EGCG inhibits critical pathways of signal transduction in human cancer cells.

CS15-02

Epidemiologic studies suggest that the consumption of green tea may be protective for certain types of human cancer, although there are inconsistencies in this data base. Nevertheless, numerous studies in rodents provide definitive evidence that extracts of green tea have antitumor activity for a wide range of malignancies, including both inhibition of de novo tumor formation and inhibition of the growth of established tumors. In addition, extracts of green tea and the compound epigallocatechin-3-gallate EGCG, a major biologically active component of green tea, can inhibit growth and induce apoptosis in a variety of rodent and human cancer cell lines. Various mechanisms have been proposed to explain these anticancer activities. Our laboratory has focused on the effects of EGCG and related compounds on specific receptor tyrosine kinases (RTKs) and the related downstream signaling pathways. We found that EGCG inhibits the growth of human squamous carcinoma, breast carcinoma and colon carcinoma cells. This is associated with rapid inhibition of activation of the RTKs, EGFR, HER2 and HER3 inhibition of activation or the expression of several downstream signaling molecules involved in cell proliferation and survival and angiogenesis, including: Stat3, Erk, Akt, c-fos, AP-1, NFKB, cyclin D1, COX-2, Bcl-xL and VEGF. Similar results were obtained with the standardized catechin mixture Polyphenon E (Poly E) which is enriched with EGCG. Indeed, Poly E may be more effective than EGCG. By treating colon cancer cells for a prolonged period of time (96 hours) some of these results could be obtained with even a very low concentration of EGCG (1µg/ml), which approaches the serum concentration in patients administered extracts of green tea. In addition, low concentrations of EGCG synergize with (-)-epicatechin, 5-flourouracil or taxotere, in inhibiting the growth of carcinoma cells. Therefore EGCG or Poly E may be useful when used alone or in combination with other agents in the prevention and/or treatment of colon and other types of human cancer. The insulin-like growth factor (IGF) and the IGF-receptor IGF-1R play important roles in the development and growth of colon and other types of human cancer. In recent studies we found that EGCG also inhibits activation of IGF-1R in colon cancer and hepatoma cells. Furthermore, this is associated with decreased expression of IGF-1, which activates IGF-1R, and increased expression of IGFBP-3, which can sequester IGF-1. These inhibitory effects on the IGF/IGF-R system provide a further rationale for the use of EGCG in cancer chemoprevention and therapy. In view of the ability of EGCG to inhibit activation of several RTKs, in recent studies we have examined the possibility that EGCG might act, at least in part, by disrupting the lipid microenvironment in regions of the plasma membrane in which these receptors are embedded. Evidence will be presented that treatment of colon cancer cells with a low concentration of EGCG causes rapid disruption of ordered lipid membrane domains, so-called "lipid rafts," and that this effect impairs activation of the EGFR. Studies are in progress to confirm this mechanism and examine whether it may also explain other growth inhibitory effects of EGCG and related compounds. Taken together the above findings, and those by numerous other investigators, should encourage randomized clinical trials with EGCG and related compounds for both cancer chemoprevention and therapy. In view of the synergistic effects seen in vitro, combinations of EGCG with other anticancer agents should also be explored in clinical trials.