Refereed journal article or data article (A1)

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




List of AuthorsAliceO'Farrell AC, Evans R, Silvola JMU, Miller IS, Conroy E, Hector S, Cary M, Murray DW, Jarzabek MA, Maratha A, Alamanou M, Udupi GM, Shiels L, Pallaud C, Saraste A, Liljenback H, Jauhiainen M, Oikonen V, Ducret A, Cutler P, McAuliffe FM, Rousseau JA, Lecomte R, Gascon S, Arany Z, Ky B, Force T, Knuuti J, Gallagher WM, Roivainen A, Byrne AT, Byrne AT

PublisherPUBLIC LIBRARY SCIENCE

Publication year2017

JournalPLoS ONE

Journal name in sourcePLOS ONE

Journal acronymPLOS ONE

Article numberARTN e0169964

Volume number12

Issue number1

Number of pages18

ISSN1932-6203

DOIhttp://dx.doi.org/10.1371/journal.pone.0169964

Self-archived copy’s web addresshttps://research.utu.fi/converis/portal/detail/Publication/20529905


Abstract
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 [F-18]-fluorodeoxyglucose (FDG)-PET revealed increased glucose uptake after 48 hours. [C-11] 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 beta-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.

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Last updated on 2022-07-04 at 16:26