Rebamipide suppresses 5-fluorouracil-induced cell death via the activation of Akt/mTOR pathway and regulates the expression of Bcl-2 family proteins

• Published in: Toxicology in vitro 2018-02, Vol.46, p.284-293
• Main Authors: Tsubaki, Masanobu, Takeda, Tomoya, Asano, Ryo-ta, Matsuda, Tomoyuki, Fujimoto, Shin-ichiro, Itoh, Tatsuki, Imano, Motohiro, Satou, Takao, Nishida, Shozo
• Format: Article
• Language: English
• Subjects: 5-Fluorouracil; 5-FU; Akt; AKT protein; Alanine - analogs & derivatives; Alanine - pharmacology; Animals; Antimetabolites - toxicity; Antioxidants - toxicity; Bax protein; Bcl-2 protein; Bcl-x protein; BIM protein; Cell activation; Cell death; Cell Death - drug effects; Cell Survival; Cells; Chemoradiotherapy; Chemotherapy; Fluorouracil - toxicity; Gene Expression Regulation - drug effects; Humans; Keratinocytes; Keratinocytes - drug effects; Molecular chains; mTOR; Mucosa; Mucositis; Mucous membrane; Oral mucositis; Proteins; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; Proto-Oncogene Proteins c-bcl-2 - genetics; Proto-Oncogene Proteins c-bcl-2 - metabolism; Quinolones - pharmacology; Rebamipide; Studies; TOR protein; TOR Serine-Threonine Kinases
• ISSN: 0887-2333; 1879-3177
• DOI: 10.1016/j.tiv.2017.10.019

Oral mucositis is a common adverse effect of chemotherapy that limits the required dose of chemotherapeutic agents. Numerous attempts to mitigate chemotherapy-induced oral mucositis have failed to identify an appropriate treatment. Recently, it has been indicated that rebamipide prevents chemoradiotherapy-induced oral mucositis in patients. However, the details of the underlying mechanism involved in the cytoprotective effect of rebamipide remain obscure. In the present study, we investigated the mechanism behind rebamipide cytoprotective effect in the oral mucosa using primary normal human oral keratinocytes (NHOK cells). We found that rebamipide prevented 5-fluorouracil (5-FU)-induced cell death in NHOK cells. In addition, rebamipide increased the levels of phosphorylated Akt and mTOR, enhanced the Bcl-2 and Bcl-xL expressions, and suppressed the expression of Bax and Bim. This is in contrast to 5-FU-induced suppression of Akt and mTOR activation, Bcl-2 and Bcl-xL expressions, and the enhanced expression of Bax and Bim. These findings suggest that rebamipide can potentially be used for the protection of oral mucosa from chemotherapy-induced mucositis. This is the first study that elucidates the specific molecular pathway for the cytoprotective effect of rebamipide. •Rebamipide suppresses 5-FU-induced cell death in normal human oral keratinocytes.•Rebamipide induces the Akt and mTOR activation.•Rebamipide regulates Bcl-2 family protein expressions.•Rebamipide protects the oral mucosa from chemotherapy-induced mucositis.