Among flavonoid constituents identified in rice bran tricin (4’,5,7-trihydroxy-3’,5’-dimethoxyflavone) was the most potent inhibitor of the growth of human-derived colon cancer cells (Hudson AE et al, Cancer Epidemiol Biomarkers & Prev. 2000, 9: 1167). Here the hypothesis was tested that consumption of tricin at 0.2% in the diet affects adenoma development in ApcMin+ mice, which harbor an Apc gene mutation. Initially it was ascertained that dietary consumption of tricin furnishes levels of agent in the small intestine sufficient to elicit pharmacologcial effects in vitro. This was the case, as dietary intake of tricin for a week yielded 237±64.4 nmol/g mucosa (n=5), whilst plasma levels were below the HPLC quantification limit(0.2μM). ApcMin+ mice, the genotype of which had been confirmed by PCR, were randomly assigned to two groups, a control group (AIN93G diet) and an intervention group with mice on AIN diet supplemented with tricin (0.2%) from week 4 till the end of the experiment (week 18). The total number of intestinal adenomas in the intervention group was 14.0±7.7 (mean±SD, n=23), thus 37% lower than that in control, which was 22.1±10.3 (n=15, p=0.014 by student’s t-test). Adenoma development in ApcMin+ mice is sensitive to inhibitors of cyclooxygnase (COX) enzymes such as sulindac and celecoxib. Therefore the hypothesis was tested that tricin might interfere with COX activity. Ability to inhibit COX was studied in a cell-free chemiluminescence enzyme activity assay using COX-1 and -2 (from sheep seminal vesicles and placenta). Furthermore levels of the arachidonic acid metabolite prostaglandin E2 (PGE2) generated via COX catalysis were measured by immunoassay in plasma and small intestinal mucosa. The IC50 values for inhibition of COX-1 and -2 by tricin in vitro were approximately 1.7 and 1.0 μM, respectively. The inhibitory activity of tricin on COX activity in vivo was assessed by immunoassay of PGE2 in ApcMin+ mice, which had received tricin (0.2%) for life. Levels of PGE2 in plasma and small intestinal mucosa of tricin-treated mice were 60.1% (p=0.03) and 69.1% (p=0.05 by student’s t-test), respectively, of those seen in mice on control diet. The results suggest that tricin may be an attractive alternative to nonsteroidal antiinflammatory drugs as COX-inhibitory colorectal cancer chemopreventive agent. Supported by the NCI RAPID initiative, a programme grant from the UK Medical Research Council and a grant and a grant from the Association for International Cancer Research.
[Proc Amer Assoc Cancer Res, Volume 46, 2005]