Resveratrol, a phytoalexin found in grapes and other food products, was purified and shown to have cancer chemopreventive activity in assays representing three major stages of carcinogenesis. Resveratrol was found to act as an antioxidant and antimutagen and to induce phase II drug-metabolizing enzymes (anti-initiation activity); it mediated anti-inflammatory effects and inhibited cyclooxygenase and hydroperoxidase functions (antipromotion activity); and it induced human promyelocytic leukemia cell differentiation (antiprogression activity). In addition, it inhibited the development of preneoplastic lesions in carcinogen-treated mouse mammary glands in culture and inhibited tumorigenesis in a mouse skin cancer model. These data suggest that resveratrol, a common constituent of the human diet, merits investigation as a potential cancer chemopreventive agent in humans.

We determined whether resveratrol, a phenolic antioxidant found in grapes and other food products, inhibited phorbol ester (PMA)-mediated induction of COX-2 in human mammary and oral epithelial cells. Treatment of cells with PMA induces COX-2 and causes a marked increase in the production of prostaglandin E 2 . These effects were inhibited by resveratrol. Resveratrol suppressed PMA-mediated increases in COX-2 mRNA and protein. Nuclear run-offs revealed increased rates of COX-2 transcription after treatment with PMA, an effect that was inhibited by resveratrol. PMA caused about a 6-fold increase in COX-2 promoter activity, which was suppressed by resveratrol. Transient transfections utilizing COX-2 promoter deletion constructs and COX-2 promoter constructs, in which specific enhancer elements were mutagenized, indicated that the effects of PMA and resveratrol were mediated via a cyclic AMP response element. Resveratrol inhibited PMA-mediated activation of protein kinase C. Overexpressing protein kinase C-␣, ERK1, and c-Jun led to 4.7-, 5.1-, and 4-fold increases in COX-2 promoter activity, respectively. These effects also were inhibited by resveratrol. Resveratrol blocked PMA-dependent activation of AP-1-mediated gene expression. In addition to the above effects on gene expression, we found that resveratrol also directly inhibited the activity of COX-2. These data are likely to be important for understanding the anti-cancer and anti-inflammatory properties of resveratrol.

Previous collaborative work by our group has led to the discovery of several plant isolates and derivatives with activities in in vivo models of cancer chemoprevention, including deguelin, resveratrol, bruceantin, brassinin, 4¢-bromoflavone, and oxomate. Using a panel of in vitro bioassays to monitor chromatographic fractionation, a diverse group of plant secondary metabolites has been identified as potential cancer chemopreventive agents from mainly edible plants. Nearly 50 new compounds have been isolated as bioactive principles in one or more in vitro bioassays in work performed over the last five years. Included among these new active compounds are alkaloids, flavonoids, stilbenoids, and withanolides, as well as a novel stilbenolignan and the first representatives of the norwithanolides, which have a 27-carbon atom skeleton. In addition, over 100 active compounds of previously known structure have been obtained. Based on this large pool of potential cancer chemopreventive compounds, structureactivity relationships are discussed in terms of the quinone reductase induction ability of flavonoids and withanolides and the cyclooxygenase-1 and -2 inhibitory activities of flavanones, flavones and stilbenoids. Several of the bioactive compounds were found to be active when evaluated in a mouse mammary organ culture assay, when used as a secondary discriminator in our work. The-2,4,2¢,4¢-tetrahydroxychalcone 11¢-O-coumarate, isolicoflavonol, isoliquiritigenin, and ixocarpalactone A are regarded as promising leads as potential cancer chemopreventive agents.

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Cancer chemopreventive effects of organic extracts from 29 species of lichens collected in Iceland were evaluated using a panel of in vitro bioassays whereby extracts were tested for potential to induce quinone reductase (QR) and differentiation of human promyelocytic leukemia (HL-60) cells, inhibit cyclooxygenase-1 (COX-1), phorbol ester-induced ornithine decarboxylase (ODC), aromatase and sulfatase, as well as for antioxidant, estrogenic/anti-estrogenic and antiproliferative activity. In addition, the extracts were tested for cytotoxicity against 12 cancer cell lines. The most significant results were exhibited by extracts from Xanthoria elegans and Alectoria nigricans , which respectively, induced QR activity (concentration to double activity = 4.8 µg/ml) and inhibited phorbol ester-induced ODC activity with mouse 308 cells in culture (IC 50 = 2.6 µg/ml). Moderate inhibition of [ 3 H]thymidine incorporation with HL-60 cells was exhibited by the Peltigera leucophlebia extract. Several extracts prevented estrogen formation from estrogen precursors by inhibiting the enzymatic activities of aromatase ( Sphaerophorus globosus , Cetrariella delisei , Melanelia hepatizon ) and sulfatase ( Cladonia gracilis , Sphaerophorus fragilis , S. globosus ). None of the extracts demonstrated significant cytotoxic effects with selected cell lines.

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