Molecular mechanisms of doxorubicin-induced mitochondrial cardiotoxicity

Doxorubicin (DOX) is an anticancer agent that is highly efficacious in the treatment of numerous cancers. In addition to this potent antineoplastic effect, it has also been observed to cause a dose-limiting cardiotoxicity that may become apparent many years beyond the period of treatment. A great deal of research spanning several decades has contributed to characterizing toxicological effects of DOX in hopes of defining the underlying mechanism of cardiotoxicity. Despite a wealth of data demonstrating a number of effects mediated by the drug, the precise mechanism of DOX cardiotoxicity remains a matter of debate. However, there exists a consensus that the toxicity of DOX is related to the induction of oxidative stress. Increased reactive oxygen species (ROS) production in the heart by DOX occurs via redox cycling of the drug at complex I of the electron transport chain housed within the inner membranes of mitochondria. Many studies demonstrate that mitochondria are a target of DOX toxicity, both acutely and long-term. Oxidative stress and mitochondrial dysfunction persist beyond the period of drug treatment, suggesting a permanent alteration to the myocardium. The work herein focuses on the effects of DOX on the mitochondrion, which support the hypothesis that the function of these organelles is indeed a major factor in drug-induced cardiotoxicity. By evaluating the impact of DOX on mitochondrial DNA and the fidelity of its gene products, in addition to the impact on signaling pathways related to mitochondrial processes such as biogenesis and metabolic regulation, these data will hopefully contribute to the understanding of drug-induced cardiotoxicity and enhance the definition of the mechanism of DOX toxicity.