Preclinical colorectal cancer chemopreventive efficacy and p53-modulating activity of 3',4',5'-trimethoxyflavonol, a quercetin analogue.
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.
Howells
Lynne M
LM
Department of Cancer Studies and Molecular Medicine, University of Leicester, United Kingdom.
Britton
Robert G
RG
Mazzoletti
Marco
M
Greaves
Peter
P
Broggini
Massimo
M
Brown
Karen
K
Steward
William P
WP
Gescher
Andreas J
AJ
Sale
Stewart
S
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
D000972:Antineoplastic Agents, Phytogenic; D005419:Flavonoids; D011794:Quercetin; C441202:3',4',5'-trimethoxyflavone