The rationale for this proposal is based, in large measure, upon our recent exciting studies that show that selected polyphenols, including extracts from black and green tea, may be inducing apoptosis (programmed cell-death) by targeting proteins of the Bcl-2 family. Bcl-2 and Bcl-x L are over-expressed in approximately 70% of prostate and breast cancers, preventing cancer cells from dying despite radiation and chemotherapy. As such, it is reasonable to hypothesize that dietary compounds capable to neutralize the protective effects of Bcl-2 family proteins in vitro may possess chemopreventive activity in vivo. On the premises, we propose to use biophysical assays to screen large libraries of natural dietary compounds for inhibition of Bcl-x L and Bcl-2 proteins and to study the cytotoxic effects of such compounds on human cancer cell lines. We anticipate that promising pro-apoptotic compounds would arise from our studies and that such dietary substances would have an impact not only in cancer chemoprevention but also in the development of new clinical therapies for the treatment of cancer.
| Rega, Michele F; Leone, Marilisa; Jung, Dawoon et al. (2007) Structure-based discovery of a new class of Bcl-xL antagonists. Bioorg Chem 35:344-53 |
| Becattini, Barbara; Pellecchia, Maurizio (2006) SAR by ILOEs: an NMR-based approach to reverse chemical genetics. Chemistry 12:2658-62 |
| Fattorusso, Roberto; Jung, Dawoon; Crowell, Kevin J et al. (2005) Discovery of a novel class of reversible non-peptide caspase inhibitors via a structure-based approach. J Med Chem 48:1649-56 |
