Piceatannol inhibits phorbol ester-induced NF-κB activation and COX-2 expression in cultured human mammary epithelial cells.

Abstract

There are multiple lines of evidence supporting that inflammation is causally linked to carcinogenesis. Abnormal upregulation of cyclooxygenase-2 (COX-2), a rate-limiting enzyme in the prostaglandin biosynthesis, has been implicated in carcinogenesis. Trans-3,4,3',5'-tetrahydroxystilbene (piceatannol), a naturally occurring hydroxylated stilbene with potent anti-inflammatory and antioxidative activities, has been shown to inhibit the proliferation of several cancer cells by inducing apoptosis or blocking cell cycle progression. In this study, we examined the effect of piceatannol on activation of the nuclear transcription factor NF-kappa B, one of the major transcription factors that regulate proinflammatory COX-2 gene transcription, in human mammary epithelial (MCF-10A) cells treated with the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). When pretreated to MCF-10A cells, piceatannol markedly inhibited TPA-induced NF-kappa B DNA binding to a greater extent than resveratrol and oxyresveratrol, stilbene analogs structurally related to piceatannol. Piceatannol also inhibited TPA-induced phosphorylation and degradation of I kappa B alpha as well as nuclear translocation of the phosphorylated form of p65, the functionally active subunit of NF-kappa B. Likewise, TPA-induced expression of COX-2 was abrogated by piceatannol pretreatment. The thiol reducing agent dithiothreitol abolished the inhibitory effects of piceatannol on NF-kappa B DNA binding activity, suggesting that piceatannol may directly modify NF-kappa B or its regulator through reaction with the cysteine thiol(s).