New life for an "old" drink

Abstract

According to Chinese myth, green tea was first identified by Shennong (∼5000 B.C.), the legendary creator of ancient Chinese agriculture and medicine. The effect of green tea on health was documented in Shennong Food (written between 221 B.C. and 475 A.D.) as “green tea improves body strength and mental sharpness”. The anticancer effect of tea extract was reported in the early 1990s.1 Green tea extract contains many polyphenols, known as catechins, including epigallocatechin-3-gallate (EGCG), epigallocatechin (EGC), epicatechin-3-gallate (ECG) and catechin-3-gallate (CG). Among them, EGCG is the most abundant and studied. The mechanism for anticancer activity of EGCG is still under elucidation. It appears that EGCG inhibits cancer growth and metastasis via multiple signaling pathways. Using computational modeling, Jankun et al. proposed that EGCG inhibits cancer by binding to urokinase (uPA), which plays a critical role in promoting cancer growth and metastasis.2 However, the most studied anticancer activity of EGCG was its ability to induce cell cycle arrest and apoptosis of various cancer cells, but not normal cells,3 via multiple signaling pathways,4 including, but not limited to, NFκB inhibition,5 p53 and WAF1/p21 activation,6 cdks inhibition and ckis activation,7 JNK and MAPK activation8 and AKT inhibition.9 The potential use of EGCG as an anticancer reagent has attracted much attention in recent years. In this issue of Cell Cycle, Nihal et al. report a novel finding that EGCG improved efficacy of interferon-α2 (IFN) in treating human melanoma in a mouse model. Melanoma has a high mortality and its incidence is increasing. As the disease progresses to stage III and stage IV, treatment becomes less successful and five-year survival rates drop precipitously. IFN has been used to treat melanoma patients. It was suggested that while IFN inhibits melanoma growth via a PKC-dependent mechanism, it also interfered with Fas-mediated apoptosis.10 Previous studies from Nihal et al. demonstrate that EGCG alone inhibits progression of melanoma cells, but not melanocytes, by inducing cell cycle arrest and apoptosis.7 In this study, Nihal et al. tested the ability of EGCG to sensitize human melanoma cells to the IFN-induced growth arrest and apoptosis in cell culture and animal model. They demonstrated that melanoma growth was more efficiently inhibited by a combined treatment of EGCG and IFN than treated with either reagent alone. The percentage of apoptotic cells was also increased in the combined treatment. Interestingly, while the combined treatment didn't further increase the expression of Fas on the surface of melanoma cells than IFN did, it did increase the sensitivity of the cells to FasL-induced apoptosis. The results suggest that EGCG is likely to sensitize melanoma cells by restoring the Fas-mediated apoptotic signaling pathway, which was inhibited by IFN. Further more, EGCG dramatically reduced the persistent NFκB activity in melanoma cells. Comparing to IFN, EGCG was more efficient in reducing the activity than nuclear translocation, which suggest that EGCG may inhibit NFκB activity by interfering with its DNA binding. Finally, treating mice bearing melanoma cells with EGCG alone or in combination with IFN significantly reduced the tumor volume accompanied by the expression of proliferation marker PCNA. These results indicate that the extract from green tea, a thousand year old drink, has the potential of being a new therapeutic for melanoma treatment.