Chemoprevention of Prostate Cancer by Curcumin

姜黄素化学预防前列腺癌

• 批准号: 7468044
• 负责人: Sharmila Shankar
• 金额: $ 5.89万
• 依托单位: UNIVERSITY OF TEXAS HLTH CTR AT TYLER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-10 至 2009-09-18
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7468044
• 关键词: Androgen Receptor; Androgens; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Apoptosis; Apoptotic; Biological Response Modifier Therapy; Cancer Etiology; Caspase; Cells; Cessation of life; Chemoprevention; Chemopreventive Agent; Clinical Trials; Cultured Cells; Curcumin; Data; Development; Disease; Employee Strikes; Epidemiologic Studies; Event; Exhibits; Family; Food; Generations; Goals; Growth; Hormones; Implant; In Vitro; Induction of Apoptosis; Knowledge; LNCaP; Malignant neoplasm of prostate; Mitochondria; Modeling; Molecular; Mus; North America; Nude Mice; Operative Surgical Procedures; PC3 cell line; Pathway interactions; Pigments; Prevention strategy; Prostate; Prostatic Neoplasms; Radiation therapy; Reactive Oxygen Species; Refractory; Research Design; Resistance; Role; Staging; TNFSF10 gene; TP53 gene; Testing; Tumeric; Tumor Tissue; Up-Regulation; base; cancer cell; cancer diagnosis; caspase-3; caspase-8; chemotherapy; dietary constituent; hormone therapy; in vivo; interest; member; men; neoplastic cell; novel; novel strategies; prostate cancer prevention; receptor; response; tumor; tumor initiation

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.

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活性。它对与肿瘤发生、促进和进展相关的多种细胞事件具有显着的抑制作用，因此作为前列腺癌的化学预防剂具有广阔的发展前景。使用姜黄素作为化学预防剂的基本原理来自流行病学研究和我们的初步数据。姜黄素通过参与细胞凋亡的线粒体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上的这一空白，还将产生数据来指导我们制定姜黄素和基于 TRAIL 的策略来预防和/或治疗人类前列腺癌。根据我们的初步研究结果，我们假设姜黄素能够非常有效地抑制人类前列腺癌细胞的生长，因为它能够通过上调死亡受体和 Bcl-2 家族促凋亡成员以及激活 caspase 来诱导细胞凋亡。我们建议通过以下方式检验这一假设：(1) 确定姜黄素抑制人前列腺癌细胞增殖并诱导细胞凋亡的分子机制，以及 (2) 确定姜黄素和/或 TRAIL 对人前列腺癌细胞原位生长的影响植入裸鼠体内。在具体目标 2 中，将检查来自媒介物治疗对照和姜黄素和/或 TRAIL 治疗小鼠的肿瘤，以确定姜黄素和/或 TRAIL 诱导的与培养细胞中观察到的细胞凋亡诱导有关的分子变化的程度（具体目标 1）与其体内作用相关。具体来说，研究旨在确定线粒体和/或死亡受体途径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，并使用动物模型确定姜黄素和/或TRAIL对抗前列腺癌的体内功效，这是启动临床试验的先决条件。确定其对抗人类前列腺癌活性的试验。我们期望拟议的研究能够产生支持我们假设的数据，并成为开发前列腺癌预防新方法的关键一步。