This work was funded by AngioTox [www.angiotox.com], a European Commission FP7 Industry Academia Pathways and Partnerships Marie Curie Award (Grant Agreement 251528). Oncomark Ltd, Pathology Experts GmBH andRoche Innovation Center Basel are partner organizations within AngioTox and thus received funding towards salaries and consumables supporting this work. The specific roles of industry co-authors are described in the ’author contributions’ section. ACOF received a Travel Fellowship of £2000 from the British Association of Cancer Research for travel costs incurred whilst undertaking work at the Turku PET Center, Turku, Finland.
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.
Physics | Physiology
O'Farrell AC, Evans R, Silvola JM, Miller IS, Conroy E, Hector S, Cary M, Murray DW, Jarzabek MA, Maratha A, Alamanou M, Udupi GM, Shiels L, Pallaud C, Saraste A, Liljenbäck 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. A Novel Positron Emission Tomography (PET) Approach to Monitor Cardiac Metabolic Pathway Remodeling in Response to Sunitinib Malate. PloS One. 2017;12(1):e0169964.
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