIb knockout mice are less sensitive to anthracyclines. Formation of the topoII-DNA-cleavable complex does not only result in DSBs in the nuclear DNA, it also causes mitochondrial DNA damage which is paralleled by ROS generation and apoptosis. Overall, topIIb appears to be a promising target for prevention of cardiac DNA damage and ROS formation as it might be relevant for both acute and chronic cardiotoxicity following anthracycline treatment.

We have shown that inhibition of small GTPases with lovastatin or Rac1-specific ‘small molecule’ inhibitors protects endothelial cells and cardiomyocytes from doxorubicin-induced DSB formation in vitro and from cardiotoxicity in vivo. We hypothesise that the small GTPase Rac1 is required for the formation of the cleavable complexes. Based on the data we suggest the Rho-GTPase Rac1 as a promising novel pharmacological target for prevention and therapy of AIC.