Chemopreventive Signaling Mechanisms in Prostate Cancer

前列腺癌是美国男性最常见的恶性肿瘤，每年夺走约4万人的生命。转移性 前列腺癌是不可治愈的，与平均2-3年的生存期有关。局限性前列腺癌的进展 癌症到转移性和侵袭性疾病的特点通常是从发生到 前驱病变表现为临床疾病。为了降低前列腺癌的发病率，癌症 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际的方法。最近，我们作为 和其他人一样，发现众所周知的第二阶段基因诱导异硫氰酸酯(ITCs)，包括 十字花科蔬菜中存在的苯乙基异硫氰酸酯(PEITC)和萝卜硫醚(SFN)，以及姜黄素 众所周知，黄酮类核因子-kappaB抑制剂存在于肿瘤粉状食品制剂中，具有强大的抑制作用 对不同人前列腺细胞系体外及体内裸鼠的影响。在这份名为 “前列腺癌中化学预防药物的信号传递”，我们将集中在异硫氰酸酯单独或在前列腺癌中的作用。 与酚类化合物姜黄素结合，通过检验假设抑制致癌 异硫氰酸酯和姜黄素单独和/或联合通过抑制细胞来预防癌症的发生 促进前列腺细胞增殖和促进细胞凋亡。我们将研究异硫氰酸酯的剂量效应和 姜黄素及其相关药物的代谢、分布、药代动力学和组织水平 体外细胞培养模型的抗癌机制及相关分子机制。以下是 具体的目的是为了解决我们的假设。 1.检测和建立PEITC和姜黄素单独或联合应用对裸鼠PC-3肿瘤的作用 异种移植物。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 姜黄素在短期或长期治疗中单独或联合使用。 2.研究并建立PEITC和姜黄素单独或联合应用对小鼠子宫内膜的影响。我们 将研究不同剂量的PEITC和姜黄素单独对细胞增殖和肿瘤进展的抑制作用 或者结合起来，在长期治疗中。 3.检测PEITC和姜黄素单独或联合应用的体内抑癌作用机制。 裸鼠和流浪鼠。我们将研究是否通过抑制细胞增殖和肿瘤进展 目标1和目标2中描述的PEITC和姜黄素单独或组合可能与相关的活性有关 短期和长期裸鼠和流浪鼠实验中的信号通路(例如，核因子-KB、AKT、MAPK)。 4.对前列腺癌细胞系的生长信号通路进行深入的机制研究 PEITC和姜黄素单独或联合诱导的抑制和凋亡，包括IKKS-NF-KB作用 生长因子/酪氨酸激酶-AKT通路和MAPK-caspase-凋亡通路。 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 单独或联合使用，并确定其化学预防作用的分子靶点。这样的知识将会有所帮助 开发更好的化学预防化合物和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.