Chemoprevention of Prostate Cancer by Allspice Derived Polyphenol: Ericifolin

描述(由申请人提供)：这个项目的主要目标是开发一种预防前列腺癌的化学饮食策略，使用一种从牙买加植物(Pimenta Dioica)的芳香浆果中提取的新化合物，称为allspice，这是所有烹饪中常见的香料。新化合物Ericifolin(EF)是一种多酚类化合物，是从多香料水提取物(AAE)中分离得到的。初步研究表明，AAE具有强大而特异的抗前列腺癌细胞增殖活性，并诱导多种抗肿瘤活性，包括细胞凋亡、细胞周期停滞、抑制雄激素受体转录和抑制肿瘤生长。纯化的Ericifolin在细胞培养研究中显示了AAE的关键生物学功能。该项目旨在对EF在前列腺癌临床前模型上的抗癌活性进行全面研究，以确定EF作为癌症化学预防药物的翻译潜力。假设：1.在前列腺癌的原位和转基因模型中，EF将控制前列腺癌的生长和进展，全身毒性最小。2.EF的抗肿瘤作用可能与其下调雄激素受体和AKT及其下游促生存信号有关。具体目的：1.研究EF和AAE对前列腺癌细胞(LNCaP、LAPC-4和PC-3)原位和异种移植的体内效应。2.从分子、细胞和遗传学角度探讨EF对雄激素依赖型和去势抗性前列腺癌细胞的抗肿瘤作用机制；3.在前列腺癌-PTEN基因敲除转基因模型中研究EF的阶段特异性化学预防作用，以确定其剂量和阶段特异性效应。将建立EF的全身毒性、药代动力学，以供进一步的临床试验。这是对一种新的、潜在有效的抗癌药物EF的首次研究。在临床前模型、生物利用度和毒性方面的疗效评估应允许在本研究结束时设计前列腺癌的I期临床试验。

DESCRIPTION (provided by applicant): The main goal of this project is to develop a chemo-dietary prevention strategy against prostate cancer using a novel compound from the aromatic berries of a Jamaican plant (Pimenta dioica), known as Allspice, a common spice in all cuisines. The new compound, Ericifolin (EF), a polyphenol, was isolated from the Aqueous Allspice Extract (AAE). Preliminary studies using the AAE showed strong and specific activity against prostate cancer cell proliferation and induced multiple anti-tumor activities including apoptosis, cell cycle arrest, and repression of androgen receptor transcription and tumor growth inhibition. The purified Ericifolin showed key biological functions of AAE in cell culture studies. The project is to perform a comprehensive investigation of the anticancer activities of EF on preclinical models of prostate cancer to establish the translational potential of EF for human consumption as a cancer chemo-preventive agent. Hypotheses: 1. EF will control prostate cancer growth and progression in orthotopic and and transgenic models of prostate cancer, with minimal systemic toxicity. 2. The antitumor effects of EF are due to the down regulation of androgen receptor and AKT and their down-stream pro-survival signals. Specific Aims: 1. Investigate in vivo efficacy of EF and AAE in orthotopic and xenografts of prostate cancer cells (LNCaP, LAPC-4 and PC-3). 2: Establish the mechanism of antitumor action of EF using molecular, cellular and genetic approaches in both androgen-dependent and castration resistant prostate cancer cells; 3. Investigate the stage-specific chemo preventive effects of EF in the Prostate-PTEN knockout transgenic model to determine the dose and stage-specific efficacy. Systemic toxicity, pharmacokinetics of EF will be established for further clinical testing in patients. This is the first investigation of a new, potentially effective anticancer agent, EF. Evaluation of the efficacy in pre-clinical models, bioavailability, and toxicity should allow designing of phase I clinical trials for prostate cancer, at the end of this investigation.