Summary of Study ST000895

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.

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Study IDST000895
Study TitleAnalysis of the effects of Tyrosine Kinase Inhibitors Sunitinib and Erlotinib on Serum Metabolism In Vivo using Non-Targeted Metabolomics Analysis
Study SummaryBackground.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
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 Date2017-05-16
Study CommentsCardiac tissue, Gastrocnemius Muscle, Liver, and Serum
Raw Data AvailableYes
Raw Data File Type(s)d
Analysis Type DetailGC-MS
Release Date2017-11-20
Release Version1
Monte Willis Monte Willis
https://dx.doi.org/10.21228/M88H42
ftp://www.metabolomicsworkbench.org/Studies/ application/zip

Select appropriate tab below to view additional metadata details:

Project:

Project ID:PR000622
Project DOI:doi: 10.21228/M88H42
Project Title:Analysis of the effects of Tyrosine Kinase Inhibitors Sunitinib and Erlotinib on Heart, Muscle, Liver, and Serum Metabolism In Vivo using Non-Targeted Metabolomics Analysis
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 Pathology & Laboratory 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:SU000932
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 Treatment
SA052638S2430mg/kg Sor
SA052639S2330mg/kg Sor
SA052640S2230mg/kg Sor
SA052641S2530mg/kg Sor
SA052642S4330mg/kg Sor
SA052643S4530mg/kg Sor
SA052644S4430mg/kg Sor
SA052645S2130mg/kg Sor
SA052646S4230mg/kg Sor
SA052647S4130mg/kg Sor
SA052648S133mg/kg Trm
SA052649S143mg/kg Trm
SA052650S153mg/kg Trm
SA052651S73mg/kg Trm
SA052652S123mg/kg Trm
SA052653S63mg/kg Trm
SA052654S113mg/kg Trm
SA052655S93mg/kg Trm
SA052656S83mg/kg Trm
SA052657S103mg/kg Trm
SA052658S1940mg/kg Sun
SA052659S1840mg/kg Sun
SA052660S1740mg/kg Sun
SA052661S2040mg/kg Sun
SA052662S3840mg/kg Sun
SA052663S4040mg/kg Sun
SA052664S3940mg/kg Sun
SA052665S3740mg/kg Sun
SA052666S3640mg/kg Sun
SA052667S1640mg/kg Sun
SA052668S3050mg/kg Erl
SA052669S2950mg/kg Erl
SA052670S2850mg/kg Erl
SA052671S4650mg/kg Erl
SA052672S4750mg/kg Erl
SA052673S5050mg/kg Erl
SA052674S4950mg/kg Erl
SA052675S4850mg/kg Erl
SA052676S2750mg/kg Erl
SA052677S2650mg/kg Erl
SA052678S31PBS Ctl
SA052679S5PBS Ctl
SA052680S4PBS Ctl
SA052681S2PBS Ctl
SA052682S1PBS Ctl
SA052683S32PBS Ctl
SA052684S35PBS Ctl
SA052685S34PBS Ctl
SA052686S33PBS Ctl
SA052687S3PBS Ctl
Showing results 1 to 50 of 50

Collection:

Collection ID:CO000926
Collection Summary:Whole blood was collected, allowed to clot in serum separator tubes for 30 min, centrifuged, and stored at -80C.
Sample Type:Blood

Treatment:

Treatment ID:TR000946
Treatment Summary:Fraction of liver weighed (~25-50 mg wet weight), then the finely cut up tissue quickly added to fresh pre-made buffer (50 % acetyl-nitrile, 50 % water, 0.3% formic acid) at a standard concentration of 25 mg/475 mcl buffer then fully homogenized on ice for ~20 s and placed on dry ice/stored at - 80C. Fraction of liver weighed (~25-50 mg wet weight), then the finely cut up tissue quickly added to fresh pre-made buffer (50 % acetyl-nitrile, 50 % water, 0.3% formic acid) at a standard concentration of 25 mg/475 mcl buffer then fully homogenized on ice for ~20 s and placed on dry ice/stored at - 80C.

Sample Preparation:

Sampleprep ID:SP000939
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 AN001457
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:CH001024
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, 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:MS001345
Analysis ID:AN001457
Instrument Name:Agilent 5975
Instrument Type:Single quadrupole
MS Type:EI
Ion Mode:POSITIVE
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