Chemoprevention of Prostate Cancer by Allspice Derived Polyphenol: Ericifolin

多香果衍生的多酚：Ericifolin 对前列腺癌的化学预防

• 批准号: 9170131
• 负责人: Bal L Lokeshwar
• 金额: $ 15.8万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9170131
• 关键词: Ablation; Affect; Allspice; Androgen Receptor; Androgens; Animal Testing; Antineoplastic Agents; Apoptosis; Aromatic Compounds; Berry; Biochemical; Biological Assay; Biological Availability; Biological Process; CDK4 gene; Cancer Control; Carbon; Castration; Cell Culture Techniques; Cell Cycle Arrest; Cell Proliferation; Cells; Cessation of life; Chemicals; Chemoprevention; Chemopreventive Agent; Chromatin; Consumption; Cyclin D1; Development; Diagnostic Neoplasm Staging; Diet; Disease; Disease Progression; Dose; Down-Regulation; Drug Kinetics; Elderly; Eugenol; Evaluation; Event; Failure; Family; Fractionation; Genetic Transcription; Goals; Growth; Health; High Pressure Liquid Chromatography; Human; Immunohistochemistry; Incidence; Insulin-Like Growth Factor I; Interphase; Investigation; Knock-out; LNCaP; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of prostate; Mass Spectrum Analysis; Measurement; Messenger RNA; Modeling; Molecular; Mus; Myrtaceae; NMR Spectroscopy; Names; Oral Administration; Organ; PC3 cell line; PTEN gene; Palpable; Pathway interactions; Patients; Phase; Phase I Clinical Trials; Pimenta; Plants; Plasma; Pre-Clinical Model; Precipitation; Prevention; Prevention strategy; Preventive; Promoter Regions; Prostate; Proto-Oncogene Proteins c-akt; Protocols documentation; Protons; Recurrence; Repression; Resistance; Signal Pathway; Signal Transduction; Source; Spices; Staging; Stream; TdT-Mediated dUTP Nick End Labeling Assay; Toxic effect; Transgenic Model; Treatment Efficacy; Tumor stage; United States; Weight; Xenograft Model; Xenograft procedure; anticancer activity; antitumor effect; aqueous; caspase-3; castration resistant prostate cancer; chemo-dietary; chemotherapy; clinical application; cytotoxic; density; deprivation; design; efficacy evaluation; genetic approach; in vivo; men; mortality; novel; novel therapeutics; polyphenol; prevent; promoter; prostate cancer cell; receptor expression; research clinical testing; success; transcription factor; tumor; tumor growth; uptake

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.

描述（由申请人提供）：该项目的主要目标是使用牙买加植物（Pimenta dioica）芳香浆果中的一种新型化合物，开发一种针对前列腺癌的化学饮食预防策略，这种化合物被称为多香果，是所有美食中常见的香料。新化合物 Ericifolin (EF) 是一种多酚，是从多香果水提取物 (AAE) 中分离出来的。使用 AAE 的初步研究显示，它对前列腺癌细胞增殖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、细胞周期停滞、雄激素受体转录抑制和肿瘤生长抑制。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 作为癌症化学预防剂供人类食用的转化潜力。假设： 1. EF 将控制前列腺癌原位和转基因模型中前列腺癌的生长和进展，且全身毒性最小。 2. EF的抗肿瘤作用是由于雄激素受体和AKT及其下游促生存信号的下调所致。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。 2：使用分子、细胞和遗传学方法在雄激素依赖性和去势抵抗性前列腺癌细胞中建立 EF 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疗效。将建立 EF 的全身毒性和药代动力学，以便在患者中进行进一步的临床测试。这是对一种潜在有效的新型抗癌药物 EF 的首次研究。在本研究结束时，对临床前模型的疗效、生物利用度和毒性的评估应允许设计针对前列腺癌的 I 期临床试验。