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PLoS One. 2017 Jan 27;12(1):e0169964. doi: 10.1371/journal.pone.0169964. eCollection 2017.

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

Author information

1
Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland.
2
Turku PET Centre, Turku University Hospital and Åbo Akademi University, Turku, Finland.
3
UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Belfield, Dublin, Ireland.
4
Roche Innovation Center Basel, F Hoffman La Roche, Basel, Switzerland.
5
Pathology Experts GmbH, Basel, Switzerland.
6
Oncomark Ltd, Dublin, Ireland.
7
Heart Center, Turku University Hospital and Åbo Akademi University, Turku, Finland.
8
Public Health Genomics Unit, National Institute for Health and Welfare, Helsinki, Finland.
9
UCD Obstetrics & Gynaecology, School of Medicine, University College, Dublin, National Maternity Hospital, Dublin, Ireland.
10
Université de Sherbrooke, Québec, Canada.
11
Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, United States of America.
12
Vanderbilt University School of Medicine, Nashville, United States of America.
13
Turku Center for Disease Modeling, University of Turku, 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.

PMID:
28129334
PMCID:
PMC5271313
DOI:
10.1371/journal.pone.0169964
[Indexed for MEDLINE]
Free PMC Article

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