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http://dx.doi.org/10.5352/JLS.2016.26.10.1214

A Potential Efficacy of Rebamipide as Anti-gastric Cancer Drug  

Min, Do Sik (Department of Molecular Biology, Pusan National University)
Publication Information
Journal of Life Science / v.26, no.10, 2016 , pp. 1214-1217 More about this Journal
Abstract
Rebamipide is a mucosal-protective antiulcer drug, but its mechanism of action in gastric cancer remains elusive. CagA, a major virulence factor of Helicobacter pylori (H. pylori), is associated with the risk of gastric cancer. CagA protein is injected into gastric epithelial cells and deregulates a variety of cellular signaling molecules. CagA from H. pylori induces phospholipase D1 (PLD1) expression through NFκB activation in gastric epithelial cells, followed by invasion and proliferation of gastric epithelial cancer cells. Infection with cagA-positive H. pylori and expression of CagA enhances the binding of NFκB to the PLD1 promoter. Rebamipide abolishes H. pylori cagA-induced PLD1 expression via inhibition of binding of NFκB to the PLD1 promoter and also inhibits PLD activity. Moreover, rebamipide abolishes H. pylori CagA-induced β-catenin and the expression of a target cancer stem cell (CSC) marker gene via upregulation of miRNA-320a and -4496, followed by attenuation of self-renewal capacity of H. pylori CagA-infected gastric CSCs. In addition, rebamipide increases the chemosensitivity of CagA-expressed gastric CSCs and suppresses gastric carcinogenesis. Thus, it is speculated that rebamipide might show a potent efficacy as chemotherapeutic drug against gastric cancer cells. In this review, we summarizes recent results regarding the novel insights for the efficacy of rebamipide in gastric cancer cells.
Keywords
CagA; cancer stem cells; gastric cancer; Helicobacter pylori; rebamipide;
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1 Wroblewski, L. E., Piazuelo, M. B., Chaturvedi, R., Schumacher, M., Aihara, E., Feng, R. Noto, J. M., Delgado, A., Israel, D. A., Zavros, Y., Montrose, M. H., Shroyer N., Wilson, K. T. and Peek, R. M. Jr. 2015. Helicobacter pylori targets cancer-associated apical-junctional constituents in gastroids and gastric epithelial cells. Gut 64, 720-730.   DOI
2 Zhang, X. Y., Chan, W. Y., Whitney, B. M., Fan, D. M., Chow, J. H., Liu, Y., Ng, E. K. and Chung, S. C. 2002. Changes of interleukin expression correlate with Helicobacter pylori infection and lymph node metastases in gastric carcinoma. Diagn. Mol. Pathol. 11, 135-139.   DOI
3 Kang, D. W., Park, M. H., Lee, Y. J., Kim, H. S., Kwon, T. K., Park, W. S and Min, D. S. 2008. Phorbol ester up-regulates phospholipase D1 but not phospholipase D2 expression through a PKC/Ras/ERK/NFκB-dependent pathway and enhances matrix metalloproteinase-9 secretion in colon cancer cells. J. Biol. Chem. 283, 4094-4104.   DOI
4 Kang, D. W., Noh, Y. N., Hwang, W. C., Choi, K. Y. and Min, D. S. 2016. Rebamipide attenuates Helicobacter pylori CagA-induced self-renewal capacity via modulation of bcatenin signaling axis in gastric cancer-initiating cells. Biochem. Pharmacol. 113, 36-44.   DOI
5 Lamb, A., Yang, X. D., Tsang, Y. H., Li, J. D., Higashi, H., Hatakeyama, M., Peek, R. M., Blanke, S. R. and Chen, L. F. 2009. Helicobacter pylori CagA activates NFκB by targeting TAK1 for TRAF6-mediated Lys 63 ubiquitination. EMBO Rep. 10, 1242-1249.   DOI
6 Hanahan, D. and Weinberg, R. A. The hallmarks of cancer. Cell 100, 57-70.   DOI
7 Sier, C. F., Kubben, F. J., Ganesh, S., Heerding, M. M., Griffioen, G., Hanemaaijer, R. van Krieken, J. H., Lamers, C. B. and Verspaget, H. W. 1996. Tissue levels of matrix metalloproteinases MMP-2 and MMP-9 are related to overall survival of patients with gastric carcinomas. Br. J. Cancer 74, 413-417.   DOI
8 Mori, N., Sato, H., Hayashibara, T., Senba, M., Geleziunas, R., Wada, A., Hirayama, T. and Yamamoto, N. 2003. Helicobacter pylori induces matrix metalloproteinase-9 through activation of NFκB. Gastroenterology 124, 983-992.   DOI
9 Murakami, K., Okajima, K., Uchiba, M., Harada, N., Johno, M. Okabe, H. and Takarsuki, K. 1997. Rebamipide attenuates indomethacin-induced gastric mucosal lesion formation by inhibiting activation of leukocytes in rats. Dig. Dis. Sci. 42, 319-325   DOI
10 Ohnishi, N., Yuasa, H., Tanaka, S., Sawa, H., Miura, M., Matsui, A., Iwabuchi, K., Suzuki, M., Yamada, G., Azuma, T. and Hatakeyama, M. 2008. Transgenic expression of Helicobacter pylori CagA induces gastrointestinal and hematopoietic neoplasms in mouse. Proc. Natl. Acad. Sci. USA 105, 1003-1008.   DOI
11 Styczynski, J. and Drewa, T. 2007. Leukemic stem cells: from metabolic pathways and signaling to a new concept of drug resistance targeting. Acta. Biochim. Pol. 54, 717-726.
12 Su, W., Chen, Q. and Frohman, M. A. 2009. Targeting phospholipase D with small molecule inhibitors as a potential therapeutic approach for cancer metastasis. Future Oncol. 5, 1477-1486.   DOI
13 Tanigawa, T., Pai, R., Arakawa, T. and Tarnawski, A. S. 2007. Rebamipide inhibits gastric cancer cell growth. Dig. Di.s Sci. 52, 240-247.   DOI
14 Yamasaki, K., Kanbe, T., Chijiwa, T., Ishiyama, H. and Morita, S. 1987. Gastric mucosal protection by OPC-12759, a novel antiulcer compound in rats. Eur. J. Pharmacol. 142, 23-29.   DOI
15 Tarnawski, A., Pai, R., Chiou, S. K., Chai, J. and Chu, E. C. 2005. Rebamipide inhibits gastric cancer growth by targeting survivin and Aurora-B. Biochem. Biophys. Res. Commun. 334, 207-212.   DOI
16 Tsukamoto, H., Mizoshita, T., Katano, T., Hayashi, N., Ozeki, K., Ebi, M. Shimura, T., Mori, Y., Tanida, S., Kataoka H., Tsukamoto, T., Tatematsu, M. and Joh, T. 2015. Preventive effect of rebamipide on N-methyl-N'-nitro-N-nitrosoguanidine-induced gastric carcinogenesis in rats. Exp. Toxicol. Pathol. 67, 271-277.   DOI
17 Yamane, T., Nakatani, H., Matsumoto, H., Iwata, Y., Kikuoka, N. and Takahashi, T. 1998. Inhibitory effects of rebamipide on ENNG-induced duodenal carcinogenesis in mice: a possible strategy for chemoprevention of gastrointestinal cancers. Dig. Dis. Sci. 43, 11S-207S.
18 Yasuda, Y., Chiba, H., Satomi, T., Matsuo, A., Kaneko, T. and Chikazu, D. 2012. Preventive effect of rebamipide gargle on chemoradiotherpy-induced oral mucositis in patients with oral cancer: a pilot study. J. Oral Maxillofac. Res. 2, 1-8.
19 Yin, Y., Grabowska, A. M., Clarke, P. A., Whelband, E., Robinson, K., Argent, R. H., Tobias, A., Kumari, R., Atherton, J. C. and Watson, S. A. 2010. Helicobacter pylori potentiates epithelial:mesenchymal transition in gastric cancer: links to soluble HB-EGF, gastrin and matrix metalloproteinase-7. Gut 59, 1037-1045.   DOI
20 Yoshikawa, T., Naito, Y. and Kondo, M. 1993. Free radical scavenging activity of the novel anti-ulcer agent rebamipide studied by electron spin resonance. Arzneimittelforschung 43, 363-366.
21 Charafe-Jauffret, E., Monville, F., Ginestier, C., Dontu, G., Birnbaum, D. and Wicha, M. S. 2008. Cancer stem cells in breast: current opinion and future challenges. Pathobiology 75, 75-84.   DOI
22 Aihara, M., Azuma, A., Takizawa, H., Tsuchimoto, D., Funakoshi, Y., Shindo, Y. Ohmoto, Y., Imagawa, K., Kikuchi, M., Mukaida, N. and Matsushima, K. 1998. Molecular analysis of suppression of interleukin-8 production by rebamipide in Helicobacter pylori-stimulated gastric cancer cell lines. Dig. Dis. Sci. 43, 174S-180S.
23 Arakawa, T., Kobayashi, K., Yoshikawa, T. and Tarnawski, A. 1998. Rebamipide: overview of its mechanisms of action and efficacy in mucosal protection and ulcer healing. Dig. Dis. Sci. 43, S5-13.
24 Bagnoli, F., Buti, L., Tompkins, L., Covacci, A. and Amieva, M. R. 2005. Helicobacter pylori CagA induces a transition from polarized to invasive phenotypes in MDCK cells. Proc. Natl. Acad. Sci. USA 102, 16339-16344.   DOI
25 Baud, J., Varon, C., Chabas, S., Chambonnier, L., Darfeuille, F. and Staedel, C. Helicobacter pylori initiates a mesenchymal transition through ZEB1 in gastric epithelial cells. PLoS One 8, e60315.   DOI
26 Bessède, E., Staedel, C., Acuña Amador, L. A., Nguyen, P. H., Chambonnier, L., Hatakeyama, M., Belleannée G., Mégraud, F. and Varon, C. 2014. Helicobacter pylori generates cells with cancer stem cell properties via epithelial–mesenchymal transition-like changes. Oncogene 33, 4123-4131.   DOI
27 Kang, D. W., Min, G., Park, D. Y., Hong, K. W. and Min, D. S. 2010. Rebamipide-induced downregulation of phospholipase D inhibits inflammation and proliferation in gastric cancer cells. Exp. Mol. Med. 42, 555-564.   DOI
28 Ishihara, K., Komuro, Y., Nishiyama, N., Yamasaki, K. and Hotta, K. 1992. Effect of rebamipide on mucus secretion by endogenous prostaglandin-independent mechanism in rat gastric mucosa. Arzneimittelforschung 2, 1462-1466.
29 Kang, D. W., Hwang, W. C., Park, M. H., Ko, G. H., Ha, W. S., Kim, K. S., Lee, Y. C., Choi, K. Y. and Min, D. S. 2013. Rebamipide abolishes Helicobacter pylori CagA-induced phospholipase D1 expression via inhibition of NFkappaB and suppresses invasion of gastric cancer cells. Oncogene 32, 3531-3542.   DOI