Chronic treatment with multi-kinase inhibitors causes differential toxicities on skeletal and cardiac muscles

Joshua R. Huot, Alyson L. Essex, Maya Gutierrez, Rafael Barreto, Meijing Wang, David L. Waning, Lilian I. Plotkin, Andrea Bonetto

Research output: Contribution to journalArticle

Abstract

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 GSK3+, 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.

Original languageEnglish (US)
Article number571
JournalCancers
Volume11
Issue number4
DOIs
StatePublished - Apr 2019

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Myocardium
Skeletal Muscle
Phosphotransferases
Muscles
Cachexia
Muscular Atrophy
Mitochondrial Proteins
Muscle Weakness
Autophagy
Muscle Strength
Therapeutics
Pharmaceutical Preparations
Stroke Volume
Neoplasms
Phosphorylation
Phenotype
Drug Therapy

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Huot, Joshua R. ; Essex, Alyson L. ; Gutierrez, Maya ; Barreto, Rafael ; Wang, Meijing ; Waning, David L. ; Plotkin, Lilian I. ; Bonetto, Andrea. / Chronic treatment with multi-kinase inhibitors causes differential toxicities on skeletal and cardiac muscles. In: Cancers. 2019 ; Vol. 11, No. 4.
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abstract = "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 GSK3+, 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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Huot, JR, Essex, AL, Gutierrez, M, Barreto, R, Wang, M, Waning, DL, Plotkin, LI & Bonetto, A 2019, 'Chronic treatment with multi-kinase inhibitors causes differential toxicities on skeletal and cardiac muscles', Cancers, vol. 11, no. 4, 571. https://doi.org/10.3390/cancers11040571

Chronic treatment with multi-kinase inhibitors causes differential toxicities on skeletal and cardiac muscles. / Huot, Joshua R.; Essex, Alyson L.; Gutierrez, Maya; Barreto, Rafael; Wang, Meijing; Waning, David L.; Plotkin, Lilian I.; Bonetto, Andrea.

In: Cancers, Vol. 11, No. 4, 571, 04.2019.

Research output: Contribution to journalArticle

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T1 - Chronic treatment with multi-kinase inhibitors causes differential toxicities on skeletal and cardiac muscles

AU - Huot, Joshua R.

AU - Essex, Alyson L.

AU - Gutierrez, Maya

AU - Barreto, Rafael

AU - Wang, Meijing

AU - Waning, David L.

AU - Plotkin, Lilian I.

AU - Bonetto, Andrea

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