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

Autor: O'Farrell AC; Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland., Evans R; Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland., Silvola JM; Turku PET Centre, Turku University Hospital and Åbo Akademi University, Turku, Finland., Miller IS; Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland., Conroy E; UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Belfield, Dublin, Ireland., Hector S; Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland.; Roche Innovation Center Basel, F Hoffman La Roche, Basel, Switzerland., Cary M; Pathology Experts GmbH, Basel, Switzerland., Murray DW; Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland.; Oncomark Ltd, Dublin, Ireland., Jarzabek MA; Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland.; Roche Innovation Center Basel, F Hoffman La Roche, Basel, Switzerland., Maratha A; Oncomark Ltd, Dublin, Ireland., Alamanou M; Oncomark Ltd, Dublin, Ireland., Udupi GM; Oncomark Ltd, Dublin, Ireland., Shiels L; Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland., Pallaud C; Roche Innovation Center Basel, F Hoffman La Roche, Basel, Switzerland., Saraste A; Turku PET Centre, Turku University Hospital and Åbo Akademi University, Turku, Finland.; Heart Center, Turku University Hospital and Åbo Akademi University, Turku, Finland., Liljenbäck H; Turku PET Centre, Turku University Hospital and Åbo Akademi University, Turku, Finland., Jauhiainen M; Public Health Genomics Unit, National Institute for Health and Welfare, Helsinki, Finland., Oikonen V; Turku PET Centre, Turku University Hospital and Åbo Akademi University, Turku, Finland., Ducret A; Roche Innovation Center Basel, F Hoffman La Roche, Basel, Switzerland., Cutler P; Roche Innovation Center Basel, F Hoffman La Roche, Basel, Switzerland., McAuliffe FM; UCD Obstetrics & Gynaecology, School of Medicine, University College, Dublin, National Maternity Hospital, Dublin, Ireland., Rousseau JA; Université de Sherbrooke, Québec, Canada., Lecomte R; Université de Sherbrooke, Québec, Canada., Gascon S; Université de Sherbrooke, Québec, Canada., Arany Z; Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, United States of America., Ky B; Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, United States of America., Force T; Vanderbilt University School of Medicine, Nashville, United States of America., Knuuti J; Turku PET Centre, Turku University Hospital and Åbo Akademi University, Turku, Finland., Gallagher WM; UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Belfield, Dublin, Ireland.; Oncomark Ltd, Dublin, Ireland., Roivainen A; Turku PET Centre, Turku University Hospital and Åbo Akademi University, Turku, Finland.; Turku Center for Disease Modeling, University of Turku, Turku, Finland., Byrne AT; Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland.
Jazyk: angličtina
Zdroj: PloS one [PLoS One] 2017 Jan 27; Vol. 12 (1), pp. e0169964. Date of Electronic Publication: 2017 Jan 27 (Print Publication: 2017).
DOI: 10.1371/journal.pone.0169964
Abstrakt: 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.
Competing Interests: There are no competing interests associated with the publication of this manuscript and the commercial affiliations do not alter our adherence to PLOS ONE policies on sharing data and materials.
Databáze: MEDLINE
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