Authors

Alice C. O'Farrell, Royal College of Surgeons in IrelandFollow
Rhys Evans, Royal College of Surgeons in Ireland
Johanna MU Silvola, Åbo Akademi University
Ian S. Miller, Royal College of Surgeons in Ireland
Emer Conroy, University College Dublin
Suzanne Hector, Royal College of Surgeons in Ireland
Maurice Cary, Pathology Experts GmbH, Basel
David W. Murray, Royal College of Surgeons in Ireland
Monika A. Jarzabek, Royal College of Surgeons in Ireland
Ashwini Maratha, Oncomark Ltd, Dublin
Marina Alamanou, Oncomark Ltd, Dublin
Girish Mallya Udupi, Oncomark Ltd, Dublin
Liam Shiels, Royal College of Surgeons in Ireland
Celine Pallaud, Roche Innovation Center, Basel
Antti Saraste, Åbo Akademi University
Heidi Liljenbäck, Åbo Akademi University
Matti Jauhiainen, National Institute for Health and Welfare, Helsinki
Vesa Oikonen, Åbo Akademi University
Axel Ducret, Roche Innovation Center, Basel
Paul Cutler, Roche Innovation Center, Basel
Fionnuala M McAuliffe, National Maternity Hospital, Dublin
Jacques A Rousseau, Université de Sherbrooke, Québec
Roger Lecomte, Université de Sherbrooke, Québec
Suzanne Gascon, Université de Sherbrooke, Québec
Zoltan Arany, Hospital of the University of Pennsylvania
Bonnie Ky, Hospital of the University of Pennsylvania
Thomas Force, Vanderbilt University School of Medicine, Nashville
Juhani Knuuti, Åbo Akademi University
William M. Gallagher, University College Dublin
Anne Roivainen, Åbo Akademi University
Annette T. Byrne, Royal College of Surgeons in Ireland

Peer Reviewed

1

Document Type

Article

Publication Date

1-1-2017

Funder/Sponsor

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.

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 [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.

Disciplines

Physics | Physiology

Citation

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.

PubMed ID

28129334

DOI Link

10.1371/journal.pone.0169964

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-Share Alike 4.0 License.

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