Cargando…

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

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Huot, Joshua R., Essex, Alyson L., Gutierrez, Maya, Barreto, Rafael, Wang, Meijing, Waning, David L., Plotkin, Lilian I., Bonetto, Andrea
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6520777/
https://www.ncbi.nlm.nih.gov/pubmed/31018508
http://dx.doi.org/10.3390/cancers11040571
_version_ 1783418809378406400
author Huot, Joshua R.
Essex, Alyson L.
Gutierrez, Maya
Barreto, Rafael
Wang, Meijing
Waning, David L.
Plotkin, Lilian I.
Bonetto, Andrea
author_facet Huot, Joshua R.
Essex, Alyson L.
Gutierrez, Maya
Barreto, Rafael
Wang, Meijing
Waning, David L.
Plotkin, Lilian I.
Bonetto, Andrea
author_sort Huot, Joshua R.
collection PubMed
description 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.
format Online
Article
Text
id pubmed-6520777
institution National Center for Biotechnology Information
language English
publishDate 2019
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-65207772019-05-31 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 Cancers (Basel) Article 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. MDPI 2019-04-23 /pmc/articles/PMC6520777/ /pubmed/31018508 http://dx.doi.org/10.3390/cancers11040571 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
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
title Chronic Treatment with Multi-Kinase Inhibitors Causes Differential Toxicities on Skeletal and Cardiac Muscles
title_full Chronic Treatment with Multi-Kinase Inhibitors Causes Differential Toxicities on Skeletal and Cardiac Muscles
title_fullStr Chronic Treatment with Multi-Kinase Inhibitors Causes Differential Toxicities on Skeletal and Cardiac Muscles
title_full_unstemmed Chronic Treatment with Multi-Kinase Inhibitors Causes Differential Toxicities on Skeletal and Cardiac Muscles
title_short Chronic Treatment with Multi-Kinase Inhibitors Causes Differential Toxicities on Skeletal and Cardiac Muscles
title_sort chronic treatment with multi-kinase inhibitors causes differential toxicities on skeletal and cardiac muscles
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6520777/
https://www.ncbi.nlm.nih.gov/pubmed/31018508
http://dx.doi.org/10.3390/cancers11040571
work_keys_str_mv AT huotjoshuar chronictreatmentwithmultikinaseinhibitorscausesdifferentialtoxicitiesonskeletalandcardiacmuscles
AT essexalysonl chronictreatmentwithmultikinaseinhibitorscausesdifferentialtoxicitiesonskeletalandcardiacmuscles
AT gutierrezmaya chronictreatmentwithmultikinaseinhibitorscausesdifferentialtoxicitiesonskeletalandcardiacmuscles
AT barretorafael chronictreatmentwithmultikinaseinhibitorscausesdifferentialtoxicitiesonskeletalandcardiacmuscles
AT wangmeijing chronictreatmentwithmultikinaseinhibitorscausesdifferentialtoxicitiesonskeletalandcardiacmuscles
AT waningdavidl chronictreatmentwithmultikinaseinhibitorscausesdifferentialtoxicitiesonskeletalandcardiacmuscles
AT plotkinliliani chronictreatmentwithmultikinaseinhibitorscausesdifferentialtoxicitiesonskeletalandcardiacmuscles
AT bonettoandrea chronictreatmentwithmultikinaseinhibitorscausesdifferentialtoxicitiesonskeletalandcardiacmuscles