Summary of Study ST000894
This data is available at the NIH Common Fund's National Metabolomics Data Repository (NMDR) website, the Metabolomics Workbench, https://www.metabolomicsworkbench.org, where it has been assigned Project ID PR000622. The data can be accessed directly via it's Project DOI: 10.21228/M88H42 This work is supported by NIH grant, U2C- DK119886.
See: https://www.metabolomicsworkbench.org/about/howtocite.php
| Study ID | ST000894 |
| Study Title | Analysis of the effects of Tyrosine Kinase Inhibitors Sunitinib and Erlotinib on Liver Metabolism In Vivo |
| Study Summary | 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. |
| Institute | University of North Carolina at Chapel Hill |
| Department | McAllister heart Institute, Department of Internal medicine |
| Laboratory | Multiple Centers |
| Last Name | Willis |
| First Name | Monte |
| Address | 111 Mason Farm road, Chapel Hill, North Carolina, 27599-7126, USA |
| monte_willis@med.unc.edu | |
| Phone | 919-360-7599 |
| Submit Date | 2017-05-16 |
| Study Comments | Cardiac tissue, Gastrocnemius Muscle, Liver, and Serum |
| Raw Data Available | Yes |
| Raw Data File Type(s) | d |
| Analysis Type Detail | GC-MS |
| Release Date | 2017-11-20 |
| Release Version | 1 |
Select appropriate tab below to view additional metadata details:
Factors:
Subject type: Animal; Subject species: Mus musculus (Factor headings shown in green)
| mb_sample_id | local_sample_id | Treatment |
|---|---|---|
| SA052608 | L19 | 40mg/kg Sun |
| SA052609 | L18 | 40mg/kg Sun |
| SA052610 | L17 | 40mg/kg Sun |
| SA052611 | L20 | 40mg/kg Sun |
| SA052612 | L38 | 40mg/kg Sun |
| SA052613 | L40 | 40mg/kg Sun |
| SA052614 | L39 | 40mg/kg Sun |
| SA052615 | L16 | 40mg/kg Sun |
| SA052616 | L37 | 40mg/kg Sun |
| SA052617 | L36 | 40mg/kg Sun |
| SA052618 | L30 | 50mg/kg Erl |
| SA052619 | L29 | 50mg/kg Erl |
| SA052620 | L28 | 50mg/kg Erl |
| SA052621 | L46 | 50mg/kg Erl |
| SA052622 | L47 | 50mg/kg Erl |
| SA052623 | L50 | 50mg/kg Erl |
| SA052624 | L49 | 50mg/kg Erl |
| SA052625 | L48 | 50mg/kg Erl |
| SA052626 | L27 | 50mg/kg Erl |
| SA052627 | L26 | 50mg/kg Erl |
| SA052628 | L32 | PBS Ctl |
| SA052629 | L33 | PBS Ctl |
| SA052630 | L34 | PBS Ctl |
| SA052631 | L2 | PBS Ctl |
| SA052632 | L1 | PBS Ctl |
| SA052633 | L31 | PBS Ctl |
| SA052634 | L3 | PBS Ctl |
| SA052635 | L4 | PBS Ctl |
| SA052636 | L5 | PBS Ctl |
| SA052637 | L35 | PBS Ctl |
| Showing results 1 to 30 of 30 |
