Dietary prevention of prostate cancer

前列腺癌的饮食预防

• 批准号: 8927339
• 负责人: Chendil Damodaran
• 金额: $ 30.19万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8927339
• 关键词: Address; African Traditional Medicine; Age; Androgens; Animal Model; Animals; Apoptosis; Apoptotic; Area; Ashwagandha; Asians; Binding; Biological Assay; Cancer Etiology; Cancer Model; Cell Culture Techniques; Cell Death; Cell Line; Cell Survival; Cells; Cessation of life; Chemoprevention; Chemopreventive Agent; Clinical; Clinical Trials; Cyclic AMP Response Element; Cyclic AMP-Responsive DNA-Binding Protein; Data; Development; Diet; Environment; Event; Exposure to; Gap Junctions; Goals; Growth; Health; Histopathology; Immunofluorescence Immunologic; Immunoprecipitation; In Vitro; Induction of Apoptosis; Inhibition of Apoptosis; Intervention; Lead; Lesion; Lipids; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Modality; Modeling; Molecular; Mus; Northern Blotting; Outcome; Outcome Study; PTEN gene; Pathway interactions; Pattern; Phosphoric Monoester Hydrolases; Phosphorylation; Prevention; Prevention approach; Property; Prostate; Prostatic Neoplasms; Protein Kinase; Proteins; Refractory; Research; Resistance; Role; S-Phase Fraction; Serum; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Small Interfering RNA; Specimen; Staging; Tissues; Transactivation; Tumor Suppressor Proteins; Tumor Tissue; Western Blotting; androgen independent prostate cancer; angiogenesis; arm; base; cancer cell; cell growth; chemotherapy; chromatin immunoprecipitation; design; dietary supplements; feeding; in vivo; insight; novel therapeutics; prevent; pro-apoptotic protein; promoter; prostate cancer cell; prostate cancer prevention; research clinical testing; research study; response; transgenic adenocarcinoma of mouse prostate; tumor; tumor growth; tumor progression

DESCRIPTION (provided by applicant): Our research focuses on natural compounds that possess chemotherapeutic and/or chemopreventive properties with respect to cancer. In the proposed study, we will characterize the mechanism of action of the compound Withaferin-A (WA), a bioactive compound of Withania somnifera, which is extensively used in Asian and African traditional medicine. WA displays impressive and selective activity against androgen- dependent and androgen-independent prostate cancer (ADPC and AIPC, respectively), of which the latter is refractory to all current forms of treatment. Our preliminary in vitro and in vivo data indicate WA targets ADPC and AIPC cells by inhibiting the activity of Akt, a protein kinase that activates cell survival pathways. Our preliminary data demonstrate that, concomitant to Akt inhibition in ADPC and AIPC cells, WA activates FOXO3a, which in turn activates prostate apoptosis response-4 (Par-4), a protein that selectively induces apoptosis in cancer cells Based on our results, we hypothesize WA overrides the negative effects of Akt on CREB/Par-4 signaling to achieve chemopreventive and/or chemotherapeutic effects on AIPC. To address this hypothesis, we propose the following aims: investigate the interaction between Akt/CREB and Par-4 signaling, (Aim 1); and how WA modulates the pro-apoptotic signaling in AIPC (Aim 2); evaluate the effects of WA on androgen- -independent prostate tumor growth in the transgenic adenocarcinoma of mouse prostate (TRAMP) model (Aim 3); and examine the mechanisms of WA-mediated tumor inhibition in TRAMP and/or TRAMP cell lines (Aim 4). For the in vitro arm of our studies we will use a variety of approaches (immunoprecipitation, siRNA strategies, immunofluorescence, Western blot, Northern blots, Chip assays, siRNA strategies, pull down assays, pharmacological blocking) in order to determine the molecular junction at which Akt/CREB 3aand Par-4 converge. For our in vivo studies, we will conduct tumor regression studies, yet we will also examine histopathology, cell death, expression patterns of pro-survival proteins and pro-apoptotic proteins in the tumor tissues, and WA levels in the serum and prostate tissue. Our long term goal is to promote natural compounds to a clinical environment, where these agents can be thoroughly assessed for their chemopreventive and chemotherapeutic properties. Our preliminary data indicate WA is a potential candidate for such clinical evaluation, and our proposed studies will elucidate at a mechanistic level its potency against prostate cancer, both from a chemopreventive and chemotherapeutic standpoint.

描述(申请人提供)：我们的研究重点是具有化疗和/或化学预防癌症特性的天然化合物。在拟议的研究中，我们将表征化合物Withaferin-A(Withaferin-A，Withaferin-A，Withaferin-A)的作用机理，Withaferin-A(Withaferin-A，Withaferin-A)是一种广泛应用于亚洲和非洲传统医药中的生物活性化合物。Wa对雄激素依赖型和雄激素非依赖型前列腺癌(ADPC和AIPC)表现出令人印象深刻的选择性活性，后者对目前所有的治疗形式都是无效的。我们的初步体外和体内数据表明，WA通过抑制Akt的活性来靶向ADPC和AIPC细胞，Akt是一种激活细胞生存途径的蛋白激酶。我们的初步数据表明，在抑制Akt抑制ADPC和AIPC细胞的同时，WA激活FOXO3a，进而激活选择性诱导癌细胞凋亡的蛋白质-前列腺癌凋亡反应-4(PAR-4)。根据我们的结果，我们假设WA推翻Akt对CREB/PAR-4信号转导的负面影响，从而实现对AIPC的化学预防和/或化疗作用。为了解决这一假设，我们提出了以下目标：研究Akt/CREB和PAR-4信号之间的相互作用(目标1)；以及WA如何调节AIPC中的促凋亡信号(目标2)；在转基因小鼠前列腺癌(TRAMP)模型中评估WA对雄激素非依赖性前列腺癌生长的影响(AIM 3)；以及检测WA介导的TRAMP和/或TRAMP细胞系的肿瘤抑制机制(AIM 4)。对于我们研究的体外手臂，我们将使用各种方法(免疫沉淀、siRNA策略、免疫荧光、Western印迹、Northern blots、芯片分析、siRNA策略、下拉实验、药理学阻断)来确定Akt/CREB 3a和PAR-4的分子连接。对于我们的体内研究，我们将进行肿瘤回归研究，但我们也将检查组织病理学、细胞死亡、肿瘤组织中促生存蛋白和促凋亡蛋白的表达模式，以及血清和前列腺组织中的WA水平。我们的长期目标是将天然化合物推广到临床环境中，在那里可以彻底评估这些药物的化学预防和化疗特性。我们的初步数据表明，WA是此类临床评估的潜在候选者，我们拟议的研究将从化学预防和化学治疗的角度从机制水平阐明其抗前列腺癌的有效性。