Chemopreventive Signaling Mechanisms in Prostate Cancer

前列腺癌是美国男性中最常见的恶性肿瘤，每年夺去约40，000人的生命。转移性 前列腺癌是不可治愈的，并且与2-3年的平均生存期相关。局限性前列腺的进展 从癌症到转移性和侵袭性疾病的特征通常是从癌症的发生开始相对长的潜伏期。 临床疾病表现的前驱病变。为了降低前列腺癌的发病率， 通过饮食和/或化学干预进行化学预防将是一种合乎逻辑和实用的方法。最近，我们作为 以及其他人已经发现，众所周知的2期基因诱导异硫氰酸酯（ITC），包括 苯乙基异硫氰酸酯（PEITC）和萝卜硫素（SFN），存在于十字花科蔬菜，和姜黄素， 存在于肿瘤粉末食品制剂中的公知的类黄酮NF-κ B抑制剂具有有效的抑制作用， 体外以及体内无胸腺裸鼠中的各种人前列腺细胞系中的作用。在这个名为 “前列腺癌中化学预防剂的信号传导”，我们将重点关注异硫氰酸酯单独或联合 与酚类化合物姜黄素的组合对抑制致癌作用的作用， 异硫氰酸酯和姜黄素单独和/或组合通过抑制细胞增殖 增殖和增强前列腺细胞凋亡。我们将检查异硫氰酸酯的剂量反应， 姜黄素及其相关的药物代谢、分布、药代动力学和组织水平，体内 体外细胞培养模型中的抗癌机制及相关分子机制。以下 具体的目标是为了解决我们的假设。 1.研究PEITC和姜黄素单独或联合应用对裸鼠PC-3肿瘤的抑制作用 异种移植我们将研究不同剂量的PEITC对细胞增殖和肿瘤进展的抑制作用， 姜黄素单独或组合用于短期和长期治疗。 2.研究并建立PEITC和姜黄素单独或联合应用对TRAMP小鼠模型的作用。我们 将研究单独使用不同剂量的PEITC和姜黄素对细胞增殖和肿瘤进展的抑制作用 或两者结合，用于长期治疗。 3.检查PEITC和姜黄素单独或组合抑制癌发生的体内机制， 裸鼠和TRAMP小鼠中。我们将研究是否抑制细胞增殖和肿瘤进展， 目的1和2中描述的PEITC和姜黄素单独或组合，可能与相关的免疫抑制剂的活性相关。 信号通路（例如，NF-κ B、AKT、MAPK）在短期和长期裸鼠和TRAMP小鼠实验中的表达。 4.阐明前列腺癌细胞系中导致生长的信号通路的深入机制研究 PEITC和姜黄素单独或组合诱导的抑制和凋亡，包括IKKs-NF-KB的作用， 生长因子/酪氨酸激酶-AKT途径和MAPK-半胱天冬酶-凋亡途径。 我们的长期目标是阐明PEITC和姜黄素抑制前列腺癌发生的机制 单独或组合，并鉴定其化学预防作用的分子靶点。这样的知识会帮助 开发更好的化学预防化合物，设计更有效的癌症化学预防临床试验， 前列腺癌

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.