Chemoprevention of Prostate Cancer by Allspice Derived Polyphenol: Ericifolin

描述（由申请人提供）：该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，使用一种来自牙买加植物（Pimenta dioica）芳香浆果的新型化合物，这种植物被称为多香果（Allspice），是所有菜系中常见的香料。从多香果水提物（AAE）中分离得到了一种新的多酚化合物——苦苣苔素（EF）。初步研究表明，AAE对前列腺癌细胞增殖具有很强的特异性活性，并诱导多种抗肿瘤活性，包括细胞凋亡、细胞周期阻滞、雄激素受体转录抑制和肿瘤生长抑制。在细胞培养研究中，纯化的鸢尾草素显示出AAE的关键生物学功能。该项目旨在全面研究EF对前列腺癌临床前模型的抗癌作用，以确定EF作为癌症化学预防剂在人类消费中的转化潜力。假设:1。EF将在前列腺癌原位和转基因模型中控制前列腺癌的生长和进展，并具有最小的全身毒性。2. EF的抗肿瘤作用是由于下调雄激素受体和AKT及其下游促生存信号。具体目标：1；探讨EF和AAE对原位和异种前列腺癌细胞（LNCaP、LAPC-4和PC-3）的体内疗效。2：从分子、细胞和遗传等方面建立EF对雄激素依赖性和去势抵抗性前列腺癌细胞的抗肿瘤作用机制；3. 研究EF在前列腺pten基因敲除转基因模型中的分期特异性化疗预防作用，以确定剂量和分期特异性疗效。EF的全身毒性和药代动力学将被建立，以进一步在患者中进行临床试验。这是对一种新的、可能有效的抗癌剂EF的首次研究。对临床前模型的疗效、生物利用度和毒性的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.