Irsogladine maleate, a gastric mucosal protectant, suppresses intestinal polyp development in Apc-mutant mice
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Wakana Onuma1,2, Susumu Tomono3, Shinngo Miyamoto1, Gen Fujii4, Takahiro Hamoya1, Kyoko Fujimoto5, Noriyuki Miyoshi3, Fumio Fukai2, Keiji Wakabayashi3, Michihiro Mutoh1,4
1Epidemiology and Prevention Division, Research Center for Cancer Prevention and Screening, National Cancer Center, Tokyo, Japan
2Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba, Japan
3Graduate Division of Nutritional and Environmental Sciences, University of Shizuoka, Shizuoka, Japan
4Division of Carcinogenesis and Cancer Prevention, National Cancer Center Research Institute, Tokyo, Japan
5Division of Molecular Biology, Nagasaki International University, Nagasaki, Japan
Michihiro Mutoh, e-mail: [email protected]
Keywords: Apc-mutant mice, irsogladine maleate, NF-kB, reactive carbonyl species, cancer chemoprevention
Received: August 31, 2015 Accepted: January 19, 2016 Published: January 30, 2016
This study aimed to identify gastric mucosal protectants that suppress intestinal tumorigenesis in a mouse model. We chose six gastric mucosal protectants (ecabet sodium hydrate, irsogladine maleate, rebamipide, sofalcone, teprenone and troxipide) and examined their effects on the activity of oxidative stress-related transcriptional factors, including AP-1, NF-jB, NRF2, p53 and STAT3, in Caco-2 cells using a luciferase reporter gene assay. Among the six protectants, irsogladine maleate clearly inhibited NF-jB and AP-1 transcriptional activity. Furthermore, the chemopreventive property of irsogladine maleate was examined in a Min mouse model of familial adenomatous polyposis. Treatment with irsogladine maleate at doses of 5 and 50 ppm significantly reduced the number of intestinal polyps to 69% and 66% of the untreated control value, respectively. In these polyps, mRNA levels of the downstream targets of NF-jB, such as IL-1β and IL-6, were decreased by irsogladine maleate treatment. Moreover, the levels of oxidative stress-related markers, reactive carbonyl species, in the livers of Min mice were clearly decreased following the administration of irsogladine maleate. This study demonstrated that irsogladine maleate suppresses intestinal polyp formation in Min mice partly through the NF-jB signaling pathway, thus reducing oxidative stress.
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