Are anthocyanins necessary for oral cancer chemoprevention by berries?

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DESCRIPTION (provided by applicant): Numerous epidemiological studies have shown a strong correlation between consumption of fresh fruits and vegetables and a decreased risk of oral cancer. Several preclinical studies demonstrate the remarkable chemopreventive activity of two berry fruits, black raspberries and strawberries, that inhibit human oral cancer cell proliferation in vitro and development of chemically-induced aerodigestive tract tumors in animals. A pressing, yet unanswered, question remains "What types of polyphenols in fruit are primarily responsible for these activities?" Prior studies have employed lyophilized powders or extracts of ripe fruits containing a complex mixture of berry polyphenols of which a major group is the anthocyanins. Epidemiological evidence suggests that diets rich in anthocyanins (colored fruits and vegetables) reduce the overall risk of cancer and laboratory evidence illustrates the inhibition of proliferation of tumor cells in culture and prevention of tumors in animal models. However, there are numerous other fruit phenolics in berries that have demonstrated antioxidant, antiproliferative, and chemopreventive activity in both cell cultures and animal models of cancer. Among these are the phenolic acids, (gallic, procatechuic, p-hydroxybenzoic, caffeic, p- coumaric, ferulic, chlorogenic, and ellagic acids), the flavonols (quercetin, kaempferol, mycetrin, and isorhamntin), and complex polyphenols (lignans, ellagitannin, and gallotannin). To examine the chemopreventive capacity of these latter berry phenolics, separate from their combined activity with anthocyanins, we propose to evaluate green berry fruits (with minimal anthocyanin content) and ripe berry fruits (with high levels of anthocyanins) for inhibition of oral tumorigenesis in an animal model and to determine their effect on modulation of cancer-associated genes. Hypothesis: We hypothesize that bioactive phenolics found in green strawberries and black raspberries, independent of the anthocyanins, will inhibit tumorigenesis just as effectively as ripe berries in an animal model of oral cancer and will modulate the expression of critical genes associated with oral cancer. Methods: Hamster pellets will be prepared using 5% and 10% green and ripe strawberries and black raspberries. Beginning 7 days after commencement of feeding with berry pellets, cheek pouches will be painted 3x/week for six weeks with the chemical carcinogen 7,12-dimethylbenz(a)anthracene. Berry pellets will be given during, and for six weeks after, carcinogen treatment. At 12-13 weeks, cheek pouches will be evaluated for total lesions and tumors and for modulation of caner- associated gene expression. Significance: The novel studies outlined herein will provide a practical assessment of the chemopreventive potential of berries that are essentially devoid of anthocyanins, as well as an opportunity to determine their ability to modulate specific molecular targets in oral cancers. The outcome will provide a suitable foundation for in-depth studies designed to elucidate the chemoprevention potential for oral cancer of various bioactive berry components.