Roles of oxidative stress and Akt signaling in doxorubicin cardiotoxicity

Cardiotoxicity is a treatment-limiting side effect of the anticancer drug doxorubicin (DOX). We have now investigated the roles of oxidative stress and signaling by the protein kinase Akt in DOX-induced cardiotoxicity as well as the effects on such toxicity both of fenofibrate, an agonist of peroxisome proliferator-activated receptor-α, and of polyethylene glycol-conjugated superoxide dismutase (PEG–SOD), an antioxidant. Mice injected intraperitoneally with DOX were treated for 4 days with fenofibrate or PEG–SOD. Fenofibrate and PEG–SOD each prevented the induction of cardiac dysfunction by DOX. Both drugs also inhibited the activation of the transcription factor NF-κB and increase in lipid peroxidation in the left ventricle induced by DOX, whereas only PEG–SOD inhibited the DOX-induced activation of Akt and Akt-regulated gene expression. These results suggest that fenofibrate and PEG–SOD prevented cardiac dysfunction induced by DOX through normalization of oxidative stress and redox-regulated NF-κB signaling.