Myricetin down-regulates phorbol ester-induced cyclooxygenase-2 expression in mouse epidermal cells by blocking activation of nuclear factor kappa B.

Abnormal expression of cyclooxygenase-2 (COX-2) has been implicated in the development of cancer. There are multiple lines of evidence that red wine exerts chemopreventive effects, and 3,5,4'-trihydroxy- trans-stilbene (resveratrol), which is a non-flavonoid polyphenol found in red wine, has been reported to be a natural chemopreventive agent. However, other phytochemicals might contribute to the cancer-preventive activities of red wine, and the flavonol content of red wines is about 30 times higher than that of resveratrol. Here we report that 3,3',4',5,5',7-hexahydroxyflavone (myricetin), one of the major flavonols in red wine, inhibits 12-O-tetradecanoylphorbol-13-acetate (phorbol ester)-induced COX-2 expression in JB6 P+ mouse epidermal (JB6 P+) cells by suppressing activation of nuclear factor kappa B (NF-kappaB). Myricetin at 10 and 20 microM inhibited phorbol ester-induced upregulation of COX-2 protein, while resveratrol at the same concentration did not exert significant effects. The phorbol ester-induced production of prostaglandin E 2 was also attenuated by myricetin treatment. Myricetin inhibited both COX-2 and NF-kappaB transactivation in phorbol ester-treated JB6 P+ cells, as determined using a luciferase assay. Myricetin blocked the phorbol ester-stimulated DNA binding activity of NF-kappaB, as determined using an electrophoretic mobility shift assay. Moreover, TPCK (N-tosyl-l-phenylalanine chloromethyl ketone), a NF-kappaB inhibitor, significantly attenuated COX-2 expression and NF-kappaB promoter activity in phorbol ester-treated JB6 P+ cells. In addition, red wine extract inhibited phorbol ester-induced COX-2 expression and NF-kappaB transactivation in JB6 P+ cells. Collectively, these data suggest that myricetin contributes to the chemopreventive effects of red wine through inhibition of COX-2 expression by blocking the activation of NF-kappaB.