Increased chemoprevention by a mixture of three phytochemicals in prostate cancer

三种植物化学物质的混合物增强了前列腺癌的化学预防作用

• 批准号: 9450492
• 负责人: Piwen Wang
• 金额: $ 7.77万
• 依托单位: CHARLES R. DREW UNIVERSITY OF MED & SCI
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-08 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9450492
• 关键词: Androgen Antagonists; Androgen Receptor; Animal Model; Anti-inflammatory; Antioxidants; Apoptosis; Apple; Biological Availability; Catechol O-Methyltransferase; Cell Culture Techniques; Cell Proliferation; Cells; Chemicals; Chemoprevention; Chemopreventive Agent; Chinese Traditional Medicine; Clinical Trials; Coughing; Disease; Dose; Epigallocatechin Gallate; Event; Exhibits; Flavonoids; Future; Goals; Greater Burdock; Green tea; Growth; Health Benefit; Herb; Human; In Vitro; Individual; Induction of Apoptosis; Inflammation; Insulin-Like Growth Factor I; Investigation; Knockout Mice; LNCaP; Lignans; Malignant Neoplasms; Malignant neoplasm of prostate; Methylation; Molecular; Molecular Target; Multidrug Resistance Inhibition process; Multidrug Resistance-Associated Proteins; Mus; Natural Products; Nature; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Onions; PTEN gene; Pathway interactions; Patients; Pattern; Pharyngeal structure; Phosphotransferases; Physiological; Phytochemical; Plants; Population; Premalignant; Prevention; Prostate; Prostatic Neoplasms; Quercetin; Regimen; Risk Factors; Seeds; Severe Combined Immunodeficiency; Signal Pathway; Swelling; Testing; Tissues; Transgenic Organisms; Tumor Tissue; Tumor Volume; Tumor stage; Xenograft procedure; absorption; androgen sensitive; anticancer activity; arctigenin; carcinogenesis; clinical practice; disorder control; high risk; improved; in vivo; inhibitor/antagonist; mouse model; novel; polyphenol; prostate cancer cell; prostate cancer prevention; prostate cancer risk; prostate carcinogenesis; success; synergism; tumor growth; tumor xenograft; uptake

Project Summary/Abstract The objective of the proposed studies is to determine whether a novel anti-inflammatory lignan arctigenin will enhance the chemopreventive effect of green tea (GT) and quercetin (Q) in mouse models, and to identify the underlying mechanisms. GT and its bioactive components GT polyphenols (GTPs) are promising agents in the prevention of prostate cancer. However, the low bioavailability of GTPs limits the success of GT in humans. My previous cell culture and mouse studies demonstrated that the anti-cancer activity of GT can be significantly increased by combination with Q, a natural methylation inhibitor from onions and apples. The combination treatment of Q with GT increases the tissue concentrations of GTPs and decreases the conversion of GTPs to their less bioactive methyl metabolites. Further, we demonstrated in vitro that the combination of very low dose of arctigenin, a novel anti-inflammatory compound mainly from the seed of the herb Arctium lappa, with GT and Q synergistically enhanced the anti-proliferative effect of GT+Q by 2-3 fold in androgen-dependent LNCaP cells. Mechanistic investigations revealed an increase in apoptosis and in inhibition of PI3K/Akt and androgen receptor (AR) pathways by the combination treatment compared to individual compound. A similar pattern in anti-proliferation was also observed in pre-malignant prostate WPE1-NA22 cells with the combination treatment. The proposed project will determine whether this synergistic effect of the combination also occurs in vivo in mouse models. The specific aims include: 1) To determine whether co-treatment of arctigenin with GT and Q will enhance the chemopreventive activity of GT and Q in prostate specific PTEN knockout mice using tumor volume and tumor stage as study endpoints; 2) To validate in vivo the molecular mechanisms responsible for the combined effect of GT, Q and arctigenin with focus on the PI3K/Akt and AR pathways in tumor tissues. The proposed project will make significant contributions to clinical practice by providing a highly effective non-toxic regimen to enhance chemoprevention of prostate cancer at physiologically achievable concentrations of natural compounds. In addition to their direct activity to inhibit carcinogenesis, these natural compounds provide health benefits in prevention and treatment of risk factors of prostate cancer such as obesity and type 2 diabetes.

项目总结/摘要 这项研究的目的是确定一种新的抗炎木脂素牛蒡子苷元是否 增强绿色茶（GT）和槲皮素（Q）在小鼠模型中的化学预防作用，并鉴定 基本机制。GT及其生物活性成分GT多酚（GT polyphones，GTPs）是治疗糖尿病的有前途的药物。 前列腺癌的预防然而，GTP的低生物利用度限制了GT在人类中的成功。我 先前的细胞培养和小鼠研究表明，GT的抗癌活性可以显著地 增加与Q的组合，从洋葱和苹果的天然甲基化抑制剂。相结合 用GT处理Q增加了GTP的组织浓度，并降低了GTP向 它们的活性较低的甲基代谢物。此外，我们在体外证明，非常低剂量的 牛蒡苷元是一种主要来自草药牛蒡子的新型抗炎化合物，具有GT和 Q协同增强GT+Q在雄激素依赖性LNCaP中的抗增殖作用2-3倍 细胞机制研究显示，细胞凋亡增加，PI 3 K/Akt和雄激素抑制增加， 与单个化合物相比，通过组合处理的AR受体（AR）途径。模式相似 在癌前前列腺WPE 1-NA 22细胞中也观察到抗增殖， 治疗拟议的项目将确定这种结合的协同效应是否也发生在 在小鼠模型中体内。具体目的包括：1）确定牛蒡子苷元与GT合用是否 和Q将增强GT和Q在前列腺特异性PTEN敲除小鼠中的化学预防活性， 肿瘤体积和肿瘤分期作为研究终点; 2）在体内验证分子机制 负责GT，Q和牛蒡子苷元的联合作用，重点是PI 3 K/Akt和AR途径， 肿瘤组织拟议的项目将通过提供一个高度的临床实践作出重大贡献， 在生理上可达到水平上增强前列腺癌的化学预防的有效无毒方案 天然化合物的浓度。除了它们抑制致癌作用的直接活性外，这些天然的 化合物在预防和治疗前列腺癌的危险因素中提供健康益处 肥胖和2型糖尿病。