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.