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.
Highlights
We and others have shown that chemotherapeutic drugs, while effectively combating tumors, can induce very debilitating side toxicities, including loss of body weight and muscle mass, along with muscle weakness and fatigue [1]
To thethe extent of investigating the when a condition of mild-to-severe cachexia had become evident, as we previously described in models causative mechanisms for the occurrence of defects in skeletal and cardiac muscles, the animals were of cancer- and chemotherapy-induced cachexia [3,25]
The present findings indicate that both regorafenib and sorafenib negatively affect growth and apromote role of multi-targeted kinase inhibitors (MKIs) in causing muscle-associated deficits.inIndeed, regorafenib wasis recently shown worsen skeletal and cardiac muscle wasting normal mice
Summary
We and others have shown that chemotherapeutic drugs, while effectively combating tumors, can induce very debilitating side toxicities, including loss of body weight and muscle mass, along with muscle weakness and fatigue [1]. In an attempt to effectively halt tumor progression and metastases, waves of new alternative therapeutics have surfaced in recent years Among these new classes of drugs are multi-targeted kinase inhibitors (MKIs), two of which, namely sorafenib and regorafenib, have shown significant survival rate improvement in various cancers, including hepatocellular carcinoma, metastatic colorectal cancer, and advanced gastrointestinal stromal tumors [1,7,8]. Despite these promising results, recent studies have identified a myriad of adverse side effects associated with prolonged administration of MKIs, including, but not limited to, arterial hypertension, diarrhea, potential hemorrhage, fatigue and muscle weakness [9,10,11,12,13,14]. Despite early investigations on adverse effects with MKI treatments, the direct molecular impact that these drugs have on skeletal and cardiac muscle is largely unexplored, and studies examining the long-term toxic effects on the musculoskeletal system are lacking
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