Summary of Study ST000893

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 IDST000893
Study TitleAnalysis of the effects of Tyrosine Kinase Inhibitors Sunitinib and Erlotinib on Heart, Metabolism In Vivo
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:SU000930
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
SA052578H1940mg/kg Sun
SA052579H1840mg/kg Sun
SA052580H1740mg/kg Sun
SA052581H2040mg/kg Sun
SA052582H3840mg/kg Sun
SA052583H4040mg/kg Sun
SA052584H3940mg/kg Sun
SA052585H1640mg/kg Sun
SA052586H3740mg/kg Sun
SA052587H3640mg/kg Sun
SA052588H3050mg/kg Erl
SA052589H2950mg/kg Erl
SA052590H2850mg/kg Erl
SA052591H4650mg/kg Erl
SA052592H4750mg/kg Erl
SA052593H5050mg/kg Erl
SA052594H4950mg/kg Erl
SA052595H4850mg/kg Erl
SA052596H2750mg/kg Erl
SA052597H2650mg/kg Erl
SA052598H32PBS Ctl
SA052599H33PBS Ctl
SA052600H34PBS Ctl
SA052601H2PBS Ctl
SA052602H1PBS Ctl
SA052603H31PBS Ctl
SA052604H3PBS Ctl
SA052605H4PBS Ctl
SA052606H5PBS Ctl
SA052607H35PBS Ctl
Showing results 1 to 30 of 30

Collection:

Collection ID:CO000924
Collection Summary:Cardiac (LV) tissue was harvested and immediately flash frozen in a liquid nitrogen cooled biopress.
Sample Type:Muscle

Treatment:

Treatment ID:TR000944
Treatment Summary:Fraction of cardiac tissue 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:SP000937
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 AN001455
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:CH001022
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:MS001343
Analysis ID:AN001455
Instrument Name:Agilent 5975
Instrument Type:Single quadrupole
MS Type:EI
Ion Mode:POSITIVE
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