title: Differences in effects on myocardium and mitochondria by angiogenic inhibitors suggest separate mechanisms of cardiotoxicity.
abstract: 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.
authors.affiliation: Department of Safety Assessment, GlaxoSmithKline, King of Prussia, Pennsylvania 19406, USA.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: French
authors.forename: Robert W
authors.initials: RW
authors.lastname: Coatney
authors.forename: Jon P
authors.initials: JP
authors.lastname: Renninger
authors.forename: Catherine X
authors.initials: CX
authors.lastname: Hu
authors.forename: Tracy L
authors.initials: TL
authors.lastname: Gales
authors.forename: Shufang
authors.initials: S
authors.lastname: Zhao
authors.forename: Laura M
authors.initials: LM
authors.lastname: Storck
authors.forename: Charles B
authors.initials: CB
authors.lastname: Davis
authors.forename: Jeanelle
authors.initials: J
authors.lastname: McSurdy-Freed
authors.forename: Emile
authors.initials: E
authors.lastname: Chen
authors.forename: Kendall S
authors.initials: KS
authors.lastname: Frazier
mesh_terms: D020533:Angiogenesis Inhibitors / Q000009:adverse effects*; D000818:Animals; D001557:Benzenesulfonates / Q000009:adverse effects; D004452:Echocardiography; D006321:Heart / Q000187:drug effects*; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007191:Indazoles; D007211:Indoles / Q000009:adverse effects; D008297:Male; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000187:drug effects* / Q000648:ultrastructure; D009206:Myocardium / Q000648:ultrastructure*; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D011725:Pyridines / Q000009:adverse effects; D011743:Pyrimidines / Q000009:adverse effects; D011758:Pyrroles / Q000009:adverse effects; D051381:Rats; D000077157:Sorafenib; D013449:Sulfonamides / Q000009:adverse effects; D000077210:Sunitinib; D019210:Troponin I / Q000096:biosynthesis
chemical_list: D020533:Angiogenesis Inhibitors; D001557:Benzenesulfonates; D007191:Indazoles; D007211:Indoles; D010671:Phenylurea Compounds; D011725:Pyridines; D011743:Pyrimidines; D011758:Pyrroles; D013449:Sulfonamides; D019210:Troponin I; D009536:Niacinamide; C516667:pazopanib; D000077157:Sorafenib; D000077210:Sunitinib