Doxorubicin (DOX) is a highly effective anticancer anthracycline used in the treatment of a wide variety of solid tumor malignancies. However, clinical use of this powerful chemotherapeutic is limited by the prevalence of irreversible cardiac tissue damage, which carries a poor prognosis and is often fatal. While efforts have been made to identify risk factors, develop less-toxic derivatives and detect subclinical toxicity earlier, there is currently no consensus on the best approach to prevent anthracycline-induced cardiomyopathy. Thus, further advances in the understanding of the molecular basis of DOX-induced pathology are needed to generate preventative strategies. DOX accumulates rapidly within cardiac tissue following exposure, where it preferentially localizes to the mitochondria and promotes free radical production through redox cycling with NADH dehydrogenase and iron cycling between Fe2+ and Fe3+. Elevated free radical production in the mitochondria can lead to severe damaging events resulting in cell death, and evidence suggests that prevention of mitochondrial dysfunction is sufficient to attenuate the cardiotoxic effects of DOX. Therefore, elucidating ways in which the mitochondrial accumulation of DOX can be reduced could result in the development of a therapeutic approach to mitigate the cardiotoxic effects of DOX. In this regard, we recently discovered that endurance exercise training prior to DOX treatment is sufficient to reduce the mitochondrial accumulation of DOX and preserve cardiac function. While the mechanisms responsible for the exercise-induced reduction in the levels of cardiac mitochondrial DOX are unknown, we hypothesize that activity-induced changes in the expression of xenobiotic transport proteins and/or changes in vascular tight junction integrity may play a role in mediating the entry of DOX into the cardiomyocytes. Therefore, the goal of this proposal is to establish the effects of exercise training on the expression of solute carrier transport proteins and on vascular permeability, and to determine if targeting these mechanisms has therapeutic potential to prevent DOX-induced cardiac dysfunction. We will accomplish this by testing the following specific aims:
Specific Aim 1) will determine the effects of exercise and doxorubicin on the expression of solute carrier proteins in the heart;
and Specific Aim 2) will determine if exercise-induced protection against DOX cardiotoxicity is related to changes in endothelial function and tight junction permeability.
Although doxorubicin (DOX) is a highly efficacious chemotherapeutic agent used in the treatment of a wide variety of cancers, its clinical use is limited by the development of cardiomyopathy. The long-term goal of this project is to identify biological targets that will assist in the development of a therapeutic strategy to reduce the risk of cardiovascular disease in cancer patients. The results from this study will advance the understanding of the molecular basis of DOX-induced myocardial toxicity and serve as the foundation for future translational studies to generate preventative strategies.
