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.

A Diet Containing Whey Protein, Glutamine, and TGFβ Modulates Gut Protein Metabolism During Chemotherapy-Induced Mucositis in Rats

“…In the placebo diet, whey proteins and TGFb-rich casein were replaced by TGFb-free casein and free glutamine by free alanine (Table 1). Mucositis was induced by three subcutaneous injections of 2.5 mg/kg MTX (Teva Pharma, Courbevoie, France) for 3 consecutive days (day 0, 1 and 2) as previously described [3,4]. Control rats received injections of saline (0.9%).…”

“…In rats, we recently reported that MTX treatment alters intestinal barrier function and protein metabolism [3] independent of the anorectic effect of MTX [4]. Indeed, MTX treatment was associated with a decrease of protein synthesis [4] and an increase of lysosomalmediated proteolysis in jejunal mucosa [3,4], which may contribute to the disruption of the gut barrier.…”

The Effectiveness of Grape Extract in Rats with Methotrexate Induced Intestinal Mucositis

“…24 MTX has been shown to induce shortening or fusion of villi, and both atrophy and desquamation of the surface epithelium in various studies. [26][27][28] In the present study, the tissue sections of the rats showed normal intestinal structures in the salinetreated group.…”

“…Rapidly proliferative cells of the gastrointestinal system are vulnarable to the methotrexate toxicity. 24 In this context, we thought that naturally occurring dietary supplements could be used in combination with chemotherapy to ameliorate the mucosal damage and stimulate the tissue repairing of intestine. The major objectives of the current study were to assess the preventive effect of GE histopathologically on MTX-induced villus damage, epithelial atrophy, crypt loss, neutrophil accumulation in the lamina propria and goblet cell depletion in the small intestine of rats.…”

oral-ingestion-of-spondias-pinnata-bark-extract-trim-down-severity-of-small-intestinal-mucositis

“…the tubes were centrifuged for 5 min, to remove precipitate. The supernatant was used for phosphate estimation by Fiske-Subba Row method [27].…”