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: 9302003
• 负责人: Piwen Wang
• 金额: $ 7.85万
• 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/9302003
• 关键词: Androgen Antagonists; Androgen Receptor; Animal Model; Anti-Inflammatory Agents; 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; Proteins; 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; carcinogenicity; clinical practice; disorder control; high risk; improved; in vivo; inhibitor/antagonist; mouse model; novel; polyphenol; prostate cancer cell; prostate cancer prevention; 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.

项目概要/摘要 拟议研究的目的是确定一种新型抗炎木脂素牛蒡甙元是否会 增强绿茶 (GT) 和槲皮素 (Q) 在小鼠模型中的化学预防作用，并确定 底层机制。 GT 及其生物活性成分 GT 多酚 (GTP) 是有前景的药物 预防前列腺癌。然而，GTP 的低生物利用度限制了 GT 在人类中的成功。我的 之前的细胞培养和小鼠研究表明，GT 的抗癌活性可以显着增强。 与 Q（一种来自洋葱和苹果的天然甲基化抑制剂）结合使用会增加。组合 用 GT 处理 Q 会增加 GTP 的组织浓度，并降低 GTP 转化为 它们的甲基代谢物生物活性较低。此外，我们在体外证明，极低剂量的组合 牛蒡甙元是一种新型抗炎化合物，主要来自草本植物牛蒡子的种子，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。机制研究表明细胞凋亡增加以及 PI3K/Akt 和雄激素抑制 与单独化合物相比，联合治疗的受体（AR）途径。类似的模式在 联合用药在癌前前列腺 WPE1-NA22 细胞中也观察到抗增殖作用 治疗。拟议的项目将确定这种组合的协同效应是否也发生在 小鼠模型体内。具体目的包括： 1) 确定牛蒡甙元是否与 GT 联合处理 Q 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 以肿瘤体积和肿瘤分期作为研究终点； 2) 体内验证分子机制 负责 GT、Q 和牛蒡甙元的联合作用，重点关注 PI3K/Akt 和 AR 通路 肿瘤组织。拟议的项目将通过提供高度的临床实践做出重大贡献 有效的无毒方案，在生理上可实现的情况下增强前列腺癌的化学预防 天然化合物的浓度。除了直接抑制致癌作用外，这些天然物质 化合物在预防和治疗前列腺癌的危险因素方面提供健康益处，例如 肥胖和2型糖尿病。