title: Chemotherapy-induced mucositis is associated with changes in proteolytic pathways.
abstract: Mucositis, a common toxic side effect of chemotherapy, is characterized by an arrest of cell proliferation and a loss of gut barrier function, which may cause treatment reduction or withdrawal. Gut integrity depends on nutritional and metabolic factors, including the balance between protein synthesis and proteolysis. The effects of methotrexate (MTX; a frequently used chemotherapeutic agent) on intestinal proteolysis and gut barrier function were investigated in rats. Male Sprague-Dawley rats received 2.5 mg/kg of MTX subcutaneously during 3 days and were euthanized at Day 4 (D4) or Day 7 (D7). We observed at D4 that MTX induced mucosal damage and increased intestinal permeability (7-fold) and the mucosal concentration of interleukin (IL)-1beta and IL-6 (4- to 6-fold). In addition, villus height and glutathione content significantly decreased. Intestinal proteolysis was also affected by MTX as cathepsin D activity increased at D4, whereas chymotrypsin-like proteasome activity decreased and calpain activities remained unaffected. At D7, cathepsin D activity was restored to control levels, but proteasome activity remained reduced. This disruption of proteolysis pathways strongly contributed to mucositis and requires further study. Lysosomal proteolytic activity may be considered the main proteolytic pathway responsible for alteration of mucosal integrity and intestinal permeability during mucositis, as cathepsin D activity was found to be correlated with mucosal atrophy and intestinal permeability. Proteasome regulation could possibly be an adaptive process for survival. Future investigation is warranted to target proteolytic pathways with protective nutritional or pharmacological therapies during mucositis.
authors.affiliation: Appareil Digestif Environnement Nutrition (EA3234), Institut Hospitalo-Universitaire de Recherche Biomédicale and Institut Fédératif de Recherches Multidisciplinaires sur les Peptides (IFRMP23), University of Rouen and Rouen University Hospital, France.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Leblond
authors.forename: Florence
authors.initials: F
authors.lastname: Le Pessot
authors.forename: Aurélie
authors.initials: A
authors.lastname: Hubert-Buron
authors.forename: Célia
authors.initials: C
authors.lastname: Duclos
authors.forename: Jacques
authors.initials: J
authors.lastname: Vuichoud
authors.forename: Magali
authors.initials: M
authors.lastname: Faure
authors.forename: Denis
authors.initials: D
authors.lastname: Breuillé
authors.forename: Pierre
authors.initials: P
authors.lastname: Déchelotte
authors.forename: Moïse
authors.initials: M
authors.lastname: Coëffier
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D004435:Eating / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D007408:Intestinal Absorption / Q000187:drug effects; D007583:Jejunum / Q000378:metabolism; D008297:Male; D008727:Methotrexate / Q000494:pharmacology*; D052016:Mucositis / Q000139:chemically induced* / Q000201:enzymology* / Q000473:pathology; D010447:Peptide Hydrolases / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D016207:Cytokines; D010447:Peptide Hydrolases; D005978:Glutathione; D008727:Methotrexate