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.

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Study IDST000894
Study TitleAnalysis of the effects of Tyrosine Kinase Inhibitors Sunitinib and Erlotinib on Liver 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
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

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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:SU000931
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
SA052608L1940mg/kg Sun
SA052609L1840mg/kg Sun
SA052610L1740mg/kg Sun
SA052611L2040mg/kg Sun
SA052612L3840mg/kg Sun
SA052613L4040mg/kg Sun
SA052614L3940mg/kg Sun
SA052615L1640mg/kg Sun
SA052616L3740mg/kg Sun
SA052617L3640mg/kg Sun
SA052618L3050mg/kg Erl
SA052619L2950mg/kg Erl
SA052620L2850mg/kg Erl
SA052621L4650mg/kg Erl
SA052622L4750mg/kg Erl
SA052623L5050mg/kg Erl
SA052624L4950mg/kg Erl
SA052625L4850mg/kg Erl
SA052626L2750mg/kg Erl
SA052627L2650mg/kg Erl
SA052628L32PBS Ctl
SA052629L33PBS Ctl
SA052630L34PBS Ctl
SA052631L2PBS Ctl
SA052632L1PBS Ctl
SA052633L31PBS Ctl
SA052634L3PBS Ctl
SA052635L4PBS Ctl
SA052636L5PBS Ctl
SA052637L35PBS Ctl
Showing results 1 to 30 of 30

Collection:

Collection ID:CO000925
Collection Summary:Liver was harvested and immediately flash frozen in a cryo tube in iquid nitrogen. Liver was harvested and immediately flash frozen in a cryo tube in iquid nitrogen.
Sample Type:Liver

Treatment:

Treatment ID:TR000945
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:SP000938
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. 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. 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. 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 AN001456
Analysis type MS
Chromatography type GC
Chromatography system Agilent 6890N
Column Agilent DB5-MS (15m × 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:CH001023
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 × 0.25mm, 0.25um)
Chromatography Type:GC

MS:

MS ID:MS001344
Analysis ID:AN001456
Instrument Name:Agilent 5975
Instrument Type:Single quadrupole
MS Type:EI
Ion Mode:POSITIVE
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