Chemopreventive Signaling Mechanisms in Prostate Cancer

前列腺癌的化学预防信号机制

• 批准号: 7023230
• 负责人: Ah-Ng Tony Kong
• 金额: $ 26.74万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7023230
• 关键词: apoptosis; athymic mouse; carcinogenesis; cell proliferation; model; neoplasm /cancer; prostate; prostate neoplasms

DESCRIPTION (provided by applicant): 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 gene 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 in athymic nude mice. In this new application entitled "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 investigate and establish the effect of PEITC and curcumin alone or in combination in the 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. Elucidate in-depth mechanistic studies in prostate cancer cell lines on the signaling pathways leading to growth inhibition and apoptosis induced by PEITC and curcumin alone 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 and curcumin alone or in combination, and to identify the molecular targets of their chemopreventive effects. Such knowledge will help to develop better chemopreventive compounds and to design more effective cancer chemoprevention clinical trials in prostate cancer.

描述（由申请人提供）：前列腺癌是美国男性最常见的恶性肿瘤，每年约有40,000人生命。转移性前列腺癌无法治愈，并且平均存活率为2 - 3年。局部前列腺癌对转移性疾病和侵入性疾病的发展通常以相对较长的潜伏期为特征，从前体病变到临床疾病的表现。为了降低前列腺癌的发生率，通过饮食和/或化学干预进行的癌症化学预防将是一种逻辑和实用方法。最近，我们和其他人都发现，众所周知的2期基因诱导剂，异硫氰酸盐（ITC），包括苯乙甲基异硫氰酸盐（PEITC）（PEITC）和磺胺硫烷（SFN），它们存在于十字花科蔬菜中，以及姜黄素（姜黄素）中的姜黄素，众所周知的NF-kabpab抑制剂的作用，对粉碎的粉碎作用，对粉碎的粉丝构成了粉末性，这些作用是粉碎的粉碎作用，对粉碎的粉丝构成了粉碎的粉碎作用，这些粉状构成了粉碎的作用，这些粉状构成了粉碎的粉碎作用。无胸腺裸鼠的体外和体内线。在这一新应用中，标题为“前列腺癌中化学预防剂的信号传导”，我们将重点关注单独或与异硫代苯酸盐的影响或与酚类化合物姜黄素结合的影响，对癌变的抑制，通过测试单独的甲硫代和姜黄素构成的假说来抑制癌变，并抑制car虫的作用。前列腺。我们将检查异硫氰酸酯和姜黄素的剂量反应以及药物的相关代谢，分布，药代动力学和组织水平，体内抗癌发生机制以及相关的体内体内体内抗分子机制。以下特定目标旨在解决我们的假设。 1。检查和建立PEITC和姜黄素的作用，单独或在裸鼠PC-3肿瘤异种移植物中的效果。我们将单独或在短期治疗中单独或合并不同剂量的PEITC和姜黄素对细胞增殖和肿瘤进展的抑制作用。 2。单独研究和建立PEITC和姜黄素的效果或在流浪汉模型中组合的效果。我们将在长期治疗中，通过不同剂量的PEITC和姜黄素或组合研究细胞增殖和肿瘤进展的抑制作用。 3。检查单独使用PEITC和姜黄素抑制癌发生的体内机理，或在裸鼠和流浪汉小鼠中的组合。我们将研究单独使用PEITC和姜黄素对细胞增殖和肿瘤进展的抑制或AIM 1和2中所述的组合是否可能与在短期和长期的裸体小鼠和长期的裸体小鼠和Tramp小鼠实验中相关的信号通路（例如NF-KB，AKT，MAPK）的活性。 4。单独或组合PEITC和姜黄素诱导的生长抑制和凋亡，包括IKKS-NF-KB的作用，生长因子/酪氨酸激酶-AKT途径，以及MAPK-Caspase-Caspase-popoptoptopis途径。我们的长期目标是单独或组合使用PEITC和姜黄素抑制前列腺癌发生的机制，并确定其化学预防作用的分子靶标。这些知识将有助于开发更好的化学预防化合物，并在前列腺癌中设计更有效的癌症化学预防临床试验。