Effects of the kinase inhibitor sorafenib on heart, muscle, liver and plasma metabolism <i>in vivo</i> 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 S.

doi:10.1111/bph.14062

Cited by 27 publications

(18 citation statements)

References 45 publications

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“…In the present study we also showed that mitochondrial proteins, such as OPA1 and cytochrome C, that we previously reported down-regulated in models of cancer- or chemotherapy-induced muscle wasting [2,43], were reduced in cardiac muscle with MKI treatment, whereas these same proteins were unchanged in skeletal muscle, also in line with previously published evidence investigating the mitochondrial toxicity induced by sorafenib [31,47] or supporting the MKI-induced disruption of mitochondrial membrane polarization in tumor cell lines [48].…”

Section: Discussionsupporting

confidence: 92%

Chronic Treatment with Multi-Kinase Inhibitors Causes Differential Toxicities on Skeletal and Cardiac Muscles

Huot

Essex

Gutierrez

et al. 2019

Cancers

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Despite recent progress, chemotherapy remains the preferred treatment for cancer. We have shown a link between anticancer drugs and the development of cachexia, i.e., body wasting accompanied by muscle loss. The multi-kinase inhibitors (MKIs) regorafenib and sorafenib, used as second-line treatment for solid tumors, are frequently accompanied by several side effects, including loss of muscle mass and strength. In the present study we aimed to investigate the molecular mechanisms associated with the occurrence of muscle toxicities in in vivo conditions. Hence, we treated 8-week old healthy CD2F1 male mice with MKIs for up to six weeks and observed decreased skeletal and cardiac muscle mass, consistent with muscle weakness. Modulation of ERK1/2 and GSK3β, as well as increased expression of markers of autophagy, previously associated with muscle atrophy conditions, were shown in skeletal muscle upon treatment with either drug. MKIs also promoted cardiac abnormalities consistent with reduced left ventricular mass, internal diameter, posterior wall thickness and stroke volume, despite unchanged overall function. Notably, different signaling pathways were affected in the heart, including reduced expression of mitochondrial proteins, and elevated AKT, GSK3β, mTOR, MEK1/2 and ERK1/2 phosphorylation. Combined, our data demonstrate detrimental effects on skeletal and cardiac muscle in association with chronic administration of MKIs, although different mechanisms would seem to contribute to the cachectic phenotype in the two tissues.

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Section: Discussionsupporting

confidence: 92%

Chronic Treatment with Multi-Kinase Inhibitors Causes Differential Toxicities on Skeletal and Cardiac Muscles

Huot

Essex

Gutierrez

et al. 2019

Cancers

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“…acyl-carnitines, acyl-CoAs, intact lipid species, phosphorylated intermediates, α-keto-acids). Despite this drawback, GC-MS is used routinely for profiling of organic/amino acids in tissues and bodily fluids 32–34 as well as breakdown products of therapeutic and drugs of abuse. 35, 36 GC-MS based metabolomics has also been used for non-esterified and esterified fatty acid analyses in plasma samples, 37, 38 although GC-MS is not the preferred approach for wide-scale lipidomics.…”

Section: Metabolomics Study Considerations and Designmentioning

confidence: 99%

Cardiovascular Metabolomics

McGarrah

Crown²,

Zhang

et al. 2018

Circulation Research

297

216

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Disturbances in cardiac metabolism underlie most cardiovascular diseases. Metabolomics, one of the newer omics technologies, has emerged as a powerful tool for defining changes in both global and cardiac-specific metabolism that occur across a spectrum of cardiovascular disease states. Findings from metabolomics studies have contributed to better understanding of the metabolic changes that occur in heart failure and ischemic heart disease and have identified new cardiovascular disease biomarkers. As technologies advance, the metabolomics field continues to evolve rapidly. In this review, we will discuss the current state of metabolomics technologies, including consideration of various metabolomics platforms and elements of study design; the emerging utility of stable isotopes for metabolic flux studies; and the use of metabolomics to better understand specific cardiovascular diseases, with an emphasis on recent advances in the field.

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“…A non-targeted GC–MS metabolomics approach was used to analyse the heart, skeletal muscle, liver and plasma collected from FVB/N mice (10 per group) treated with sorafenib or vehicle control every day, for two weeks. In sorafenib-treated mice, compared to controls, echocardiography showed CTX-induced systolic dysfunction, while metabolomic analysis revealed significant alterations in 11 metabolites, including a markedly altered taurine/hypotaurine metabolism [59].…”

Section: Metabolomic Studies In Cardiotoxicity and Cardioprotectionmentioning

confidence: 99%

Metabolomic Perspectives in Antiblastic Cardiotoxicity and Cardioprotection

Deidda

Mercurio

Cuomo

et al. 2019

IJMS

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Despite advances in supportive and protective therapy for myocardial function, cardiovascular diseases due to antineoplastic therapy—primarily cardiomyopathy associated with contractile dysfunction—remain a major cause of morbidity and mortality. Because of the limitations associated with current therapies, investigators are searching for alternative strategies that can timely recognise cardiovascular damage—thus permitting a quick therapeutic approach—or prevent the development of the disease. Damage to the heart can result from both traditional chemotherapeutic agents, such as anthracyclines, and new targeted therapies, such as tyrosine kinase inhibitors. In recent years, metabolomics has proved to be a practical tool to highlight fundamental changes in the metabolic state in several pathological conditions. In this article, we present the state-of-the-art technology with regard to the metabolic mechanisms underlying cardiotoxicity and cardioprotection.

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

Cited by 27 publications

References 45 publications

Chronic Treatment with Multi-Kinase Inhibitors Causes Differential Toxicities on Skeletal and Cardiac Muscles

Chronic Treatment with Multi-Kinase Inhibitors Causes Differential Toxicities on Skeletal and Cardiac Muscles

Cardiovascular Metabolomics

Metabolomic Perspectives in Antiblastic Cardiotoxicity and Cardioprotection

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