This Article Full Text Full Text (PDF) All Versions of this Article: 1940-6207.CAPR-09-0081v1 2/8/743    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Cai, H. Articles by Gescher, A. J. Search for Related Content PubMed PubMed Citation Articles by Cai, H. Articles by Gescher, A. J. Related Collections Preclinical Intervention Preclinical Intervention: In Vivo (Animals): Drugs, Nutritional Interventions, Mechanisms Preclinical Intervention: In Vitro: Drugs, Mechanisms

Flavones as Colorectal Cancer Chemopreventive Agents—Phenol-O-Methylation Enhances Efficacy

Authors' Affiliations: ¹ Cancer Biomarkers and Prevention Group, Department of Cancer Studies and Molecular Medicine and ² Department of Biochemistry, University of Leicester, Leicester, United Kingdom

Requests for reprints: Andreas J. Gescher, Department of Cancer Studies and Molecular Medicine, University of Leicester, Robert Kilpatrick Clinical Sciences Building, Leicester LE2 7LX, United Kingdom. Phone: 44-1162231856; Fax: 44-1162231855; E-mail: ag15{at}le.ac.uk.

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 µmol/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 µmol/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.

Key Words: Flavones • apigenin • tricin • chemoprevention • drug development