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化学饮食预防策略，用于预防前列腺癌，使用来自牙买加植物（Pimenta dioica）芳香浆果的新型化合物，称为多香果，是所有烹饪中的常见香料。从多香果水提物（AAE）中分离得到一种新的多酚化合物Ericifolin（EF）。使用AAE的初步研究显示出对前列腺癌细胞增殖的强的和特异性的活性，并诱导多种抗肿瘤活性，包括细胞凋亡、细胞周期阻滞、雄激素受体转录的抑制和肿瘤生长抑制。纯化的Ericifolin在细胞培养研究中显示出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作为癌症化学预防剂用于人类消费的转化潜力。假设：1. EF将在前列腺癌的原位和转基因模型中控制前列腺癌的生长和进展，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。研究EF和AAE在前列腺癌细胞（LNCaP、LAPC-4和PC-3）的原位和异种移植物中的体内功效。第二章：从分子、细胞和遗传学角度探讨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敲除转基因模型中的阶段特异性化疗预防作用，以确定剂量和阶段特异性功效。将确定EF的全身毒性、药代动力学，用于患者的进一步临床试验。这是对一种新的、潜在有效的抗癌剂EF的首次研究。在临床前模型、生物利用度和毒性中的疗效评价应允许在本研究结束时设计前列腺癌的I期临床试验。 公共卫生相关性：本研究旨在探讨多香果水提物中的天然多酚Ericifolin对前列腺癌的化学预防和治疗作用。评价其在前列腺癌临床前模型中的功效并确定生物利用度、潜在的全身毒性和从血浆中的清除率应允许进一步开发Ericifolin用于临床应用。

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. PUBLIC HEALTH RELEVANCE: This project is to investigate the chemopreventive and therapeutic efficacy of Ericifolin, a natural polyphenol from aqueous extract of Allspice berries against prostate cancer. Evaluation of its efficacy in pre-clinical models of prostate cancer and determining bioavailability, potential systemic toxicity and clearance from plasma should allow further development of Ericifolin for clinical applications.