A Novel Positron Emission Tomography (PET) Approach to Monitor Cardiac Metabolic Pathway Remodeling in Response to Sunitinib Malate

• Published in: PloS one Vol. 12; no. 1; p. e0169964
• Main Authors: O'Farrell, Alice C, Evans, Rhys, Silvola, Johanna M U, Miller, Ian S, Conroy, Emer, Hector, Suzanne, Cary, Maurice, Murray, David W, Jarzabek, Monika A, Maratha, Ashwini, Alamanou, Marina, Udupi, Girish Mallya, Shiels, Liam, Pallaud, Celine, Saraste, Antti, Liljenbäck, Heidi, Jauhiainen, Matti, Oikonen, Vesa, Ducret, Axel, Cutler, Paul, McAuliffe, Fionnuala M, Rousseau, Jacques A, Lecomte, Roger, Gascon, Suzanne, Arany, Zoltan, Ky, Bonnie, Force, Thomas, Knuuti, Juhani, Gallagher, William M, Roivainen, Anne, Byrne, Annette T
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.01.2017; Public Library of Science (PLoS)
• Subjects: Acetic acid; Adenosine triphosphate; Animals; Biology and Life Sciences; Blood pressure; Cancer; Cardiomyocytes; Cardiotoxicity; Cell metabolism; Dosage and administration; Electron microscopy; Emission analysis; Emissions; Energy metabolism; Energy resources; Enzyme inhibitors; Fatty acids; Fluorodeoxyglucose F18 - therapeutic use; Glucose; Glucose metabolism; Glycolysis; Growth factors; Health physics; Heart - diagnostic imaging; Heart - drug effects; Heart diseases; Heart failure; Hospitals; Humans; Indoles - administration & dosage; Indoles - adverse effects; Inhibitor drugs; Kinases; Malate; Male; Medical imaging; Medicine; Medicine and Health Sciences; Metabolic Networks and Pathways - drug effects; Metabolism; Mitochondria; Myocardium; Myocardium - metabolism; Myocardium - pathology; Oxidation; Oxidative metabolism; Perfusion; Physics; Physiology; Positron emission; Positron emission tomography; Protein-tyrosine kinase; Proteomics; Pyrroles - administration & dosage; Pyrroles - adverse effects; Rats; Rats, Sprague-Dawley; Research and Analysis Methods; Signal transduction; Signaling; Solid tumors; Substrates; Sunitinib; Targeted cancer therapy; Tomography; Tumors; Tyrosine; Ventricle; Ventricular Function, Left - drug effects
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0169964

Sunitinib is a tyrosine kinase inhibitor approved for the treatment of multiple solid tumors. However, cardiotoxicity is of increasing concern, with a need to develop rational mechanism driven approaches for the early detection of cardiac dysfunction. We sought to interrogate changes in cardiac energy substrate usage during sunitinib treatment, hypothesising that these changes could represent a strategy for the early detection of cardiotoxicity. Balb/CJ mice or Sprague-Dawley rats were treated orally for 4 weeks with 40 or 20 mg/kg/day sunitinib. Cardiac positron emission tomography (PET) was implemented to investigate alterations in myocardial glucose and oxidative metabolism. Following treatment, blood pressure increased, and left ventricular ejection fraction decreased. Cardiac [18F]-fluorodeoxyglucose (FDG)-PET revealed increased glucose uptake after 48 hours. [11C]Acetate-PET showed decreased myocardial perfusion following treatment. Electron microscopy revealed significant lipid accumulation in the myocardium. Proteomic analyses indicated that oxidative metabolism, fatty acid β-oxidation and mitochondrial dysfunction were among the top myocardial signalling pathways perturbed. Sunitinib treatment results in an increased reliance on glycolysis, increased myocardial lipid deposition and perturbed mitochondrial function, indicative of a fundamental energy crisis resulting in compromised myocardial energy metabolism and function. Our findings suggest that a cardiac PET strategy may represent a rational approach to non-invasively monitor metabolic pathway remodeling following sunitinib treatment.