Effects of the Kinase Inhibitor Sorafenib on Muscle Metabolism In Vivo using Non-targeted Metabolomics Analysis tissue).
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ABSTRACT: The human kinome consists of ~500 kinases, including 150 proposed as therapeutic targets. progression, cell death, differentiation, and survival. It is not surprising, then, that new tyrosine kinase inhibitors (TKIs) developed to treat cancer also exhibit cardiotoxicity, including sorafenib. We hypothesized that sorafenib cardiotoxicity is related to its deleterious effects on specific cardiac metabolic pathways given the critical role of TKs in cardiac metabolism. FVB/N mice (10/group) were challenged with sorafenib or vehicle control daily for two weeks. Echocardiographic assessment of the heart identified systolic dysfunction consistent with cardiotoxicity compared to vehicle treated controls. Cardiac, skeletal muscle, liver, and serum were flash frozen and prepped for non-targeted GC-MS metabolomics analysis. Compared to vehicle treated controls, sorafenib-treated hearts exhibited significant alterations in 11 metabolites, including markedly altered taurine/hypotaurine metabolism by pathway enrichment analysis (25-fold enrichment). These studies identify sorafenib-induced alterations in cardiac alanine and taurine/hypotaurine metabolic. Interventions to rescue or prevent sorafenib-related cardiotoxicity warrant consideration of therapies targeting the taurine/hypotaurine deficiency identified in the current study.
INSTRUMENT(S): Single quadrupole
ORGANISM(S): Mouse Mus Musculus
TISSUE(S): Muscle
DISEASE(S): Cancer
SUBMITTER: Monte Willis
PROVIDER: ST000575 | MetabolomicsWorkbench | Fri Mar 24 00:00:00 GMT 2017
REPOSITORIES: MetabolomicsWorkbench
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