|Budget Amount *help
¥12,000,000 (Direct Cost : ¥12,000,000)
Fiscal Year 2002 : ¥2,600,000 (Direct Cost : ¥2,600,000)
Fiscal Year 2001 : ¥2,600,000 (Direct Cost : ¥2,600,000)
Fiscal Year 2000 : ¥6,800,000 (Direct Cost : ¥6,800,000)
Enhanced and sustained expressions of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) are involved in many oncogenic processes, including that in the colon of experimental rodents and human as well. Accordingly, recent laboratory studies have demonstrated the effectiveness of selective inhibitors of iNOS/COX-2 in terms of reduction of the carcinogen-induced development of adenocarcinoma in rats and mice. Of importance, human intervention trials revealed that celecoxib, a cox-2 selective inhibitor, diminished polyp formation of a population of the familial adenomatous polyposis patients. While the cox-2 inhibitors block the catalytic activity, other types of chemicals that suppress or delay the de novo synthesis of iNOS/COX-2 may be considered as a new generation of the anti-iNOS/COX-2 regulators. In the present study, we have identified two food factors, zerumbone (ZER) and nobiletin (NOB), markedly suppressed expression of COX-2 and thereby reducing formation of pr
ostaglandin E2 in the colonic mucosa of the azoxymethane treated rats. Conversely, these phytochemicals markedly inhibited azoxymethane-induced foramtoin of aberrant crypt foci (ACF) in rat colon. In addition, we observed elevated induction of phase 2 xenobiotic enzyme activities such as glutathione S-transferase and quinone reductase in the colon and liver as compared with the basal diet group. ZER, a sesquiterpene carrying an α,β-unsaturated carbonyl group, a major constituent of Zingiber zerumbet Smith that occurs widely in southea st Asian countries and used as a ingredient of traditional cousins and folk medicine for anti-inflammation as well. On the other hand, NOB, a polymethylated flavonoid, is found in citrus fruits including satsuma mandarin. Our mechanistic studies provided some data that these compounds suppress degradation of the combined lipopolysaccharide and interferon-γ-induced IκBα, a suppressive factor of NF-κB, in RAW murine macrophages. Because NF-κB is one of the major transcription factor for iNOS/COX-2 genes, both ZER and NOB attenuate these gene expressions through suppression of IκB degradation.
In conclusion, we have presented an experimental rationale for the used of the iNOS/COX-2 de novo synthesis suppressants, in addition of the cox-2 inhibitors, for preventing and treating large bowel disease such as ulcerative colitis and colorectal cancer. Less