Epigallocatechin 3-gallate and green tea catechins: United they work, divided they fail.

Epidemiologic studies indicate that green tea consumption decreases cancer risk (1–3). These data are supported by the results of numerous preclinical studies, which have shown that green and black tea are potent inhibitors of carcinogenesis in various rodent models (4–6), including models for cancers of the skin, lung, esophagus, stomach, liver, duodenum, small intestine, pancreas, colon-rectum, and mammary gland (1, 4, 6–11). Different tea preparations contain varying amounts of polyphenols, and epigallocatechin 3-gallate (EGCG) is the most abundant, best-studied, and possibly most potent (against cancer) polyphenol found in tea (4–6, 12–15). Besides EGCG, which may account for 50% to 80% of the total antioxidant polyphenols called catechins in tea (6, 12–16), other tea catechins include (−)-epigallocatechin, (−)-epicatechin gallate, and (−)-epicatechin. The achievable tissue concentrations of these polyphenols are in the low micromolar range, and therefore, anticarcinogenic effects observed with much higher concentrations in vitromay not be relevant to the in vivo anticarcinogenic process (4, 5, 17). Green tea, EGCG, or other dietary components clearly have both direct and indirect effects. Numerous proteins that can directly bind with EGCG include the plasma proteins fibronectin, fibrinogen, and histidine-rich glycoprotein (18), which may act as carrier proteins for EGCG. EGCG also binds with Fas (19), which might trigger the Fas-mediated apoptosis cascade. Laminin and the 67 kDa laminin receptor (20, 21) also interact with EGCG, and this binding seems to regulate the biological functions of the 67 kDa laminin receptor that have possible implications for prion-related diseases. Other directly bound protein targets include the intermediate filament protein, vimentin (22), ζ chain–associated 70 kDa protein (ZAP70) kinase (23), Fyn (24), insulin-like growth factor-1 receptor (25), and the molecular chaperone glucose-regulated protein 78 (26; Fig. 1). All of these directly bound proteins play important roles in carcinogenesis. Zap-70 plays a critical role in Tcell receptor–mediated signal transduction and in the immune response of leukemia cells, and Fyn plays a major role in malignant cell transformation. Insulin-like growth factor-1 receptor plays a functional role in cell transformation and cancer formation, and glucose-regulated protein 78 is associated with the multidrug resistance phenotype of many types of cancer cells. The many targets of polyphenols that have been discovered and continue to be discovered are very likely dependent on the concentration of the tea polyphenol used and the specific cell, tissue, or organ—for example, proteins that bind EGCG in the lung, breast, colon, or skin might be very different from one another, and EGCG very likely targets multiple proteins in each tissue. EGCG and other polyphenols also exert strong indirect effects on a number of important regulatory proteins and transcription factors, adding further complexity to these agents' multitargeted anticancer effects. In particular, EGCG inhibited tumor promoter–induced activator protein-1 (15, 27), signal transducers and activators of transcription (28), phosphatidylinositol 3-kinase/Akt (29), and nuclear factorκB (30) activation. Phorbol ester tumor promoters such as 12-O-tetradecanoylphorbol-13-acetate are known to stimulate activator protein-1 activity through protein kinase C and the epidermal growth factor receptor (EGFR; ref. 31). Theaflavins and EGCG were reported to down-regulate the EGFR (32) or its phosphorylation (33). However, the direct target(s) of EGCG, theaflavins, and other polyphenols in suppressing EGFR, activator protein-1, signal transducers and activators of transcription, nuclear factor-κB, or other transcription factor activations have not yet been identified. Polyphenon E (Poly E) is a well-defined pharmaceuticalgrade mixture that contains at least five different catechins, including epicatechin, gallocatechin gallate, epigallocatechin, epicatechingallate, and most abundantly, EGCG (∼65%; refs. 34, 35). Poly E is the form of green tea used in clinical cancer trials funded through the National Cancer Institute to investigate the benefits of tea catechins in humans. Poly E has effectively inhibited lung cancer in a number of mouse model studies. Female A/J mice with benzo(a)pyrene-induced precancerous lesions formed over a period of 21 weeks received Poly E (1% in the diet) for an additional 25 weeks. Poly E treatment reduced the average tumor load per animal but did not significantly inhibit average tumor multiplicity (36). It is notable that Poly E reduced the largest carcinomas (compared with these tumors in untreated mice; ref. 36). Another study found that Poly E in the diet significantly reduced pulmonary adenoma multiplicity and tumor load in a dose-dependent fashion in A/J mice (37). Poly E in drinking fluid significantly reduced the incidence (by 52%) and multiplicity (by 63%) of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone–induced lung tumor progression from adenoma to adenocarcinomas in female A/J mice (38). The number of visible lung tumors was also reduced (38). These studies indicate that administration of Authors' Affiliation: The Hormel Institute, University of Minnesota, Austin, Minnesota Received 4/2/09; accepted 4/28/09; published OnlineFirst 5/26/09. Grant support: The Hormel Foundation and NIH grants R37 CA081064, CA120388, and CA111536. Requests for reprints: Zigang Dong, The Hormel Institute, 801 16th Avenue Northeast, Austin, MN 55912; Phone: 507-437-9600; Fax: 507-437-9606; E-mail: [email protected]. ©2009 American Association for Cancer Research. doi:10.1158/1940-6207.CAPR-09-0083