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

1
Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA
2
Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
3
Greenfield Central High School, Greenfield, IN 46140, USA
4
Department of Cellular and Molecular Physiology, Penn State University, Hershey, PA 17033, USA
5
Department of Otolaryngology—Head & Neck Surgery, Indiana Center for Musculoskeletal Health, Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA
*
Author to whom correspondence should be addressed.
Cancers 2019, 11(4), 571; https://doi.org/10.3390/cancers11040571
Received: 14 February 2019 / Revised: 12 April 2019 / Accepted: 18 April 2019 / Published: 23 April 2019
(This article belongs to the Special Issue Cancer Cachexia)
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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 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. View Full-Text
Keywords: chemotherapy; skeletal muscle wasting; cardiac cachexia; sorafenib; regorafenib chemotherapy; skeletal muscle wasting; cardiac cachexia; sorafenib; regorafenib
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Huot, J.R.; Essex, A.L.; Gutierrez, M.; Barreto, R.; Wang, M.; Waning, D.L.; Plotkin, L.I.; Bonetto, A. Chronic Treatment with Multi-Kinase Inhibitors Causes Differential Toxicities on Skeletal and Cardiac Muscles. Cancers 2019, 11, 571.

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