Chemopreventive Signaling Mechanisms in Prostate Cancer

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Prostate Cancer is the most common malignancy in American men claiming about 40,000 lives per year. Metastatic prostate cancer is not curable and is associated with a mean survival of 2-3 years. The progression of localized prostate cancer to metastatic and invasive disease is often characterized by a relatively long latency from the occurrence of precursor lesions to the manifestation of clinical disease. To decrease the incidence of prostate cancer, cancer chemoprevention through dietary and/or chemical intervention would be a logical and practical approach. Recently, we as well as others have found that the well known Phase 2 genes inducers isothiocyanates (ITCs) including phenethylisothiocyanate (PEITC) and sulforaphane (SFN) that are present in cruciferous vegetables, and curcumin, the well known flavonoid NF-kappaB inhibitor that is present in tumeric powdered food preparation, have potent inhibitory effects in various human prostatic cell lines in vitro as well as in vivo athymic nude mice. In this new applicationentitled "Signaling of Chemopreventive Agents in Prostate Cancer", we will focus on the effects of isothiocyanates alone or in combination with the phenolic compounds curcumin, on the inhibition of carcinogenesis by testing the hypothesis that isothiocyanate and curcumin alone and/or in combination prevent carcinogenesis by inhibiting cellular proliferation and enhancing apoptosis in the prostate. We will examine the dose-response of the isothiocyanate and curcumin and the related metabolism, distribution, pharmacokinetics and tissue levels of the drugs, the in vivo anti-carcinogenesis mechanism and the related molecular mechanisms in the in vitro cell culture models. The following specific aims are designed to address our hypothesis. 1.To examine and establish the effect of PEITC and curcumin, alone or in combination in Nude mice PC-3 tumor xenografts. We will study the inhibition of cell proliferation and tumor progression by different doses of PEITC and curcumin alone or in combination in short-term as well as in long-term treatments. 2.To investigateand establish the effect of PEITC and curcumin alone or in combination in TRAMP mice model. We will investigate the inhibition of cell proliferation and tumor progression by different doses of PEITC and curcumin alone or and in combination,in long-term treatments. 3. Examine the in vivo mechanisms of inhibition of carcinogenesis by PEITC and curcumin alone or in combination in nude mice and in TRAMP mice. We will study whether the inhibition of cell proliferation and tumor progression by PEITC and curcumin alone or in combination described in Aims 1 and 2, could be related to the activity of pertinent signaling pathways (e.g., NF-KB, AKT, MAPK) in short- and long-term Nude mice and TRAMP mice experiments. 4. Elucidatein-depth mechanistic studies in prostate cancer cell lines on the signaling pathways leading to growth inhibition and apoptosis induced by PEITC and curcuminalone or in combination including the role of IKKs-NF-KB, growth factors/tyrosine kinase-AKT pathways and the MAPK-caspase-apoptosis pathways. Our long-term goal is to elucidate the mechanisms of inhibition of prostate carcinogenesis by PEITC andcurcumin alone or in combination, and to identify the molecular targets of their chemopreventive effects. Such knowledgewill help to develop better chemopreventive compounds and to design more effective cancer chemoprevention clinical trials in prostate cancer.