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Title: Pterostilbene Is Equally Potent as Resveratrol in Inhibiting 12-O-tetradecanoylphorbol-13-acetate Activated NFkappaB, AP-1, COX-2 and iNOS in Mouse Epidermis

Author
item CICHOCKI, MICHAL - POZNAN UNIV. OF MED. SCI.
item PALUSZCZAK, JAROSLAW - POZNAN UNIV. OF MED. SCI.
item SZAEFER, HANNA - POZNAN UNIV. OF MED. SCI.
item PIECHOWIAK, ADRIANA - POZNAN UNIV. OF MED. SCI.
item Rimando, Agnes
item BAER-DUBOWSKA, WANDA - POZNAN UNIV. OF MED. SCI.

Submitted to: Molecular Nutrition and Food Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/1/2008
Publication Date: 7/1/2008
Citation: Cichocki, M., Paluszczak, J., Szaefer, H., Piechowiak, A., Rimando, A.M., Baer-Dubowska, W. 2008. Pterostilbene Is Equally Potent as Resveratrol in Inhibiting 12-O-tetradecanoylphorbol-13-acetate Activated NFkappaB, AP-1, COX-2 and iNOS in Mouse Epidermis. Molecular Nutrition and Food Research. 52(S1):S62-S70.

Interpretive Summary: The effect of the phenolic compounds resveratrol and pterostilbene on development of skin cancer was investigated using mouse skin. Skin cancer was induced using a chemical carcinogen, which activates proteins involved in cell communications that lead to cancer. Treatment of mouse skin with either resveratrol or pterostilbene prior to application of the chemical carcinogen resulted in significant reduction of activation of two proteins involved in cell-to-cell signaling that play a role in cancer development. These two proteins are activator protein 1 and NF-kB. Furthermore, reduced activation of these proteins resulted in decreased activity of two enzymes involved in inflammation, cyclooxygenase-2 and inducible nitric-oxide synthase. These two enzymes are known to be highly active in the cancer state. Pterostilbene was either equal to or significantly more active than resveratrol in these tests. Overall, the results suggest that pterostilbene, a compound present in blueberries, deserves further study in cancer research.

Technical Abstract: Resveratrol, a phytoalexin present in grapes, has been reported to inhibit multistage mouse skin carcinogenesis. Recent studies showed that topically applied resveratrol significantly inhibited cyclooxygenase-2 (COX-2) expression and activation of nuclear factor-kB (NF-kB) induced by tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) in mouse epidermis. The results of these studies suggested also that resveratrol targets IkBa kinase (IKK) in blocking TPA induced NF-kB activation. The aim of the present study was to further explore the effect of resveratrol on TPA-induced signaling pathways in mouse epidermis and to compare activity with its dimethylether analogue, pterostilbene. Pretreatment of mouse skin with resveratrol or pterostilbene (16 umol) resulted in significant reduction of activator protein 1 (AP-1) and NF-kB activation. In the case of AP-1 the binding of c-Jun subunit was particularly affected, while only slight effect on c-Fos binding to TRE site was observed. Both stilbenes inhibited the activation of NF-kB by blocking the translocation of p65 to the nucleus and increasing the retention of IkBa in the cytosol. The later, which was related to decreased activity of IkB kinase and/or proteasome 20S, resulted from pretreament of mice with resveratrol or pterostilbene. Reduced activation of transcription factors decreased the expression and activity of COX-2 and inducible nitric-oxide synthase (iNOS). In all assays pterostilbene was either equally or significantly more potent inhibitor than resveratrol. Since substitution of hydroxy with methoxy group increases lipophilicity these results suggest an improved bioavailibility of pterostilbene, which might be responsible for its higher biological activity. Overall the above findings suggest that pterostilbene, a compound present in blueberries, is of great interest for the prevention of cancer including skin tumorigenesis.