Effects of the kinase inhibitor sorafenib on heart, muscle, liver and plasma metabolism in vivo using non-targeted metabolomics analysis

Brian C. Jensen, Traci L. Parry, Wei Huang, Ju Youn Beak, Amro Ilaiwy, James R. Bain, Christopher B. Newgard, Michael J. Muehlbauer, Cam Patterson, Gary L. Johnson, Monte Willis

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Background and Purpose: The human kinome consists of roughly 500 kinases, including 150 that have been proposed as therapeutic targets. Protein kinases regulate an array of signalling pathways that control metabolism, cell cycle progression, cell death, differentiation and survival. It is not surprising, then, that new kinase inhibitors developed to treat cancer, including sorafenib, also exhibit cardiotoxicity. We hypothesized that sorafenib cardiotoxicity is related to its deleterious effects on specific cardiac metabolic pathways given the critical roles of protein kinases in cardiac metabolism. Experimental Approach: FVB/N mice (10 per group) were challenged with sorafenib or vehicle control daily for 2 weeks. Echocardiographic assessment of the heart identified systolic dysfunction consistent with cardiotoxicity in sorafenib-treated mice compared to vehicle-treated controls. Heart, skeletal muscle, liver and plasma were flash frozen and prepped for non-targeted GC–MS metabolomics analysis. Key Results: Compared to vehicle-treated controls, sorafenib-treated hearts exhibited significant alterations in 11 metabolites, including markedly altered taurine/hypotaurine metabolism (25-fold enrichment), identified by pathway enrichment analysis. Conclusions and Implications: These studies identified alterations in taurine/hypotaurine metabolism in the hearts and skeletal muscles of mice treated with sorafenib. Interventions that rescue or prevent these sorafenib-induced changes, such as taurine supplementation, may be helpful in attenuating sorafenib-induced cardiac injury.

Original languageEnglish (US)
Pages (from-to)4797-4811
Number of pages15
JournalBritish Journal of Pharmacology
Volume174
Issue number24
DOIs
StatePublished - Dec 1 2017
Externally publishedYes

Fingerprint

Metabolomics
Myocardium
Phosphotransferases
Liver
Taurine
Protein Kinases
Skeletal Muscle
sorafenib
Metabolic Networks and Pathways
Cell Cycle Checkpoints
Gas Chromatography-Mass Spectrometry
Cell Differentiation
Cell Survival
Cell Death
Wounds and Injuries

ASJC Scopus subject areas

  • Pharmacology

Cite this

Effects of the kinase inhibitor sorafenib on heart, muscle, liver and plasma metabolism in vivo using non-targeted metabolomics analysis. / Jensen, Brian C.; Parry, Traci L.; Huang, Wei; Beak, Ju Youn; Ilaiwy, Amro; Bain, James R.; Newgard, Christopher B.; Muehlbauer, Michael J.; Patterson, Cam; Johnson, Gary L.; Willis, Monte.

In: British Journal of Pharmacology, Vol. 174, No. 24, 01.12.2017, p. 4797-4811.

Research output: Contribution to journalArticle

Jensen, BC, Parry, TL, Huang, W, Beak, JY, Ilaiwy, A, Bain, JR, Newgard, CB, Muehlbauer, MJ, Patterson, C, Johnson, GL & Willis, M 2017, 'Effects of the kinase inhibitor sorafenib on heart, muscle, liver and plasma metabolism in vivo using non-targeted metabolomics analysis', British Journal of Pharmacology, vol. 174, no. 24, pp. 4797-4811. https://doi.org/10.1111/bph.14062
Jensen, Brian C. ; Parry, Traci L. ; Huang, Wei ; Beak, Ju Youn ; Ilaiwy, Amro ; Bain, James R. ; Newgard, Christopher B. ; Muehlbauer, Michael J. ; Patterson, Cam ; Johnson, Gary L. ; Willis, Monte. / Effects of the kinase inhibitor sorafenib on heart, muscle, liver and plasma metabolism in vivo using non-targeted metabolomics analysis. In: British Journal of Pharmacology. 2017 ; Vol. 174, No. 24. pp. 4797-4811.
@article{20ed4bf61025454e842501c2190e0377,
title = "Effects of the kinase inhibitor sorafenib on heart, muscle, liver and plasma metabolism in vivo using non-targeted metabolomics analysis",
abstract = "Background and Purpose: The human kinome consists of roughly 500 kinases, including 150 that have been proposed as therapeutic targets. Protein kinases regulate an array of signalling pathways that control metabolism, cell cycle progression, cell death, differentiation and survival. It is not surprising, then, that new kinase inhibitors developed to treat cancer, including sorafenib, also exhibit cardiotoxicity. We hypothesized that sorafenib cardiotoxicity is related to its deleterious effects on specific cardiac metabolic pathways given the critical roles of protein kinases in cardiac metabolism. Experimental Approach: FVB/N mice (10 per group) were challenged with sorafenib or vehicle control daily for 2 weeks. Echocardiographic assessment of the heart identified systolic dysfunction consistent with cardiotoxicity in sorafenib-treated mice compared to vehicle-treated controls. Heart, skeletal muscle, liver and plasma were flash frozen and prepped for non-targeted GC–MS metabolomics analysis. Key Results: Compared to vehicle-treated controls, sorafenib-treated hearts exhibited significant alterations in 11 metabolites, including markedly altered taurine/hypotaurine metabolism (25-fold enrichment), identified by pathway enrichment analysis. Conclusions and Implications: These studies identified alterations in taurine/hypotaurine metabolism in the hearts and skeletal muscles of mice treated with sorafenib. Interventions that rescue or prevent these sorafenib-induced changes, such as taurine supplementation, may be helpful in attenuating sorafenib-induced cardiac injury.",
author = "Jensen, {Brian C.} and Parry, {Traci L.} and Wei Huang and Beak, {Ju Youn} and Amro Ilaiwy and Bain, {James R.} and Newgard, {Christopher B.} and Muehlbauer, {Michael J.} and Cam Patterson and Johnson, {Gary L.} and Monte Willis",
year = "2017",
month = "12",
day = "1",
doi = "10.1111/bph.14062",
language = "English (US)",
volume = "174",
pages = "4797--4811",
journal = "British Journal of Pharmacology",
issn = "0007-1188",
publisher = "Wiley-Blackwell",
number = "24",

}

TY - JOUR

T1 - Effects of the kinase inhibitor sorafenib on heart, muscle, liver and plasma metabolism in vivo using non-targeted metabolomics analysis

AU - Jensen, Brian C.

AU - Parry, Traci L.

AU - Huang, Wei

AU - Beak, Ju Youn

AU - Ilaiwy, Amro

AU - Bain, James R.

AU - Newgard, Christopher B.

AU - Muehlbauer, Michael J.

AU - Patterson, Cam

AU - Johnson, Gary L.

AU - Willis, Monte

PY - 2017/12/1

Y1 - 2017/12/1

N2 - Background and Purpose: The human kinome consists of roughly 500 kinases, including 150 that have been proposed as therapeutic targets. Protein kinases regulate an array of signalling pathways that control metabolism, cell cycle progression, cell death, differentiation and survival. It is not surprising, then, that new kinase inhibitors developed to treat cancer, including sorafenib, also exhibit cardiotoxicity. We hypothesized that sorafenib cardiotoxicity is related to its deleterious effects on specific cardiac metabolic pathways given the critical roles of protein kinases in cardiac metabolism. Experimental Approach: FVB/N mice (10 per group) were challenged with sorafenib or vehicle control daily for 2 weeks. Echocardiographic assessment of the heart identified systolic dysfunction consistent with cardiotoxicity in sorafenib-treated mice compared to vehicle-treated controls. Heart, skeletal muscle, liver and plasma were flash frozen and prepped for non-targeted GC–MS metabolomics analysis. Key Results: Compared to vehicle-treated controls, sorafenib-treated hearts exhibited significant alterations in 11 metabolites, including markedly altered taurine/hypotaurine metabolism (25-fold enrichment), identified by pathway enrichment analysis. Conclusions and Implications: These studies identified alterations in taurine/hypotaurine metabolism in the hearts and skeletal muscles of mice treated with sorafenib. Interventions that rescue or prevent these sorafenib-induced changes, such as taurine supplementation, may be helpful in attenuating sorafenib-induced cardiac injury.

AB - Background and Purpose: The human kinome consists of roughly 500 kinases, including 150 that have been proposed as therapeutic targets. Protein kinases regulate an array of signalling pathways that control metabolism, cell cycle progression, cell death, differentiation and survival. It is not surprising, then, that new kinase inhibitors developed to treat cancer, including sorafenib, also exhibit cardiotoxicity. We hypothesized that sorafenib cardiotoxicity is related to its deleterious effects on specific cardiac metabolic pathways given the critical roles of protein kinases in cardiac metabolism. Experimental Approach: FVB/N mice (10 per group) were challenged with sorafenib or vehicle control daily for 2 weeks. Echocardiographic assessment of the heart identified systolic dysfunction consistent with cardiotoxicity in sorafenib-treated mice compared to vehicle-treated controls. Heart, skeletal muscle, liver and plasma were flash frozen and prepped for non-targeted GC–MS metabolomics analysis. Key Results: Compared to vehicle-treated controls, sorafenib-treated hearts exhibited significant alterations in 11 metabolites, including markedly altered taurine/hypotaurine metabolism (25-fold enrichment), identified by pathway enrichment analysis. Conclusions and Implications: These studies identified alterations in taurine/hypotaurine metabolism in the hearts and skeletal muscles of mice treated with sorafenib. Interventions that rescue or prevent these sorafenib-induced changes, such as taurine supplementation, may be helpful in attenuating sorafenib-induced cardiac injury.

UR - http://www.scopus.com/inward/record.url?scp=85037988578&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85037988578&partnerID=8YFLogxK

U2 - 10.1111/bph.14062

DO - 10.1111/bph.14062

M3 - Article

C2 - 28977680

AN - SCOPUS:85037988578

VL - 174

SP - 4797

EP - 4811

JO - British Journal of Pharmacology

JF - British Journal of Pharmacology

SN - 0007-1188

IS - 24

ER -