Metformin protects 5-Fu-induced chemotherapy oral mucositis by reducing endoplasmic reticulum stress in mice

Abstract

Metformin (Met) is a first-line and essential treatment for type 2 diabetes, with anti-inflammatory effects. It has been reported Met could inhibit NF-κB activity and down-regulate the release of inflammatory factors. However, whether Met has a protective effect on chemotherapy-induced oral mucositis(CIOM) is unknown. The purpose of this study was to evaluate the protective effect of Metformin(Met) on chemotherapy-induced oral mucositis(CIOM) and further explore its possible mechanism. 5-Fu was used in the C57BL/6 mice to establish the model of CIOM. Our results showed Met could significantly improve 5-Fu-induced mucosal damage, apoptosis, ROS and releasing of inflammatory factors in the tongue tissue. In addition, Met could inhibit 5-Fu-induced high expression of endoplasmic reticulum stress(ERS)-related proteins GRP78 and CHOP. Further studies showed that the protective effect of ERS inhibitor 4-PBA on CIOM was similar to Met. Moreover, Met inhibited the phosphorylation of NF-κB in tongue tissue, independent of AMPK phosphorylation. The protective effect of PDTC, an inhibitor of NF-κB, on tongue tissue was similar to that of Met. This study confirmed the protective effect of Met on 5-Fu-induced CIOM, which was achieved by inhibiting ERS and reducing the activity of NF-κB.

Keywords: 5-Fluorouracil; Chemotherapy-induced oral mucositis; Endoplasmic reticulum stress; Metformin; NF-κB.