Pomegranate for Chemoprevention and Chemotherapy of Prostate Cancer

确定新的目标和开发常用的无毒饮食制剂以预防和 前列腺癌(PCa)的治疗已成为国家医学优先事项。最近的研究强调了 转录因子NFicB与癌细胞存活沿着这些思路，许多研究表明，NFxB是 在人的前列腺癌细胞和标本中被结构性激活。因此，NFxB已经成为一个重要的开发目标 新的前列腺癌预防和治疗方法。石榴是从石榴树的果实中提取的 已知具有抗氧化剂和抗炎特性。我们最近展示了石榴果实提取物 (PFE)通过抑制NFicB抑制小鼠皮肤二期致癌模型的肿瘤生长 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进 抗人PCa PCS细胞的凋亡剂。经MALDI-TOF质谱仪分析，发现PFE 含有六种花青素和几种鞣皮单宁以及可水解性单宁。我们的初步数据显示， PFE中存在6种花色苷，其中飞雀素含量最高，是最有效的抗增殖剂。 重要的是，已知飞雀素存在于许多其他有色水果和蔬菜中，如浆果、茄子、 黑葡萄，番茄，胡萝卜和红洋葱。这项提议的主要目的是利用我们的小说 Delphinidin和PFE在PCa细胞中的初步发现及其对PCa的化学预防和/或研究 体外和体内环境下的化疗潜力。之所以做出这个选择，是因为我们相信细胞培养 研究必须用纯试剂而不是混合试剂进行，干预性研究必须 用人类可以被说服消费的物质进行。使用PCA细胞系，我们将首先 研究Delphinidin激活的细胞死亡级联反应，并了解其如何抑制细胞生存信号 由NFicB调解。特别是利用基因操作和药理学方法，我们将研究 NFicB基因产物在抗细胞凋亡(IAP1、xlAP、BFL-1/A1、Bcl2、cFlIP、Survivin)中的作用 增殖(细胞周期蛋白D1和c-Myc)、炎症(COX-2、PPARy和iNOS)和转移(MMP9、MMP2和 血管内皮细胞生长因子)。然后，我们将确定PFE在体内情况下的PCA化学预防/治疗潜力，使用已建立的 转基因和异种移植小鼠模型。为了与人类人口相关，我们认为疗效研究 必须在疾病进展与人类相似的动物模型中进行。雇佣i)流浪汉，a 模拟人类前列腺病进展性形式的模型和II)植入人类的裸鼠 我们将建立PFE的癌症化学预防/治疗潜力。公众相关性：这一点 提案将建立前列腺癌预防和治疗的分子靶点，此外还将吸引 注意使用石榴和其他有色水果和蔬菜来预防前列腺癌。

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 Our unpublished preliminary data showed that PFE is an effective anti-proliferative and pro- apoptotic agent against human PCa PCS cells.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.