Pomegranate for Chemoprevention and Chemotherapy of Prostate Cancer

确定新的靶点，开发常用的无毒饮食制剂， 前列腺癌（PCa）的治疗已成为国家医疗优先事项。最近的研究强调了 转录因子NFicB在癌细胞存活中的作用。沿着这些路线，许多研究表明，NFxB是 在人PCa细胞和样本中组成型活化。因此，NFxB已成为开发的重要目标 新的PCa预防和治疗方法。石榴是从石榴树的果实中提取的， 已知具有抗氧化和抗炎特性。我们最近发现石榴果实提取物 (PFE)通过抑制NFicB抑制小鼠皮肤两阶段致癌模型中的肿瘤发展 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剂， 抗人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的单宁。我们的初步数据显示， PFE中存在六种花色苷，其中飞燕草素含量最多，是最有效的抗增殖剂。 重要的是，已知飞燕草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。这个提案的主要目的是利用我们的小说 在PCa细胞中用飞燕草素和PFE的初步发现，并研究其PCa化学预防和/或 在体外和体内环境下的化学治疗潜力。之所以做出这样的选择，是因为我们相信细胞培养 研究必须使用纯试剂而不是试剂的混合物进行，干预研究必须 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 研究由飞燕草素激活的细胞死亡级联反应，并了解它如何抑制细胞存活信号 由NFicB介导。特别是使用遗传操作和药理学方法，我们将研究 参与i）抗细胞凋亡（IAP 1、xIAP、Bfl-1/A1、Bcl-2、cFLIP和存活素），ii） 增殖（细胞周期蛋白D1和c-Myc），iii）炎症（考克斯-2，PPARy和iNOS）和iv）转移（MMP-9，MMP-2和 VEGF）。然后，我们将使用已建立的方法在体内情况下定义PFE的PCa化学预防/治疗潜力。 转基因和异种移植小鼠模型。为了与人类群体相关，我们推断功效研究 必须在疾病进展发生类似于人类的动物模型中进行。i）TRAMP，a 模拟人前列腺疾病的进行性形式的模型和ii）植入人前列腺疾病的无胸腺裸鼠 PCa细胞，我们将建立PFE的癌症化学预防/治疗潜力。公共关系：这 该提案将建立前列腺癌预防和治疗的分子靶点，此外还将绘制 注意使用石榴和其他色素水果和蔬菜预防前列腺癌。

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 Our unpublished preliminary data showed that PFE is an effective anti-proliferative and pro- apoptotic agent against human PCa PCS cells.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