Some naturally occurring
flavonols, exemplified by
quercetin, seem to possess experimental
cancer chemopreventive efficacy. Modulation of p53 is a mechanism thought to contribute to their activity. The hypothesis was tested that a synthetic
flavonol,
3',4',5'-trimethoxyflavonol (TMFol), can interfere with
tumor development and p53 expression in two models of colorectal
carcinogenesis, Apc(Min) mice and human-derived HCT116
adenocarcinoma-bearing nude mice. Mice received TMFol with their diet (0.2%) from weaning to week 16 in the case of Apc(Min) or from either day 7 before ("TMFol early") or day 7 after ("TMFol late")
tumor inoculation in HCT116 mice. The ability of TMFol to affect
tumor proliferation or apoptosis, as reflected by staining for Ki-67 or cleaved
caspase-3, respectively, was studied in HCT116
tumors. TMFol
tumor levels were measured by high-performance liquid chromatography. Consumption of TMFol reduced small intestinal
adenoma burden in Apc(Min) mice by 47%, compared with control mice (P < 0.002). The TMFol early regimen approximately halved HCT116
tumor size (P < 0.05), decreased
tumor proliferation, and increased apoptosis, whereas the TMFol late regimen had no significant effect when compared with controls. In
tumor tissues from mice, in which TMFol reduced
tumor development, p53 expression was increased 3-fold in Apc(Min) and 1.5-fold in HCT116
tumor-bearing mice (P = 0.02). TMFol increased p53 also in cells derived from these
tumors. TMFol was detected in HCT116
tumors, but levels did not correlate with
tumor burden. TMFol was not mutagenic in the Ames test. The results suggest that chemical modification of the
flavonol structure may generate safe and efficacious
cancer chemopreventive agents.