Dietary polyphenolic compounds in cancer prevention

SY33-04 Polyphenolic compounds are present in significant amounts in our diet through the ingestion of fruits, vegetables, beverages, and herbal products. The possible cancer preventive activities of polyphenolic compounds have received a great deal of recent attention. This presentation will use flavanols and their oligomers (such as catechins and procyanidins found in tea, grapes, cocoa, etc.), flavonols (such as quercetin and myricetin found in many vegetables, fruits, and beverages), and anthocyanins (such as glycosides of cyanidin and delphinidin found in berries, grapes, cabbages, onions, radishes, etc.) as examples to illustrate our current understanding of their potential cancer preventive activities, as well as the challenges we face in this area of research. Of these compounds, tea catechins have been studied most extensively, both as mixtures in tea and polyphenol preparations and as pure epigallocatechin-3-gallate (EGCG), the most abundant and active polyphenol in green tea (1, 2). The conclusions drawn from these studies can also be applied to many other polyphenols. Biotransformation and bioavailability are important issues in understanding the biological activities of polyphenols. The gallated catechins and oligomers of catechins have low absorbability because of their large molecular size and the multiple phenolic groups, which form hydrogen bonds with water. Many of the flavonols are ingested as glycosides and converted to the aglycones before or during intestinal absorption. Anthocyanins, with low bioavailability, appear to be absorbed in the glycoside forms in the stomach. Upon absorption, the phenolic groups are metabolized to form glucuronides and sulfates, and are readily methylated by catechol-O-methyltransferase. Many studies have demonstrated the inhibition of tumor formation at different organ sites in animal models by a variety of preparations of tea polyphenols, berry extracts, grape seed extracts, and fruit juices as well as pure compounds such as EGCG, quercetin, cyanidin, and delphinidin (1-5). Because of the bioavailability issue, some of these preparations or compounds inhibit tumorigenesis less effectively in internal organs than in the digestive tract, where the agents have direct contact with the epithelial cells (3). The mechanisms of the inhibitory actions have been studied extensively in animal models. The inhibition of tumorigenesis by these agents has been shown to be related to enhanced apoptosis, lowered cell proliferation rate, and sometimes suppressed angiogenesis. The molecular events that lead to these cellular changes are not clearly understood, although inhibition of the phosphorylation of Erk1/2, c-Jun, Akt, and IGFR-1 as well as decreased levels of IGF have been shown to be caused by some polyphenols. Studies in cell lines have generated a great deal of information on the effects of specific polyphenols in the respective experimental systems. The results, however, need to be interpreted with caution because 1) the concentrations of the polyphenols used in many of the experiments were much higher than those observed in the blood and tissues of animals; and 2) most polyphenols can be oxidized in the cell culture media to generate reactive oxygen species, which can affect a variety of molecular events, but such prooxidative activities may or may not take place in vivo. Polyphenols are generally known as antioxidants. Their antioxidative functions have been demonstrated in experimental systems involving strong oxidative stress. At excessive doses, tea polyphenols and perhaps other polyphenols can be toxic, possibly due to the generation of reactive oxgen species. It remains to be determined whether polyphenols function as antioxidants or prooxidants in other situations in vivo, especially at the doses of human consumption. Our current understanding of cancer preventive mechanisms of polyphenols are as follows: 1) multiple mechanisms are likely to be involved, and the relative importance of these mechanisms may depend on the experimental systems involved; 2) for the above discussed reasons, some of the proposed mechanisms based on studies in cancer cell lines may not be relevant to cancer prevention; 3) many of the observed effects are probably secondary or downstream events and it is important to identify the direct targets; and 4) mechanisms of cancer prevention need to be demonstrated in relevant animal models or human tissues. The possible synergistic actions among different polyphenols in a mixture, such as those occurring in foods or beverages, have been suggested; more studies are needed to confirm these actions. The possible cancer preventive effects of flavanols, flavonols, and anthocyanins have been assessed in many epidemiological studies, but clear conclusions cannot be drawn. Although the consumption of foods and beverages that are rich in these polyphenols has been shown to be inversely associated with cancer risk in some studies, other studies have not shown such cancer preventive effects. For example, upon reviewing approximately 200 epidemiological studies regarding the association between tea consumption and human cancer risks at different organ sites, we found that an inhibitory effect was frequently observed in case-control studies in Asia where green tea is consumed, but not in many other reports, especially from prospective studies. Because of the many confounding factors involved in these studies, the difficulty in determining the relationship between the consumption of a specific group of food or beverage and cancer preventive effects is understandable. Therefore, well-designed clinical trials are important in determining whether the cancer preventive effects of polyphenols can be manifested in humans. For example, there have been more than 15 studies demonstrating that short-term ingestion of green tea by humans decreases DNA damage or increases antioxidant activity in the blood (6). Similar activities of berry preparations and quercetin have also been demonstrated in humans. Several clinical trials with green tea (polyphenols) in patients with premaligmant lesions or with cancer have also showed beneficial effects in decreasing DNA damage or disease progression. For example, a recent double-blind study on individuals with high-grade prostate intraepithelial neoplasia (PIN) by Bettuzzi et al. demonstrated that taking 600 mg of green tea catechins daily for 12 months significantly decreased the rate of prostate cancer development (7). These results are very exciting, and their impact would be tremendous if the results could be reproduced in trials with larger numbers of subjects. In conclusion, the cancer preventive activities of many polyphenols, whether in pure form or as mixtures in foods or beverages, have been demonstrated in different animal models. Epidemiological studies, however, have not convincingly demonstrated a reduction of human cancer risk associated with the consumption of flavanols, flavonols, and anthocyanins. These polyphenols or foods and beverages that contain these polyphenols, however, may still be used for cancer prevention, if the activities could be demonstrated in well-designed human trials. More studies on their bioavailabilities and mechanisms of actions would help to bridge the gaps between animal and human studies (supported by NIH grant CA88961 and CA120915). References 1. Yang CS, Maliakal P, and Meng X Inhibition of carcinogenesis by tea. Annu Rev Pharmacol Toxicol 2002;42 : 25-54. 2. Ju J, Lu G, Lambert JD, and Yang CS Inhibition of carcinogenesis by tea constituents. Semin Cancer Biol 2007;17 : 395-402. 3. Stoner GD, Wang LS, Zikri N, Chen T, Hecht SS, Huang C, Sardo C, and Lechner JF Cancer prevention with freeze-dried berries and berry components. Semin Cancer Biol 2007;17 : 403-410. 4. Raina K, Singh RP, Agarwal R, and Agarwal C Oral grape seed extract inhibits prostate tumor growth and progression in TRAMP mice. Cancer Res 2007;67 : 5976-5982. 5. Syed DN, Afaq F, and Mukhtar H Pomegranate derived products for cancer chemoprevention. Semin Cancer Biol 2007;17 : 377-385. 6. Thomasset SC, Berry DP, Garcea G, Marczylo T, Steward WP, and Gescher AJ Dietary polyphenolic phytochemicals--promising cancer chemopreventive agents in humans? A review of their clinical properties. Int J Cancer 2007;120 : 451-458. 7. Bettuzzi S, Brausi M, Rizzi F, Castagnetti G, Peracchia G, and Corti A Chemoprevention of human prostate cancer by oral administration of green tea catechins in volunteers with high-grade prostate intraepithelial neoplasia: a preliminary report from a one-year proof-of-principle study. Cancer Res 2006;66 : 1234-1240.