Prostate Cancer Prevention by Procyanidins in Grape Seed

在最近的研究中，我们发现葡萄籽提取物(GSE)显著抑制DU145移植瘤的生长。 裸鼠。机制研究表明，GSE抑制ErbB1-Erki/2-AP1和核因子-kB的激活，b) 改变细胞周期调节和c)激活caspase，并且这些事件与人类 前列腺癌(Pca)DU145细胞生长抑制、G1期停滞和凋亡死亡。试图进行一次 对GSE中活性物质进行了详细的机理研究，我们能够分离出原花青素B3，该原花青素 表现出更强的对DU145细胞的生长抑制作用，并诱导S和/或G2-M期细胞停滞和凋亡死亡 在DU145细胞中的疗效优于GSE。在这项资助中，我们提出了深入的机制，然后是肿瘤的疗效 原花青素B3在细胞培养和肿瘤移植瘤中的应用研究。 中心假设是原花青素B3抑制a)有丝分裂和细胞存活信号，b) 通过改变细胞周期调节因子诱导浓度依赖的S和/或G2-M期阻滞， 和c)通过抑制生存信号、线粒体损伤和Caspase而导致细胞凋亡 激活。总而言之，这些作用导致了它对前列腺癌的预防和治疗效果。 以下具体目标被提出，将利用正常的人前列腺上皮和PCa LNCaP和 DU145细胞。 1)评估和确定原花青素B3对细胞有丝分裂和细胞存活信号的影响。 2)评估和确定原花青素B3对S和G2-M细胞周期调节因子的影响。 3)评估和确定原花青素B3对细胞凋亡调节因子的作用。 4)评价和建立原花青素B3对裸鼠移植瘤的疗效。 5)继续对GSE中生物活性部位(S)进行鉴定，并对个体进行表征 存在于其中的化合物。 作为一种实用的翻译方法，拟议研究的结果将构成以下方面的基础 在PCa患者中进行临床前PCA模型的额外研究和临床试验，以进一步 确定并确定从GSE中分离的原花青素B3的预防和治疗效果。

In recent studies, we found that grape seed extract (GSE) significantly inhibits DU145 xenograft growth in nude mice. Mechanistic studies showed that GSE inhibits erbB1-ERKI/2-AP1 and NF-kB activation, b) alters cell cycle regulators and c) activates caspases, and that these events are associated with human prostate cancer (PCA) DU145 cell growth inhibition, G1 arrest and apoptotic death. In an attempt to conduct detailed mechanistic studies with active compound in GSE, we were able to isolate procyanidin B3 that showed even stronger DU145 cell growth inhibitory, and S and/or G2-M arrest and apoptotic death inducing efficacy than GSE in DU145 cells. In this grant, we propose in depth mechanistic followed by tumor efficacy studies with procyanidin B3 in cell culture and tumor xenograffs. The central hypothesis is that procyanidin B3 inhibits a) mitogenic and cell survival signaling, b) induces S and/or G2-M arrest depending on its concentration via alteration in cell cycle regulators, and c) causes apoptosis via inhibition of survival signal, mitochondrial damage and Caspases activation. Collectively, these effects lead to its preventive and therapeutic efficacy against PCA. Following specific aims are proposed that will utilize normal human prostate epithelial and PCA LNCaP and DU145 cells. 1) To assess and define the effect of procyanidin B3 on mitogenic and cell survival signaling. 2) To assess and define the effect of procyanidin B3 on S and G2-M cell cycle regulators. 3) To assess and define the effect of procyanidin B3 on apoptosis regulators. 4) To assess and establish the efficacy of procyanidin B3 in nude mice tumor xenografts. 5) To continue identification of biologically active fraction(s) in GSE, and characterize individual compounds present therein. As a practical and translational approach, outcome of the proposed studies will form a basis for additional studies in pre-clinical PCA models followed by clinical trials in PCA patients to further define and establish the preventive and therapeutic efficacy of procyanidin B3 isolated from GSE.