Increased chemoprevention by a mixture of three phytochemicals in prostate cancer

项目摘要/摘要 拟议研究的目的是确定一种新的抗炎木脂素牛至皂苷元是否会 增强绿茶(GT)和槲皮素(Q)对小鼠模型的化学预防作用 潜在的机制。GT及其活性成分GT多酚(GTP)是一种很有前途的药物。 预防前列腺癌。然而，GTP的低生物利用度限制了GT在人类身上的成功。我的 先前的细胞培养和小鼠研究表明，GT的抗癌活性可以显著 与Q(一种来自洋葱和苹果的天然甲基化抑制剂)结合后增加。组合在一起 用GT处理Q可增加GTP的组织浓度，并降低GTP向 它们生物活性较低的甲基代谢物。此外，我们在体外证明了极低剂量的组合 牛至皂苷元是一种新的抗炎化合物，主要来自草本植物牛至的种子，具有GT和 Q协同增强GT-Q对雄激素依赖型LNCaP的抗增殖作用 细胞。机制研究显示细胞凋亡增加，抑制PI3K/Akt和雄激素 受体(AR)通路通过联合处理与单独处理的化合物进行比较。类似的模式在 联合用药对癌前前列腺癌WPE1-NA22细胞也有抗增殖作用 治疗。拟议的项目将决定这一组合的协同效应是否也发生在 在小鼠模型中进行活体实验。具体目的包括：1)确定牛至皂苷元是否与GT共治疗 Q将增强GT和Q对前列腺特异性PTEN基因敲除小鼠的化学预防活性 以肿瘤体积和肿瘤分期为研究终点；2)体内验证分子机制 负责GT、Q和Artigenin的联合作用，重点是PI3K/Akt和AR途径 肿瘤组织。拟议的项目将为临床实践做出重大贡献，提供高度的 有效的无毒方案在生理可行的情况下加强前列腺癌的化学预防 天然化合物的浓度。除了它们直接抑制癌变的活性外，这些天然的 化合物在预防和治疗前列腺癌危险因素方面有益于健康，如 肥胖和2型糖尿病。

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.