Cancer: Esophageal, colorectal, breast
Action: Anti-inflammatory, anti-oxidative
Piceatannol, a naturally occurring analogue of resveratrol found in certain plants and berries of the Vaccinium genus, including Picea abies [(L.) H.Karst.], Aiphanes horrida [(Jacq.) Burret], Gnetum cleistostachyum (C. Y. Cheng), Vaccinium arboretum (Marshall), Vaccinium angustifolium (Aiton) and Vaccinium corymbosum (L.). It was previously identified as the active ingredient in herbal preparations in folk medicine. Piceatannol is an anti-inflammatory, immunomodulatory, and anti-proliferative stilbene that has been shown to interfere with the cytokine signaling pathway. It is isolated from various types of berries, grapes, rhubarb and sugar cane.
It has been shown that a diet containing freeze-dried black raspberries (BRB) inhibits the development of chemically-induced cancer in the rat esophagus. To provide insights into possible mechanisms by which BRB inhibit esophageal carcinogenesis, an ethanol (EtOH) extract of BRB was evaluated, and two component anthocyanins (cyanidin-3-O-glucoside and cyanidin-3-O−rutinoside) in BRB, for their effects on growth, apoptosis, and gene expression in rat esophageal epithelial cell lines. The EtOH extract and both anthocyanins selectively caused significant growth inhibition and induction of apoptosis in a highly tumorigenic cell line (RE-149 DHD) but not in a weakly tumorigenic line (RE-149).
The growth-inhibitory and pro-apoptotic effects were enhanced by the daily addition of the EtOH extract and the anthocyanins to the medium.
Esophageal Cancer
This differential effect may have been related to the relative amounts of anthocyanins in the extract vs.when they were added individually to the medium. It was hence concluded that the selective effects of the EtOH extract on the growth and apoptosis of highly tumorigenic rat esophageal epithelial cells in vitro may be due to preferential uptake and retention of its component anthocyanins, and this may also be responsible for the greater inhibitory effects of freeze-dried whole berries on tumor cells in vivo (Schwartz et al., 2009).
Colorectal
The effects of piceatannol on growth, proliferation, differentiation and cell-cycle distribution profile of the human colon carcinoma cell line Caco-2 were investigated. Growth of Caco-2 and HCT-116 cells was analyzed by crystal violet assay, which demonstrated dose- and time-dependent decreases in cell numbers. Treatment of Caco-2 cells with piceatannol reduced proliferation rate. No effect on differentiation was observed.
Determination of cell-cycle distribution by flow cytometry revealed an accumulation of cells in the S phase. Immunoblotting demonstrated that cyclin-dependent kinases (cdk) 2 and 6, as well as cdc2 were expressed at steady-state levels, whereas cyclin D1, cyclin B1 and cdk 4 were down-regulated. The abundance of p27Kip1 was also reduced, whereas the protein level of cyclin E was enhanced. Cyclin A levels were enhanced only at concentrations up to 100 µmol/L. These changes also were observed in studies with HCT-116 cells. On the basis of our findings, piceatannol can be considered to be a promising chemo-preventive or anti-cancer agent (Wolter et al., 2002).
Anti-inflammatory
Treatment of human myeloid cells with piceatannol suppressed TNF-induced DNA binding activity of NF-κB. In contrast, stilbene or rhaponticin (another analog of piceatannol) had no effect, suggesting the critical role of hydroxyl groups. The effect of piceatannol was not restricted to myeloid cells, as TNF-induced NF- κB activation was also suppressed in lymphocyte and epithelial cells. Piceatannol also inhibited NF-κB activated by H2O2, PMA, LPS, okadaic acid, and ceramide.
Piceatannol abrogated the expression of TNF-induced NF-κB-dependent reporter gene and of matrix metalloprotease-9, cyclooxygenase-2, and cyclin D1. When examined for the mechanism, it was found that piceatannol inhibited TNF-induced IκBα phosphorylation, p65 phosphorylation, p65 nuclear translocation, and IκBα kinase activation, but had no significant effect on IκBα degradation. Piceatannol inhibited NF-κB in cells with deleted Syk, indicating the lack of involvement of this kinase.
Overall, these results clearly demonstrate that hydroxyl groups of stilbenes are critical and that piceatannol, a tetrahydroxystilbene, suppresses NF- κB activation induced by various inflammatory agents through inhibition of IκBα kinase and p65 phosphorylation (Ashikawa et al., 2002).
There are multiple lines of evidence supporting that inflammation is causally linked to carcinogenesis. Abnormal up-regulation 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 anti-oxidative activities, has been shown to inhibit the proliferation of several cancer cells by inducing apoptosis or blocking cell-cycle progression. The effect of piceatannol was examined on the activation of the nuclear transcription factor NF-κB, one of the major transcription factors that regulate pro-inflammatory COX- 2 gene transcription, in human mammary epithelial (MCF-10A) cells treated with the tumor promoter 12-O-tetradecanoylphorbol- 13-acetate (TPA).
When pre-treated to MCF-10A cells, piceatannol markedly inhibited TPA-induced NF-κB DNA binding to a greater extent than resveratrol and oxyresveratrol, stilbene analogs structurally related to piceatannol. Piceatannol also inhibited TPAinduced phosphorylation and degradation of IκBα as well as nuclear translocation of the phosphorylated form of p65, the functionally active subunit of NF-κB. Likewise, TPA-induced expression of COX-2 was abrogated by piceatannol pre-treatment. The thiol reducing agent dithiothreitol abolished the inhibitory effects of piceatannol on NF-κB DNA binding activity, suggesting that piceatannol may directly modify NF-kB (Liu et al., 2009).
Breast Cancer
Piceatannol (trans-3,4,3′,5′-tetrahydroxystilbene; PIC) exhibits immunosuppressive and anti-tumorigenic activities in several cell lines, and it was found that PIC inhibited migration and anchorage-independent growth of human mammary epithelial cells (MCF-10A) treated with the prototypic tumor promoter, 12-O-tetradecanoylphorbol-13-aceate (TPA). PIC treatment suppressed the TPA-induced activation of NF-κB and expression of cyclooxygenase-2 (COX-2) in MCF-10A cells. It was speculated that an electrophilic quinone formed as a consequence of oxidation of PIC bearing the catechol moiety may directly interact with critical cysteine thiols of IKKβ, thereby inhibiting its catalytic activity.
Results show that direct modification of IKKβ by PIC, presumably at the cysteine 179 residue, blocks NF-κB activation signaling and COX-2 induction in TPA-treated MCF-10A cells and also migration and transformation of these cells (Son et al., 2010).
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