Rebamipide induces dendritic cell recruitment to N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-exposed rat gastric mucosa based on IL-1β upregulation

Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Tokyo 113-8655, Japan.
Biochemical and Biophysical Research Communications (Impact Factor: 2.3). 06/2012; 424(1):124-9. DOI: 10.1016/j.bbrc.2012.06.087
Source: PubMed


Rebamipide is usually used for mucosal protection, healing of gastric ulcers, treatment of gastritis, etc., but its effects on gastric malignancy have not been elucidated. Using Lewis and Buffalo rat strains treated with peroral administration of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), we evaluated the effect of rebamipide on the induction of tumor-suppressive dendritic cells, which are known to be heterogeneous antigen-presenting cells of bone marrow origin and are critical for the initiation of primary T-cell responses. Using CD68 as a marker for dendritic cells, the stomach pyloric mucosae of Lewis and Buffalo rats were immunohistochemically analyzed in the presence or absence of rebamipide and MNNG. After a 14-day treatment of rebamipide alone, no significant change in number of CD68-expressing cells was detected in either rat strain. However, after concurrent exposure to MNNG for 14 days, treatment with rebamipide slightly increased CD68-positive cells in the Lewis strain, and significantly increased them in the Buffalo strain. Analysis of two chemotactic factors of dendritic cells, IL-1β and TNF-α, in the gastric cancer cells showed that expression of IL-1β, but not TNF-α, was induced by rebamipide in a dose-dependent manner. A luciferase promoter assay using gastric SH-10-TC cells demonstrated that an element mediating rebamipide action exists in the IL-1β gene promoter region. In conclusion, rebamipide has potential tumor-suppressive effects on gastric tumorigenesis via the recruitment of dendritic cells, based on the upregulation of the IL-1β gene in gastric epithelial cells.

8 Reads
  • [Show abstract] [Hide abstract]
    ABSTRACT: Chemoprevention strategies against gastric cancer (GC) need to be explored in light of the fact that stomach cancer still occurs in the absence of Helicobacter pylori (HP) infection and following HP eradication. We evaluated the effect of rebamipide on N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced carcinogenesis in SD rats. Thirty-nine male rats were divided into four groups based on whether or not they were treated with rebamipide and/or MNNG: Control, Rebamipide, Control-M, and Rebamipide-M groups. From 8 weeks of age, rats in the Control-M and Rebamipide-M groups received MNNG in drinking water for 30 weeks. The Rebamipide and Rebamipide-M groups were administered 5mg/kg/day of rebamipide. At 50 weeks, cancerous lesions were not observed in either the Control or Rebamipide groups. Nine rats in the Control-M group had developed GC, while four rats in the Rebamipide-M group had developed GC. The incidence of cancer in the Rebamipide-M group was significantly less than in the Control-M group (p<0.05), with a trend toward a lower incidence of invasive carcinoma in the Rebamipide-M group. Carcinomatous invasion into the muscularis propria was not observed in the Rebamipide-M group. In conclusion, the present study demonstrates that rebamipide suppresses. MNNG-induced carcinogenesis and may also inhibit progression of cancer in rats. Copyright © 2015 Elsevier GmbH. All rights reserved.
    Experimental and toxicologic pathology: official journal of the Gesellschaft fur Toxikologische Pathologie 01/2015; 67(3). DOI:10.1016/j.etp.2015.01.003 · 1.86 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Recent studies have shown that rebamipide, which suppresses reactive oxygen species, prevents chemoradiotherapy-induced oral mucositis in patients with head and neck cancers. However, anticancer action of radiotherapy and chemotherapy is believed to be partially associated with generation of reactive oxygen species. The aim of this study was to determine whether rebamipide interferes with the antitumor action of radiotherapy and chemotherapy. The effect of rebamipide on tumor cell growth was investigated using a human oral squamous carcinoma cell line, HSC-2, in vitro and in vivo. Rebamipide showed no significant effect on cell or tumor growth in HSC-2 tumor-bearing nude mice. Influences of rebamipide on the antitumor action of radiotherapy and of chemotherapy with cisplatin or docetaxel were investigated using the same animal model. In radiotherapy, the tumor was treated with 2.5 Gy of X-rays for 5 days, and rebamipide (300 mg/kg p.o.) was administered during irradiation periods. In chemotherapy, tumor-bearing mice were treated once with cisplatin (8 mg/kg, i.v.) or docetaxel (15 mg/kg i.v.) and rebamipide (300 mg/kg p.o.) was administered for 5 days following the antitumor drug treatment. Rebamipide did not interfere with the antitumor action of radiotherapy and chemotherapy. Copyright © 2015 The Authors. Production and hosting by Elsevier B.V. All rights reserved.
    Journal of Pharmacological Sciences 08/2015; 129(1). DOI:10.1016/j.jphs.2015.07.022 · 2.36 Impact Factor