Ester bond-containing tea polyphenols potently inhibit proteasome activityin vitro and in vivo

It has been discovered that proteasome inhibitors are able to induce tumor growth arrest or cell death and that tea consumption is correlated with can cer prevention. Here, we show that ester bond-containing tea polyphenols, s uch as (-)-epigallocatechin-3-gallate (EGCG), potently and specifically inh ibit the chymotrypsin-like activity of the proteasome in vitro (IC50 = 86-1 94 nM) and in vivo (1-10 muM) at the concentrations found in the serum of g reen tea drinkers. Atomic orbital energy analyses and high performance liqu id chromatography suggest that the carbon of the polyphenol ester bond is e ssential for targeting, thereby inhibiting the proteasome in cancer cells. This inhibition of the proteasome by EGCG in several tumor and transformed cell lines results in the accumulation of two natural proteasome substrates , p27(Kip1) and I kappaB-alpha, an inhibitor of transcription factor NF-kap paB, followed by growth arrest in the G, phase of the cell cycle. Furthermo re, compared with their simian virus-transformed counterpart, the parental normal human fibroblasts were much more resistant to EGCG-induced p27(Kip1) protein accumulation and G(1) arrest. Our study suggests that the proteaso me is a cancer-related molecular target of tea polyphenols and that inhibit ion of the proteasome activity by ester bond containing polyphenols may con tribute to the cancer-preventative effect of tea.