Chemoprevention of Prostate Cancer by Curcumin

描述(由申请人提供)： 姜黄素是姜黄中的一种色素，具有抗炎、抗氧化、抗肿瘤、神经保护和免疫调节等活性。它对与肿瘤启动、促进和进展相关的各种细胞事件具有显著的抑制作用，因此有望成为前列腺癌的化学预防药物。使用姜黄素作为化学预防药物的理由来自流行病学研究和我们的初步数据。姜黄素通过线粒体途径和死亡受体途径诱导细胞凋亡。此外，姜黄素虽然单独有效，但可以使前列腺癌细胞对TRAIL敏感。然而，姜黄素诱导前列腺癌细胞敏感性的机制尚不清楚。本申请中提出的研究不仅将填补我们知识的这一空白，而且还将产生指导我们制定基于姜黄素和TRAIL的预防和/或治疗人类前列腺癌的策略的数据。根据我们的初步发现，我们推测姜黄素可能通过上调死亡受体和Bcl2家族的促凋亡成员以及激活caspase而高效地抑制人前列腺癌细胞的生长(S)。我们建议通过以下两个方面来验证这一假设：(1)确定姜黄素抑制人前列腺癌细胞增殖和诱导细胞凋亡的分子机制；(2)确定姜黄素和/或TRAIL对裸鼠原位移植的人前列腺癌细胞生长的影响。在特定目标2中，将检查来自赋形剂处理的对照组以及姜黄素和/或TRAIL处理的小鼠的肿瘤，以确定姜黄素和/或TRAIL诱导的与培养细胞中观察到的与诱导细胞凋亡有关的分子变化在多大程度上与它们在体内的效果相关(特定目标1)。具体地说，研究旨在确定线粒体和/或死亡受体通路在姜黄素诱导的细胞凋亡中的作用。总之，本申请中提出的研究将确定姜黄素抑制人前列腺癌细胞生长的机制，并通过动物模型确定姜黄素和/或TRAIL对前列腺癌的体内疗效，这是启动临床试验以确定其抗人前列腺癌活性的先决条件。我们期望拟议的研究将产生支持我们的假设的数据，并作为开发前列腺癌预防新方法的关键一步。

DESCRIPTION (provided by applicant): Curcumin, a pigment in turmeric, possesses anti-inflammatory, antioxidant, antitumor, neuroprotective, and immunomodulatory activities. It exerts striking inhibitory effects on diverse cellular events associated with tumor initiation, promotion, and progression, thus holds great promise for development as a chemopreventive agent for prostate cancer. The rationale for using curcumin as a chemopreventive agent comes from the epidemiological studies and our preliminary data. Curcumin induces apoptosis through engagement of both mitochondrial and death receptor pathways of apoptosis. Furthermore, curcumin, although effective alone, can sensitize prostate cancer cells to TRAIL. However, the mechanisms by which curcumin induces sensitivity in prostate cancer cells are not known. Studies proposed in this application will not only fill this gap in our knowledge but also generate data that will guide us in formulating curcumin and TRAIL-based strategies for prevention and/or treatment of human prostate cancers. Based on our preliminary findings, we hypothesize that curcumin will be highly effective in suppressing growth of human prostate cancer cells due to its ability to induce apoptosis through upregulation of death receptors and proapoptotic members of Bcl-2 family and activation of caspase(s). We propose to test this hypothesis by: (1) Determining the molecular mechanisms by which curcumin inhibits proliferation and induces apoptosis in human prostate cancer cells, and (2) Determining the effects of curcumin and/or TRAIL on growth of human prostate cancer cells orthotopically implanted in nude mice. In Specific Aim 2, tumors from the vehicle treated control and curcumin and/or TRAIL treated mice will be examined to determine the extent to which curcumin and/or TRAIL-induced molecular changes pertaining to apoptosis induction observed in cultured cells (Specific Aim 1) correlate with their effects in vivo. Specifically, studies are designed to determine the contribution of mitochondrial and/or death receptor pathways in curcumin-induced apoptosis. In summary, the studies proposed in this application will define the mechanism by which curcumin inhibits growth of human prostate cancer cells and determine in vivo efficacy of curcumin and/or TRAIL against prostate cancer using an animal model, which is a prerequisite for initiation of clinical trials to determine its activity against human prostate cancer. We expect the proposed studies to yield data in support of our hypothesis and to serve as a critical step in developing new approaches to prostate cancer prevention.