Pomegranate for Chemoprevention and Chemotherapy of Prostate Cancer

石榴用于前列腺癌的化学预防和化疗

基本信息

批准号：
7337139
负责人：
Hasan Mukhtar
金额：
$ 27.93万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-01-01 至 2011-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7337139
关键词：
Affect Age-Years American American Cancer Society Androgens Angiogenic Factor Animal Model Anthocyanins Anti-Inflammatory Agents Anti-inflammatory Antioxidants Apoptosis Apoptotic Attention Aubergine Berry Biological Biological Process CWR22Rv1 Cancer Etiology Cancer Patient Carrots - dietary Caspase Cell Culture System Cell Cycle Cell Death Cell Proliferation Cell Survival Cells Cessation of life Chemoprevention Chemopreventive Agent Cultured Cells Cyclin D1 Cyclin-Dependent Kinase Inhibitor Cyclin-Dependent Kinases Cyclins DNA Binding DU145 Data Development Diagnosis Dietary Intervention Disease Disease Progression Dose Down-Regulation Drug resistance Ellagi-Tannins Evaluation Event Family Figs - dietary Fruit Gelatinase A Gelatinase B Genes Genetic Genetic Transcription Grapes Green tea Growth and Development function Human Hydrolyzable Tannins I Kappa B-Alpha Implant In Vitro Incidence Induction of Apoptosis Inflammation Inflammatory Infusion procedures Insulin-Like Growth Factor I Interleukin-2 Intervention Studies Invasive Investigation Juice LNCaP Light MALDI-TOF Mass Spectrometry Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of prostate Matrix Metalloproteinases Mediating Medical Metastasis Induction Metastatic Prostate Cancer Modeling Molecular Molecular Target Mus NF-kappa B Neoplasm Metastasis Nuclear Translocation Nude Mice Onions Operative Surgical Procedures Oral Outcome Study PC3 cell line PCNA gene Pathway interactions Phosphorylation Phosphotransferases Pigments Plants Pomegranate Population Prevention Preventive Principal Investigator Process Production Proliferation Marker Promoter Regions Property Prostate Prostatic Diseases Protein Family Proteins Publishing Punica granatum Reactive Oxygen Species Reporting Research Personnel Retroviridae Role Signal Pathway Signal Transduction Site Skin Skin Carcinogenesis Somatomedins Source Specimen Staging Stimulus Testing Therapeutic Therapeutic Effect Tomatoes Transgenic Organisms Trees Tumor Necrosis Factor Receptor United States Vascular Endothelial Growth Factors Work Xenograft procedure angiogenesis autocrine c-myc Genes cancer cell cancer prevention cancer therapy carcinogenesis cell growth cell type chemotherapy cyclin G1 cyclin-dependent kinase inhibitor 1B delphinidin design egg fruits and vegetables genetic manipulation human disease in vivo inhibitor/antagonist interest keratinocyte male member men mouse model mutant neoplastic cell novel oncoprotein p21 paracrine pre-clinical prevent promoter prostate cancer prevention protein expression receptor red wine research study response survivin transcription factor tumor tumor growth tumorigenesis ultraviolet

项目摘要

Identification of novel targets and the development of commonly used and non-toxic dietary agents for prevention and treatment of prostate cancer (PCa) has become a National Medical Priority. Recent studies have highlighted the role of the transcription factor NFicB in cancer cell survival. Along these lines many studies have shown that NFxB is constitutively activated in human PCa cells and specimens. Thus, NFxB has become an important target for developing novel PCa preventive and therapeutic approaches. Pomegranate derived from the fruit of the tree Punica granatum is known to possess antioxidant and anti-inflammatory properties. We recently showed that pomegranate fruit extract (PFE) inhibited tumor development in mouse skin two stage carcinogenesis model through inhibition of the NFicB signaling pathway. Our unpublished preliminary data showed that PFE is an effective anti-proliferative and pro- apoptotic agent against human PCa PCS cells. On analysis by MALDI-TOF mass spectrometry, PFE was found to contain six anthocyanins and several ellagitannins and hydrolyzable tannins. Our preliminary data showed that among six anthocyanins present in PFE, delphinidin the most abundant was the most effective anti-proliferative agent. Importantly, delphinidin is known to be present in many other pigmented fruits and vegetables like berries, eggplant, dark grapes, tomato, carrots and red onions. The primary objective of this proposal is to capitalize on our novel preliminary findings with delphinidin and PFE in PCa cells and investigate its PCa chemopreventive and/or chemotherapeutic potential under in vitro and in vivo settings. This choice is made because we believe that cell culture studies must be conducted with pure agents rather than a mixture of agents and intervention studies must be conducted with the substances that humans could be persuaded to consume. Using PCa cell lines we will first investigate the cell death cascade activated by delphinidin and understand how it inhibits cell survival signaling mediated by NFicB. In particular using genetic manipulation and pharmacological approaches we will investigate the role of NFicB gene products involved in i) anti-apoptosis (IAP1, xlAP, Bfl-1/A1, Bcl-2, cFLIP, and survivin), ii) proliferation (cyclin D1 and c-Myc), iii) inflammation (Cox-2, PPARy and iNOS) and iv) metastasis (MMP-9, MMP-2 and VEGF). We will then define PCa chemopreventive/therapeutic potential of PFE under in vivo situation using established transgenic and xenograft mouse models. To have relevance to human population, we reasoned that efficacy studies must be conducted in an animal model where disease progression occurs akin to humans. Employing i) TRAMP, a model that mimics progressive forms of human prostatic disease and ii) athymic nude mouse implanted with human PCa cells we will establish the cancer chemopreventive/therapeutic potential of PFE. PUBLIC RELEVANCE: This proposal will establish the molecular targets for prostate cancer prevention and treatment and in addition will draw attention to the use of pomegranate and other pigmented fruits and vegetables for prevention against prostate cancer.

确定新靶点并开发常用且无毒的膳食制剂以预防和治疗前列腺癌（PCa）的治疗已成为国家医疗重点。最近的研究强调了转录因子 NFicB 在癌细胞存活中的作用。沿着这些思路，许多研究表明 NFxB 在人 PCa 细胞和样本中组成型激活。因此，NFxB已成为发展的重要目标。新的 PCa 预防和治疗方法。石榴是从石榴树的果实中提取出来的已知具有抗氧化和抗炎特性。我们最近证明石榴果提取物 (PFE) 通过抑制 NFicB 抑制小鼠皮肤两阶段癌变模型中的肿瘤发展信号通路。我们未发表的初步数据表明，PFE 是一种有效的抗增殖和促增殖药物。针对人 PCa PCS 细胞的凋亡剂。通过 MALDI-TOF 质谱分析，发现 PFE 含有六种花青素和几种鞣花单宁和可水解单宁。我们的初步数据显示，其中 PFE中存在的六种花青素中，飞燕草素含量最丰富，也是最有效的抗增殖剂。重要的是，飞燕草素已知存在于许多其他有色素的水果和蔬菜中，如浆果、茄子、黑葡萄、番茄、胡萝卜和红洋葱。该提案的主要目标是利用我们的小说飞燕草素和 PFE 在 PCa 细胞中的初步研究结果，并研究其 PCa 化学预防和/或体外和体内环境下的化疗潜力。做出这个选择是因为我们相信细胞培养研究必须使用纯药物而不是药物混合物进行，并且干预研究必须使用可以说服人类消费的物质进行。使用 PCa 细胞系，我们首先研究飞燕草素激活的细胞死亡级联并了解它如何抑制细胞生存信号传导由 NFicB 介导。特别是使用基因操作和药理学方法，我们将研究 NFicB 基因产物参与 i) 抗凋亡（IAP1、xlAP、Bfl-1/A1、Bcl-2、cFLIP 和 survivin），ii) 的作用增殖（细胞周期蛋白 D1 和 c-Myc），iii) 炎症（Cox-2、PPARy 和 iNOS）和 iv) 转移（MMP-9、MMP-2 和血管内皮生长因子）。然后，我们将使用已建立的方法来定义 PFE 在体内情况下的 PCa 化学预防/治疗潜力转基因和异种移植小鼠模型。为了与人群相关，我们推断功效研究必须在疾病进展类似于人类的动物模型中进行。雇用 i) TRAMP，模拟人类前列腺疾病进展形式的模型和 ii) 植入人类前列腺的无胸腺裸鼠我们将通过 PCa 细胞确定 PFE 的癌症化学预防/治疗潜力。公众相关性：这该提案将建立前列腺癌预防和治疗的分子目标，此外还将绘制注意利用石榴等色素水果和蔬菜来预防前列腺癌。