title: Preclinical colorectal cancer chemopreventive efficacy and p53-modulating activity of 3',4',5'-trimethoxyflavonol, a quercetin analogue.
abstract: 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.
authors.affiliation: Department of Cancer Studies and Molecular Medicine, University of Leicester, United Kingdom.
authors.forename: Lynne M
authors.initials: LM
authors.lastname: Howells
authors.forename: Robert G
authors.initials: RG
authors.lastname: Britton
authors.forename: Marco
authors.initials: M
authors.lastname: Mazzoletti
authors.forename: Peter
authors.initials: P
authors.lastname: Greaves
authors.forename: Massimo
authors.initials: M
authors.lastname: Broggini
authors.forename: Karen
authors.initials: K
authors.lastname: Brown
authors.forename: William P
authors.initials: WP
authors.lastname: Steward
authors.forename: Andreas J
authors.initials: AJ
authors.lastname: Gescher
authors.forename: Stewart
authors.initials: S
authors.lastname: Sale
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use; D002277:Carcinoma / Q000235:genetics / Q000517:prevention & control*; D018890:Chemoprevention; D015179:Colorectal Neoplasms / Q000235:genetics / Q000517:prevention & control*; D004353:Drug Evaluation, Preclinical; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005419:Flavonoids / Q000627:therapeutic use*; D016158:Genes, p53 / Q000502:physiology*; D045325:HCT116 Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D011794:Quercetin / Q000031:analogs & derivatives; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D005419:Flavonoids; D011794:Quercetin; C441202:3',4',5'-trimethoxyflavone