title: Heart failure associated with sunitinib: lessons learned from animal models.
abstract: Sunitinib is a highly potent, multitargeted anticancer agent. However, there is growing clinical evidence that sunitinib induces cardiac dysfunction. Disruption of multiple signaling pathways, which are important in the maintenance of adult cardiac function, is likely to result in cardiovascular toxicity. Basic and translational evidence implicates a potential role for specific growth factor signaling pathways. This review discusses the relevant translational data from animal models of heart failure, focusing on three key pathways that are inhibited by sunitinib: AMP-activated protein kinase (AMPK), platelet-derived growth factor receptors (PDGFRs), and the vascular endothelial growth factor receptors (VEGFRs) 1, 2, and 3. We hypothesize that disruption of these pathways by sunitinib results in cardiotoxicity, and present direct and indirect evidence to support the notion that sunitinib-induced cardiac dysfunction likely involves a variety of molecular mechanisms that are critical for cardiac homeostasis.
authors.affiliation: Department of Pharmacology, Institute for Translational Medicine and Therapeutics, Department of Emergency Medicine, University of Pennsylvania School of Medicine, 3400 Spruce Street, Philadelphia, PA 19104, USA. colin.greineder@uphs.upenn.edu
authors.forename: Colin F
authors.initials: CF
authors.lastname: Greineder
authors.forename: Sarah
authors.initials: S
authors.lastname: Kohnstamm
authors.forename: Bonnie
authors.initials: B
authors.lastname: Ky
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors; D020533:Angiogenesis Inhibitors / Q000009:adverse effects*; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy; D054715:Cardiotoxins; D004195:Disease Models, Animal; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy; D006333:Heart Failure / Q000139:chemically induced*; D006801:Humans; D007211:Indoles / Q000009:adverse effects*; D007680:Kidney Neoplasms / Q000188:drug therapy; D008928:Mitochondria / Q000187:drug effects; D011758:Pyrroles / Q000009:adverse effects*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000187:drug effects; D012307:Risk Factors; D015398:Signal Transduction / Q000187:drug effects; D000077210:Sunitinib
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D054715:Cardiotoxins; D007211:Indoles; D011758:Pyrroles; D040262:Receptors, Vascular Endothelial Growth Factor; D055372:AMP-Activated Protein Kinases; C526180:PRKAA1 protein, human; D000077210:Sunitinib