Abstract
Tyrosine kinase inhibitors (TKI) have revolutionized cancer therapy, spawning over 500 clinical trials, yet cardiotoxicities are emerging. Sunitinib, a multi-targeted TKI, prolongs life in renal cell and gastrointestinal cancer patients, but hypertension and heart failure have required treatment adjustments. Objective: Sunitinib cardiotoxicity may be due, in part, to direct effects on smooth muscle and cardiac myocytes. Methods: We used C57Bl/6J mice, rat neonatal cardiomyocytes (NCM), and human coronary artery smooth muscle cells (SMC) treated with Sunitinib to measure drug-induced cardiovascular toxicity. Structural (transmission electron microscopy, immunohistochemistry (IHC)/confocal microscopy) and functional [apoptosis/survival, nitric oxide synthesis (intracellular and extracellular), signaling] effects were assessed [real-time PCR, Western blotting, receptor phosphorylation (immunoprecipitation/Western blotting)]. Results: We show mitochondrial injury in hearts from Sunitinib treated mice which persisted off of the drug. In vitro , Sunitinib accumulated in myocytes, caused myofibrillar disorganization, mitochondrial injury, and localized to the lysosomes. Sunitinib caused reductions in akt, MAPK, and AMPK signaling, and activated pro-apoptotic caspase-9 in NCM and SMC with similar effects in large and small vessel endothelial cells. In hearts of Sunitinib-treated mice, we found similar changes in signaling pathways. Conclusion: Sunitinib causes direct cardiac myocyte and smooth muscle cell toxicities, which may contribute to the cardiovascular side effects seen in patients. Further understanding of these mechanisms will guide monitoring, intervention and future rational drug design.
Published Version
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