Project description: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 tyrosine kinase inhibitor erlotinib targets epidermal growth factor receptor (EGFR), whereas sunitinib targets primarily vascular endothelial growth factor receptor (VEGRF) and platelet-derived growth factor receptor (PDGFR). TKIs impact the function of non-malignant cells had have on- and off-target toxicities, including cardiotoxicities. Most of the reports of sunitinib have identified cardiotoxic effects, whereas erlotinib was less often found to have these effects. We hypothesized that the deleterious effects of TKIs were related to their impact on cardiac metabolism. Methods. C57BL/6 mice (10/group) were treated with therapeutic doses of sunitinib (40 mg/kg), erlotinib (50 mg/kg), or vehicle daily for 2 weeks. Echocardiographic assessment of the heart in vivo identified significant systolic dysfunction consistent with cardiotoxicity compared to vehicle treated controls. 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 insystolic function, whereas erlotinib treated mice did not. Non-Targeted metabolomics analysis of heart identified identified significant decreases in Docosahexaenoic acid (DHA), Arachidonic Acid/Eicosapentaenoic acid (EPA), O-Phosphocolamine, and 6-Hydroxynicotinic acid after sunitinib treatment. DHA was significantly decreased in skeletal muscle (quadriceps femoris), with elevations in cholesterol were identified in liver and elevated ethanol amine in serum. In contrast, erlotinib affected only one metabolite elevated (spermidine significantly increased).Conclusions.Mice treated with sunitinib had 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 in the polyunsaturated fatty acids (PUFAs) and inflammatory mediators DHA and AA/EPA in the heart, possibly by affecting mitochondria function where they have vital roles on calcium channels.

Project description:Background & Aims: Non-alcoholic fatty liver disease accompanies obesity and is independently associated with cardiovascular disease. Omega-3 fatty acids, such as docosahexaenoic (DHA) and eicosapentaenoic (EPA) acid, reduce the risk of cardiovascular disease due to their anti-inflammatory and hypolipidemic effects. Recent data suggested that metabolic effects of EPA/DHA as marine phospholipids could be stronger than triglycerides (fish oil). We characterised the mechanisms underlying beneficial effects of EPA/DHA phospholipids alone or in combination with antidiabetic drugs on hepatosteatosis in dietary obese mice. Methods: Male C57BL/6N mice were fed for 7 weeks a corn oil-based high-fat diet (cHF) or subjected to cHF-based interventions: (i) cHF with DHA/EPA as phosphatidylcholine-rich concentrate replacing ~10 % of dietary lipids (PC); ii) cHF with a low-dose of thiazolidinedione rosiglitazone (10 mg/kg diet), which retains some of the beneficial effects but also potentiates hepatic lipid accumulation (R); and iii) PC+R. Metabolic profiling together with hepatic gene expression and lipidomic analyses were performed. Results: PC and PC+R prevented weight gain and glucose intolerance induced by cHF, while all interventions reduced abdominal fat and plasma triglycerides. In contrast to R, PC and PC+R lowered hepatic and plasma cholesterol and eliminated hepatosteatosis. Hepatic microarray analysis primarily revealed a complex downregulation of lipogenic and cholesterol biosynthesis pathways by PC. Lipidomic analysis identified arachidonic acid, DHA and EPA in hepatic phosphatidylcholine and phosphatidylethanolamine fractions as the most important variables. Importantly, down-regulation of genes within these pathways was enlarged by phospholipid versus triglyceride forms of EPA/DHA in an independent experiment. Conclusions: Obesity-associated hepatosteatosis and hypercholesterolemia were ameliorated by marine phospholipids in association with a complex inhibition of biosynthetic pathways in liver. Stronger effects of phospholipids versus triglyceride form of EPA/DHA suggest their preferential use in the prevention and possible treatment of obesity-associated metabolic hepatic dysfunctions.

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Analysis of the effects of Tyrosine Kinase Inhibitors Sunitinib and Erlotinib on Serum Metabolism In Vivo using Non-Targeted Metabolomics Analysis

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