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Metabolites 2017, 7(3), 31; doi:10.3390/metabo7030031

Non-Targeted Metabolomics Analysis of the Effects of Tyrosine Kinase Inhibitors Sunitinib and Erlotinib on Heart, Muscle, Liver and Serum Metabolism In Vivo

1
Department of Medicine, Division of Cardiology, University of North Carolina, Chapel Hill, NC 27599, USA
2
McAllister Heart Institute, University of North Carolina, Chapel Hill, NC 27599, USA
3
Department of Pathology & Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599, USA
4
Sarah W. Stedman Nutrition and Metabolism Center, Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC 27701, USA
5
Department of Medicine, Division of Endocrinology, Metabolism, and Nutrition, Duke University Medical Center, Durham, NC 27701, USA
6
Presbyterian Hospital/Weill-Cornell Medical Center, New York, NY 10065, USA
7
Department of Pharmacology, University of North Carolina, Chapel Hill, NC 27599, USA
*
Authors to whom correspondence should be addressed.
Academic Editor: Vidya Velagapudi
Received: 17 May 2017 / Revised: 12 June 2017 / Accepted: 15 June 2017 / Published: 22 June 2017
(This article belongs to the Special Issue Clinical Metabolomics)
View Full-Text   |   Download PDF [1688 KB, uploaded 22 June 2017]   |  

Abstract

Background: More than 90 tyrosine kinases have been implicated in the pathogenesis of malignant transformation and tumor angiogenesis. Tyrosine kinase inhibitors (TKIs) have emerged as effective therapies in treating cancer by exploiting this kinase dependency. The TKI erlotinib targets the epidermal growth factor receptor (EGFR), whereas sunitinib targets primarily vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR).TKIs that impact the function of non-malignant cells and have on- and off-target toxicities, including cardiotoxicities. Cardiotoxicity is very rare in patients treated with erlotinib, but considerably more common after sunitinib treatment. We hypothesized that the deleterious effects of TKIs on the heart were related to their impact on cardiac metabolism. Methods: Female FVB/N mice (10/group) were treated with therapeutic doses of sunitinib (40 mg/kg), erlotinib (50 mg/kg), or vehicle daily for two weeks. Echocardiographic assessment of the heart in vivo was performed at baseline and on Day 14. Heart, skeletal muscle, liver and serum were flash frozen and prepped for non-targeted GC-MS metabolomics analysis. Results: Compared to vehicle-treated controls, sunitinib-treated mice had significant decreases in systolic function, whereas erlotinib-treated mice did not. Non-targeted metabolomics analysis of heart identified significant decreases in docosahexaenoic acid (DHA), arachidonic acid (AA)/ eicosapentaenoic acid (EPA), O-phosphocolamine, and 6-hydroxynicotinic acid after sunitinib treatment. DHA was significantly decreased in skeletal muscle (quadriceps femoris), while elevated cholesterol was identified in liver and elevated ethanolamine identified in serum. In contrast, erlotinib affected only one metabolite (spermidine significantly increased). Conclusions: Mice treated with sunitinib exhibited systolic dysfunction within two weeks, with significantly lower heart and skeletal muscle levels of long chain omega-3 fatty acids docosahexaenoic acid (DHA), arachidonic acid (AA)/eicosapentaenoic acid (EPA) and increased serum O-phosphocholine phospholipid. This is the first link between sunitinib-induced cardiotoxicity and depletion of the polyunsaturated fatty acids (PUFAs) and inflammatory mediators DHA and AA/EPA in the heart. These compounds have important roles in maintaining mitochondrial function, and their loss may contribute to cardiac dysfunction. View Full-Text
Keywords: erlotinib; sorafenib; kinase inhibitors; cardiotoxicity; metabolomics; serum; liver; muscle; heart erlotinib; sorafenib; kinase inhibitors; cardiotoxicity; metabolomics; serum; liver; muscle; heart
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MDPI and ACS Style

Jensen, B.C.; Parry, T.L.; Huang, W.; Ilaiwy, A.; Bain, J.R.; Muehlbauer, M.J.; O’Neal, S.K.; Patterson, C.; Johnson, G.L.; Willis, M.S. Non-Targeted Metabolomics Analysis of the Effects of Tyrosine Kinase Inhibitors Sunitinib and Erlotinib on Heart, Muscle, Liver and Serum Metabolism In Vivo. Metabolites 2017, 7, 31.

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