Abstract
Oral mucositis (OM) is one of the main side effects of the head and neck cancer treatment, particularly radiotherapy and/or chemotherapy. OM is characterized by ulcers, erythema, dysphagia, xerostomia, and increased susceptibility to opportunistic infections. In the perspective of finding pharmacological therapies to prevent inflammation and ulceration of OM, the investigation of the pleiotropic effect of commercial drugs is needed, among them gliclazide, an antidiabetic drug. This study aimed to evaluate the effect of gliclazide in an experimental OM model induced by 5-fluorouracil. Male hamsters were pre-treated with oral gliclazide (1, 5, or 10 mg/kg) for 10 days. Cheek pouch samples were subjected to histopathological and immunohistochemical analysis (COX2, iNOS, MMP-2, NFκB P65, GPx) and imunofluorescence (P-selectin). IL-1β and TNF-α levels, Myeloperoxidase activity (MPO) and malondialdehyde (MDA) levels were investigated by ultraviolet-visible spectroscopy analysis. NFκB NLS P50 protein levels were analyzed by western blotting. The group treated with gliclazide at a dose of 10 mg/kg showed presence of erythema, no evidence of erosion, and absence of mucosal ulceration with a score of 1 (1–2) (p < 0.01). Histopathological data for the group treated with gliclazide 10 mg/kg showed re-epithelialization, discrete mononuclear inflammatory infiltrate and absence of hemorrhage, edema, ulcers and abscesses with a score of 1 (1–1) (p < 0.01). Treatment with gliclazide 10 mg/kg reduced MPO activity (p < 0.001), MDA levels (p < 0.001) and NFκB NLS P50 (p < 0.05) protein levels, resulting in low immunostaining to Cox-2, iNOS (p < 0.05), NFκB P65 (p < 0.05), and negative immunoreaction to MMP-2 (p < 0.001). However, it appeared that for Gpx1, the staining was restored in the GLI 10-FUT group compared with 5FUT/saline (p < 0.05). Immunofluorescence revealed decreased levels of P-selectin (p < 0.001) after treatment with gliclazide 10 mg/kg (p < 0.05). In summary, gliclazide accelerated mucosal recovery and reduced oxidative stress and inflammation in the 5-FU-induced OM in hamsters.
Highlights
Oral mucositis (OM) is one of the main toxicities of cancer therapy, affecting up to 60–100% of patients undergoing radiotherapy and/or chemotherapy (Chaveli-Lopez, 2014)
In the 5-FUT/saline group, a significant increase in lipid peroxidation with MDA formation and absence of glutathione peroxidases (GPx) immunolabeling was observed in the oral mucosa, and even though the GLI 10-FUT group underwent chemotherapy with 5 Fluorouracil (5-FU), a reduction of lipid peroxidation (MDA) with presence of low immunolabeling was observed for GPx
Our findings revealed low Cox-2 immunostaining in the group treated with GLI 10-FUT, corroborating literature data showing the effect of gliclazide in reducing prostaglandins formation (Fujitani et al, 1983; Mizuno et al, 1989)
Summary
Oral mucositis (OM) is one of the main toxicities of cancer therapy, affecting up to 60–100% of patients undergoing radiotherapy and/or chemotherapy (Chaveli-Lopez, 2014). 5-FU compromises the DNA and RNA biosynthesis due to the inhibition of the thymidylate synthase (TS) enzyme by its active metabolite, 5-fluoro-2 -deoxyuridine 5 -monophosphate (FdUMP). The 5-FU chemotherapy involves a series of metabolization stages to exert its antitumor action, in which some metabolites can be incorporated into DNA and RNA molecules, or in the case of FdUMP, inhibit enzymes involved in processing these molecules, compromising the cell growth (Matuo et al, 2009). In virtue of its high mitotic activity, the oral mucosa epithelium suffers greater damage by antineoplastic agents that become more effective in rapidly proliferating cells such as bone marrow, hair follicles and epithelial cells of the digestive tract (Tamaki et al, 2003)
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