This pre-clinical research project is based on the premise that sulforaphane (SFN; CH3-SO-(CH2)4-N=C=S), a constituent of many cruciferous vegetables including broccoli, may be used to inhibit onset and/or progression of human prostate cancer. Rationale for pre-clinical evaluation of SFN against prostate cancer derives from epidemiological data as well as the results of our preliminary studies, which led us to hypothesize that SFN will effectively suppress growth of prostate cancer due to its ability to trigger caspase-mediated apoptosis involving generation of reactive oxygen species (ROS) and Bcl-2 family proteins. We propose to test this hypothesis by: (1) Determining whether SFN-induced apoptosis is mediated by mitochondria-derived and/or non-mitochondrial ROS generation using PC-3 and LNCaP human prostate cancer cells as a model, (2) Determining the role of Bcl-2, Bax and Bak proteins in SFN-induced apoptosis using PC-3 and LNCaP cells, (3) Determining the relative contribution of intrinsic (mitochondria mediated activation of caspase-9) and extrinsic (death-receptor mediated activation of caspase-8) caspase pathways in apoptosis induction by SFN using PC-3 and LNCaP cells, (4) Determining the effect of oral administration of SFN on growth and regression of PC-3 and LNCaP xenografts in nude mice, and (5) Determining in vivo efficacy of SFN administration on prostate carcinogenesis using a transgenic mouse model (TRAMP).
In specific aims 4 and 5, the tumor tissues from control and SFN treated mice will be analyzed for apoptosis index and levels of cell cycle and apoptosis regulating proteins to determine the extent to which SFN-induced molecular changes observed in cells (aims 1-3) correlate with its effect in vivo. In summary, the studies proposed in this application will (a) define the mechanism by which SFN inhibits growth of human prostate cancer cells, which may lead to identification of mechanism-based biomarkers potentially useful in future clinical trials, and (b) determine in vivo efficacy of SFN against prostate cancer using two different animal models, which is a prerequisite for initiation of clinical trials to determine its activity against human prostate cancer.
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