) The relatively long latency period of the promotion stage of carcinogenesis represents a window of opportunity during which dietary factors with chemopreventive potential can inhibit the process of carcinogenesis. There is substantial evidence supporting a role for consumption of a diet rich in fruits, vegetables and plant foods in reducing the occurrence of human cancer at a number of different sites, including cancers of the stomach, lung, breast, colon and other epithelial tumors. Therefore considerable research has focused on identifying anti-tumor promoting plant-based dietary components. Among the components with chemopreventive promise, plant phenolics represent a fertile field for evaluating the potential of dietary substances which can serve as effective chemopreventives. Our research will focus on flavonoids which are known to inhibit protein kinase C (PKC), the cellular receptor for the phorbol ester tumor promoter, TPA, a free radical generator and inhibitor of the anti-oxidant defense system in promotion-sensitive murine epidermal JB6 cells. More specifically, we will focus on quercetin (QU), which inhibits PKC activity, and its structural derivatives rutin (RU) and taxifolin (TX), which do no inhibit PKC activity. Since QU or a PKC inhibitor blocked TPA-induced transformation of JB6 cells, we wish to determine whether or not the anti-promoting effects of QU is mediated by PKC. The effect of RU and TX on TPA-induced transformation and PKC activity in JB6 cells. We will accomplish our goals by performing anchorage-independent growth assays to measure transformation and kinase assays to measure PKC activity using isoform-specific PKC reagents. These investigations into the mechanisms whereby flavonoids inhibit the rate-limiting tumor promotion step of carcinogenesis could lead to rational design of novel chemopreventives for epithelially-derived cancers which account for approximately 90 percent of cancer deaths in the US.
