Differences in Effects on Myocardium and Mitochondria by Angiogenic Inhibitors Suggest Separate Mechanisms of Cardiotoxicity

Several multikinase angiogenesis inhibitors demonstrate mitochondrial and/or cardiovascular toxicity, suggesting an on-target pharmacologic effect. To evaluate whether cardiotoxicity is directly related to vascular endothelial growth factor receptor inhibition, we investigated the effects of sunitin...

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Bibliographic Details
Published in:	Toxicologic pathology Vol. 38; no. 5; pp. 691 - 702
Main Authors:	French, Kevin J., Coatney, Robert W., Renninger, Jon P., Hu, Catherine X., Gales, Tracy L., Zhao, Shufang, Storck, Laura M., Davis, Charles B., McSurdy-Freed, Jeanelle, Chen, Emile, Frazier, Kendall S.
Format:	Journal Article
Language:	English
Published:	Los Angeles, CA SAGE Publications 01-08-2010 Sage Publications
Subjects:	Angiogenesis Inhibitors - adverse effects Animals Benzenesulfonates - adverse effects Biological and medical sciences Echocardiography Heart - drug effects Immunohistochemistry In Situ Nick-End Labeling Indoles - adverse effects Male Medical sciences Microscopy, Electron, Transmission Mitochondria - drug effects Mitochondria - ultrastructure Myocardium - ultrastructure Niacinamide - analogs & derivatives Phenylurea Compounds Pyridines - adverse effects Pyrimidines - adverse effects Pyrroles - adverse effects Rats Sulfonamides - adverse effects Toxicology Troponin I - biosynthesis sunitinib kinase inhibitor cardiotoxicity sorafenib pazopanib angiogenesis Antineoplastic agent Enzyme Tyrosine kinase inhibitor Toxicity Transferases Enzyme inhibitor Cardiovascular disease Angiogenesis Mitochondria Sunitinib Kinase Heart disease Sorafenib Myocardium Circulatory system Multikinase inhibitor Neovascularization Antiangiogenic agent Mechanism of action Protein-tyrosine kinase Pazopanib
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Summary:	Several multikinase angiogenesis inhibitors demonstrate mitochondrial and/or cardiovascular toxicity, suggesting an on-target pharmacologic effect. To evaluate whether cardiotoxicity is directly related to vascular endothelial growth factor receptor inhibition, we investigated the effects of sunitinib, sorafenib, and pazopanib on myocardial function and structure. We used a rat model to assess myocardial effects of the inhibitors concurrently exposed to the cardiac stressor dobutamine. Echocardiographic abnormalities including premature ventricular contractions, decreases in heart rate, circumferential strain, and radial and circumferential strain rates were noted with sorafenib, but not with sunitinib or pazopanib. Ultrastructural analysis of ventricular cardiomyocytes by transmission electron microscopy revealed mitochondrial swelling, dense deposits, and matrix cavitation in rats given sunitinib and disrupted mitochondrial cristae in rats given sorafenib, but there were no effects with pazopanib. Effects on neonatal rat cardiomyocyte cultures were assessed, which identified decreases in mitochondrial membrane potential with sunitinib treatment, but not with sorafenib or pazopanib. Intracellular adenosine triphosphate depletion was observed with sunitinib and sorafenib, but not pazopanib. Our results show that cardiotoxicity is not necessarily related to a pharmacologic classwide effect of vascular endothelial growth factor receptor inhibition, and the rat myocardial structural and functional changes identified in this study may be instead a result of inhibition of other kinase pathways, the mechanism of which may be associated with mitochondrial toxicity.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23
ISSN:	0192-6233 1533-1601
DOI:	10.1177/0192623310373775