METHODS AND PHARMACEUTICAL COMPOSITIONS FOR TREATING CARDIOVASCULAR TOXICITY INDUCED BY ANTI-CANCER THERAPY

摘要

The invention relates to methods for treating cardiovascular toxicity induced by anti-cancer and anti-angiogenic compound. The inventors explored the cardiotoxicity induced by the antiangiogenic therapy, sunitinib, in the mouse heart. The inventors showed that sunitinib induces an anaerobic switch of cellular metabolism within the myocardium which is associated with the development of myocardial fibrosis as demonstrated by echocardiography. The capacity of positron emission tomography to detect the changes in cardiac metabolism caused by sunitinib was dependent on fasting status and duration of treatment. Pan proteomic analysis in the myocardium showed that sunitinib induced (i) an early metabolic switch with enhanced glycolysis and reduced oxidative phosphorylation, and (ii) a metabolic failure to use glucose as energy substrate, similar to the insulin resistance found in type 2 diabetes. Co-administration of macitentan, the endothelin receptor antagonist, to sunitinib-treated animals prevented both metabolic defects, restored glucose uptake and cardiac function, and prevented myocardial fibrosis. Thus, the invention relates to a compound selected from the group consisting of endothelin receptor antagonist and inhibitor of endothelin receptor expression for use in the treatment of cardiovascular toxicity induced by anti-cancer and anti-angiogenic compound.