Numerous studies have indicated the effectiveness of green tea for anti-cancer activity in both humans and experimental animals, and green tea extract has reached clinical trials for examination of its efficacy for anti- cancer therapy. Epigallocatechin-3-gallate (EGCG), the major catechin in green tea has been shown to be a primary component eliciting this biological activity. Several animal studies have shown EGCG to protect against a variety of cancers, both spontaneous and chemically induced. We made the novel discovery that EGCG is an inhibitor of the chaperone 90 kDa heat shock protein (hsp90). Our overall hypothesis is that the reported anti-cancer activity of EGCG is due, at least in part, to its ability to modulate hsp90 function. This hypothesis will be tested using a unique model of human prostate cancer in mice. As far as we are aware, this is the only such model undergoing human epithelial malignant transformation and metastasis using a hormone mix normally found in men, thus representing all stages of human carcinogenesis. Using in vivo and in vitro approaches with this model, we will determine whether differential sensitivity to EGCG will be observed as these epithelial cells progress from being non-tumorigenic, to transformed, to metastatic stages. Using the most sensitive stage, we will further determine in a concentration- and time-dependent manner whether EGCG modulates the levels and/or function of hsp90 client proteins, consistent with the notion that EGCG inhibits growth of prostate cancer cells through its ability to inhibit hsp90 activity. To further differentiate between hsp90-dependent effects and possible non-hsp90 effects, we will use an innovative proteomic approach that assess the ability of EGCG to affect a variety of signaling pathways.
The proposed studies are highly relevant for humans in that 1) they focus on dietary components that are of real and relevant human interest, 2) EGCG has been demonstrated to be an effective anti-cancer agent with an unknown mechanism, 3) the anti-prostate cancer effect of EGCG is one of the most consistent findings in both animal models and humand, 4) prostate cancer is estimated to be the most frequently diagnosed cancer in the United States, 5) the studies will test a particularly novel hypothesis for the actions of EGCG, 6) the studies will add to our understanding of the signaling pathways regulated by hsp90 and their relationship to prostate cancer, 7) the studies will test the actions of EGCG in a unique and relevant model of human prostate cancer, and 8) they will offer avenues for new and novel therapeutic approaches for cancer treatment.
|Bhat, Rohit; Adam, Amna T; Lee, Jungeun Jasmine et al. (2014) Towards the discovery of drug-like epigallocatechin gallate analogs as Hsp90 inhibitors. Bioorg Med Chem Lett 24:2263-6|