Summary of Study ST000575

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 PR000424. The data can be accessed directly via it's Project DOI: 10.21228/M87S4H This work is supported by NIH grant, U2C- DK119886.

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Study IDST000575
Study TitleEffects of the Kinase Inhibitor Sorafenib on Muscle Metabolism In Vivo using Non-targeted Metabolomics Analysis tissue).
Study SummaryThe 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.
Institute
University of North Carolina at Chapel Hill
DepartmentMcAllister heart Institute, Department of Internal medicine
LaboratoryMultiple Centers
Last NameWillis
First NameMonte
Address111 Mason Farm road, Chapel Hill, North Carolina, 27599-7126, USA
Emailmonte_willis@med.unc.edu
Phone919-360-7599
Submit Date2017-03-24
Study CommentsHeart, Liver, Skeletal Muscle (Gastrocnemius), Serum
Analysis Type DetailGC-MS
Release Date2018-04-10
Release Version1
Monte Willis Monte Willis
https://dx.doi.org/10.21228/M87S4H
ftp://www.metabolomicsworkbench.org/Studies/ application/zip

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Project:

Project ID:PR000424
Project DOI:doi: 10.21228/M87S4H
Project Title:Effects of the Kinase Inhibitor Sorafenib on Heart, Muscle, Liver, and Serum Metabolism In Vivo using Non-targeted Metabolomics Analysis Mice
Project Type:GC-MS non targeted analysis
Project Summary:Non targeted metabolomic analysis on samples from rats expressing human amylin.
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
Email:monte_willis@med.unc.edu
Phone:919-360-7599
Funding Source:NIH, Fondation Leducq

Subject:

Subject ID:SU000598
Subject Type:Animal
Subject Species:Mus musculus
Taxonomy ID:10090
Species Group:Mammal

Factors:

Subject type: Animal; Subject species: Mus musculus (Factor headings shown in green)

mb_sample_id local_sample_id Vehicle (PBS) Control Treatment
SA03038430mg/kg Sor 530 mg/kg Sorafenib Treatment
SA03038530mg/kg Sor 430 mg/kg Sorafenib Treatment
SA03038630mg/kg Sor 330 mg/kg Sorafenib Treatment
SA03038730mg/kg Sor 630 mg/kg Sorafenib Treatment
SA03038830mg/kg Sor 830 mg/kg Sorafenib Treatment
SA03038930mg/kg Sor 1030 mg/kg Sorafenib Treatment
SA03039030mg/kg Sor 930 mg/kg Sorafenib Treatment
SA03039130mg/kg Sor 230 mg/kg Sorafenib Treatment
SA03039230mg/kg Sor 730 mg/kg Sorafenib Treatment
SA03039330mg/kg Sor 130 mg/kg Sorafenib Treatment
SA030394PBS Ctl 5Vehicle (PBS) Control Treatment
SA030395PBS Ctl 4Vehicle (PBS) Control Treatment
SA030396PBS Ctl 3Vehicle (PBS) Control Treatment
SA030397PBS Ctl 2Vehicle (PBS) Control Treatment
SA030398PBS Ctl 6Vehicle (PBS) Control Treatment
SA030399PBS Ctl 7Vehicle (PBS) Control Treatment
SA030400PBS Ctl 10Vehicle (PBS) Control Treatment
SA030401PBS Ctl 9Vehicle (PBS) Control Treatment
SA030402PBS Ctl 8Vehicle (PBS) Control Treatment
SA030403PBS Ctl 1Vehicle (PBS) Control Treatment
Showing results 1 to 20 of 20

Collection:

Collection ID:CO000592
Collection Summary:Skeletal muscle (gastrocnemius) was harvested and flash frozen in a liquid nitrogen cooled biopress
Sample Type:Muscle

Treatment:

Treatment ID:TR000612
Treatment Summary:None

Sample Preparation:

Sampleprep ID:SP000605
Sampleprep Summary:The samples were crash deprotonized by methanol precipitation and spiked with D27-deuterated myristic acid (D27-C14:0) as an internal standard for retention-time locking and dried. The trimethylsilyl-D27-C14:0 standard retention time (RT) was set at 16.727 min. Reactive carbonyls were stabilized at 50C with methoxyamine hydrochloride in dry pyridine. Metabolites were made volatile with TMS groups using N-methyl-N-(trimethylsilyl) trifluoroacetamide or MSTFA with catalytic trimethylchlorosilane at 50C.

Combined analysis:

Analysis ID AN000885
Analysis type MS
Chromatography type GC
Chromatography system Agilent 6890N
Column Agilent DB5-MS (15m x 0.25mm,0.25um)
MS Type EI
MS instrument type Single quadrupole
MS instrument name Agilent 5975
Ion Mode POSITIVE
Units Peak values (Log transformed)

Chromatography:

Chromatography ID:CH000628
Chromatography Summary:GC/MS methods follow previous studies using a 6890 N GC connected to a 5975 Inert single quadrupole MS (Agilent Technologies, Santa Clara, CA) (Bonikos et al. 1975; Fiehn 2008; Kind et al. 2009). The two wall-coated, open-tubular GC columns connected in series are both from J&W/Agilent (part 122äóñ5512), DB5-MS, 15 meters in length, 0.25 mm in diameter, with an 0.25-l m luminal film. Positive ions generated with conventional electron-ionization at 70 eV are scanned broadly from 600 to 50 m/z in the detector throughout the 45 min cycle time.
Instrument Name:Agilent 6890N
Column Name:Agilent DB5-MS (15m x 0.25mm,0.25um)
Chromatography Type:GC

MS:

MS ID:MS000787
Analysis ID:AN000885
Instrument Name:Agilent 5975
Instrument Type:Single quadrupole
MS Type:EI
Ion Mode:POSITIVE
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