Abstract
Chemotherapy-induced adverse effects can reduce the relative dose intensity and quality of life. In this study, we investigated the potential benefit of supplementary anamorelin and 5-aminolevulinic acid (5-ALA) as preventive interventions against a gemcitabine and cisplatin (GC) combination chemotherapy-induced adverse effects in a mouse model. Non-cancer-bearing C3H mice were randomly allocated as follows and treated for 2 weeks—(1) non-treated control, (2) oral anamorelin alone, (3) oral 5-ALA alone, (4) gemcitabine and cisplatin (GC) chemotherapy, (5) GC plus anamorelin, and (6) GC plus 5-ALA. GC chemotherapy significantly decreased body weight, food intake, skeletal muscle mass and induced severe gastric mucositis, which resulted in decreased ghrelin production and blood ghrelin level. The supplementation of oral anamorelin to GC chemotherapy successfully mitigated decrease of food intake during the treatment period and body weight loss at day 8. In addition, analysis of the resected muscles and stomach revealed that anamorelin suppressed chemotherapy-induced skeletal muscle atrophy by mediating the downregulation of forkhead box protein O-1 (FOXO1)/atrogin-1 signaling and gastric damage. Our findings suggest the preventive effect of anamorelin against GC combination chemotherapy, which was selected for patients with some types of advanced malignancies in clinical practice.
Highlights
Gemcitabine and cisplatin chemotherapy (GC) is an active combination in the treatment of advanced/metastatic malignancies, such as urothelial carcinoma (UC) [1], non-small cell lung cancer [2], and biliary tract cancer [3]
Treatment with anamorelin alone and 5-aminolevulinic acid (5-ALA) alone did not affect body weight or food intake throughout the 2-week treatment, whereas gemcitabine and cisplatin (GC) chemotherapy led to significant body weight loss, mainly owing to decreased food intake
We found that dephosphorylation of forkhead box protein O-1 (FOXO1) protein, upregulation of total FOXO1 mRNA and decrease in serum insulin-like growth factor (IGF)-1 concentration were induced by GC chemotherapy
Summary
Gemcitabine and cisplatin chemotherapy (GC) is an active combination in the treatment of advanced/metastatic malignancies, such as urothelial carcinoma (UC) [1], non-small cell lung cancer [2], and biliary tract cancer [3]. One of the biggest clinical issues is that most patients receiving chemotherapy, cisplatin, suffer from adverse effects, including anorexia, vomiting, gastrointestinal damage, muscle loss, myelosuppression, nephrotoxicity, and ototoxicity, which can limit the effective dosage. Cancers 2020, 12, 1942 of chemotherapy drugs [4,5,6,7]. It is desirable to develop effective supplementary drugs or interventions to mitigate chemotherapy-induced adverse effects. Chemotherapy-induced acute nausea and vomiting involve serotonin secretion from enterochromaffin cells [5,8]. Anorexia and mucositis are known to be other adverse events induced by chemotherapy. The mechanisms underlying the chemotherapy-induced anorexia remains to be fully elucidated, ghrelin is one of the key gastrointestinal hormones, which regulate feeding and might serve as therapeutic targets for anorexia.
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