Rebamipide suppresses 5-fluorouracil-induced cell death via the activation of Akt/mTOR pathway and regulates the expression of Bcl-2 family proteins. (February 2018)

• Record Type: Journal Article
• Authors: Tsubaki, Masanobu; Takeda, Tomoya; Asano, Ryo-ta; Matsuda, Tomoyuki; Fujimoto, Shin-ichiro; Itoh, Tatsuki; Imano, Motohiro; Satou, Takao; Nishida, Shozo
• Is Part Of: Toxicology in vitro. Volume 46(2018)
• Page Start: 284
• Page End: 293
• Publication Date: 2018-02
• Subjects: Rebamipide -- Oral mucositis -- 5-FU -- Akt -- mTOR; Toxicity testing -- In vitro -- Periodicals; Toxicology -- Periodicals; 615.9
• DOI: 10.1016/j.tiv.2017.10.019
• Languages: English
• ISSNs: 0887-2333

Abstract

Abstract: 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. Highlight: 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.