title: Flavones as colorectal cancer chemopreventive agents--phenol-o-methylation enhances efficacy.
abstract: Flavonoids occur ubiquitously in plants, and some possess preclinical cancer chemopreventive activity. Little is known about molecular features that mediate chemopreventive efficacy of flavonoids. Here, three related flavones, apigenin (4',5,7-trihydroxyflavone), tricin (4',5,7-trihydroxy-3',5'-dimethoxyflavone), and 3',4',5',5,7-pentamethoxyflavone (PMF), were compared in terms of their effects on (a) adenoma development in Apc(Min) mice, a model of human gastrointestinal malignancies; (b) growth of APC10.1 mouse adenoma cells in vitro; and (c) prostaglandin E-2 generation in HCA-7 human-derived colorectal cancer cells in vitro. Life-long consumption of PMF with the diet at 0.2% reduced Apc(Min) mouse adenoma number and burden by 43% and 61%, respectively, whereas apigenin was inactive. Tricin has previously shown activity in this model. IC50 values for murine adenoma cell growth inhibition by PMF, tricin, and apigenin were 6, 13, and 18 micromol/L, respectively. In Apc(Min) mice that received flavones (0.2%) for 4 weeks, adenoma cell proliferation as reflected by Ki-67 staining was reduced by PMF and tricin, but not by apigenin. On incubation with HCA-7 cells for 6 hours, PMF reduced prostaglandin E-2 generation with an IC50 of 0.8 micromol/L, a fraction of the respective values reported for tricin or apigenin. In silico PMF docked into the cyclooxygenase active site with greater affinity than tricin or apigenin. The results suggest that the rank order of cancer chemopreventive efficacy in Apc(Min) mice is PMF > tricin > apigenin, supporting the notion that the presence of O-methyl in the flavone molecular scaffold promotes gastrointestinal cancer chemopreventive efficacy.
authors.affiliation: Department of Cancer Studies and Molecular Medicine, University of Leicester, Robert Kilpatrick Clinical Sciences Building, Leicester LE2 7LX, United Kingdom.
authors.forename: Hong
authors.initials: H
authors.lastname: Cai
authors.forename: Stewart
authors.initials: S
authors.lastname: Sale
authors.forename: Ralf
authors.initials: R
authors.lastname: Schmid
authors.forename: Robert G
authors.initials: RG
authors.lastname: Britton
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
mesh_terms: D000236:Adenoma / Q000235:genetics / Q000517:prevention & control*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D047310:Apigenin / Q000494:pharmacology / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000235:genetics / Q000517:prevention & control*; D019610:Cytoprotection / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D047309:Flavones / Q000737:chemistry / Q000378:metabolism* / Q000627:therapeutic use*; D005419:Flavonoids / Q000494:pharmacology / Q000627:therapeutic use; D017491:Genes, APC; D006801:Humans; D008745:Methylation; D008780:Methyltransferases / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D013329:Structure-Activity Relationship; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured
chemical_list: C488726:5,7,3',4',5'-pentamethoxyflavone; D000970:Antineoplastic Agents; D047309:Flavones; D005419:Flavonoids; D047310:Apigenin; D008780:Methyltransferases; C022335:phenol O-methyltransferase