Abstract PR-9: Differences in effects on myocardium and mitochondria by VEGF receptor inhibitors suggest separate mechanisms of cardiotoxicity

Reports have implicated vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors with mitochondrial injury and/or subsequent cardiovascular toxicity, suggesting an on‐target pharmacologic effect by this class of promising anticancer agents. Investigative studies were performed to assess myocardiotoxicity and mitochondrial toxicity of 3 VEGFRi9s (sunitinib, sorafenib and pazopanib). Mitotoxicity was evaluated in vitro using Laser Scanning Cytometry in neonatal rat ventricular myocyte cultures with endpoints including mitochondrial membrane potential (MMP), cell viability, apoptosis and ATP depletion. Cardiomyocytes were exposed with protein free concentrations of up to 4 micromolar of sunitinib, sorafenib or pazopanib for 48 hours. There were no changes in viability or apoptosis versus vehicle‐treated cells. Mitochondrial membrane potential was slightly but significantly decreased with sunitinib treatment but not with sorafenib nor pazopanib. Dose‐dependent intracellular ATP depletion was observed with sunitinib and sorafenib, but not with pazopanib. In separate in vivo studies, echocardiographic, histomorphologic and ultrastructural approaches were used to assess cardiotoxicity in rats concurrently exposed to the cardiac stressor dobutamine and one of the VEGFR inhibitors in rats for 21 days. Troponin I and TUNEL were also evaluated and were similar to controls. While hearts were morphologically unremarkable by routine microscopic examination, ultrastructural analysis of myocardiocytes by electron microscopy revealed mitochondrial swelling, dense deposits and matrix cavitation in 6/8 rats given sunitinib, disrupted mitochondrial cristae in 1/7 given sorafenib, but no effects with pazopanib. Echocardiographic abnormalities including premature ventricular contractions, alterations in heart rate, circumferential strain, and radial and circumferential strain rates were also noted with sorafenib, but not with sunitinib or pazopanib after dobutamine stress challenge. Our results indicate there are marked differences in the potential for myocardial toxicity and mitochondrial toxicity between VEGFR inhibitors. Since sunitinib and sorafenib have previously been shown to have differential effects on mitochondria, the mechanism of cardiac/mitochondrial injury with various VEGFRi9s may not be a result of similar class‐based VEGFR2 pharmacology, but instead reflect separate kinase selectivity profiles. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):PR-9.