Differential modulation of cyclooxygenase-mediated prostaglandin production by the putative cancer chemopreventive flavonoids tricin, apigenin and quercetin

Objectives: Diet-derived flavonoids possess cancer chemopreventive properties in preclinical models. The knowledge of the pharmacology of most flavonoids is insufficient to warrant their advancement to clinical evaluation. Methods: Here the three flavonoids tricin from rice bran, apigenin from leafy vegetables, and quercetin from onions and apples, were compared in terms of their ability to modulate cyclooxygenase- (COX-) catalyzed prostaglandin E-2 (PGE-2) generation. Specifically their effects on the following parameters were studied: (1) COX enzyme activity, (2) COX-2 expression in human-derived colon cancer cells HCA-7, which express COX-2 constitutively, (3) phorbol ester-mediated COX-2 induction in human colon epithelial cells (HCEC), and (4) PGE-2 levels in cellular incubations. Results: Tricin and quercetin inhibited enzyme activity in purified COX-1 and -2 preparations with IC50 values of near 1 (tricin) and 5 mu M (quercetin). Apigenin at up to 25 mu M did not affect COX enzyme activity. Flavonoids were incubated with cells for 6 or 24 h and COX-2 protein expression and PGE-2 levels were assessed by Western blot and competitive immunoassay, respectively. None of the agents affected constitutive COX-2 expression in HCA-7 cells. Apigenin, but not tricin or quercetin, down-regulated inducible COX-2 expression in HCEC cells on 6 h incubation. All three flavonoids reduced cellular levels of PGE-2 in the supernatant of HCA-7 cells at both time points and of HCEC cells at 6 h. Conclusions: The results demonstrate that these structurally similar flavonoids regulate COX-mediated PGE-2 production in different fashions. Their ability to attenuate prostanoid levels may contribute to their cancer chemopreventive efficacy.