Prostate Cancer Prevention by Procyanidins in Grape Seed

超出所提供的空间。在最近的研究中，我们发现葡萄籽提取物（GSE）显着抑制DU 145裸鼠移植瘤的生长。机制研究表明，GSE抑制erbB 1-ERKI/2-AP 1和NF-κ B活化，B）改变细胞周期调节因子和c）活化半胱天冬酶，并且这些事件与人前列腺癌（PCA）DU 145细胞生长抑制、G1期阻滞和凋亡性死亡相关。在尝试用GSE中的活性化合物进行详细的机制研究时，我们能够分离原花青素B3，其在DU 145细胞中显示比GSE更强的DU 145细胞生长抑制、S和/或G2-M停滞和凋亡死亡诱导功效。在这项资助中，我们提出了深入的机制，随后是原花青素B3在细胞培养和肿瘤异种移植中的肿瘤疗效研究。中心假设是原花青素B3抑制a）促有丝分裂和细胞存活信号传导，B）根据其浓度通过改变细胞周期调节剂诱导S和/或G2-M停滞，和c）通过抑制存活信号、线粒体损伤和胱天蛋白酶活化引起细胞凋亡。总的来说，这些作用导致其对五氯苯甲醚的预防和治疗功效。提出了以下具体目标，其将利用正常人前列腺上皮和PCA LNCaP和DU 145细胞。1)评估和确定原花青素B3对有丝分裂和细胞存活信号的影响。2)目的：研究原花青素B3对S期和G2-M期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)目的：观察原花青素B3对裸鼠移植瘤的抑制作用。5)继续鉴别GSE中的生物活性组分，并表征其中存在的单个化合物。作为一种实用和转化的方法，所提出的研究结果将为临床前PCA模型中的其他研究奠定基础，然后在PCA患者中进行临床试验，以进一步定义和建立从GSE中分离的原花青素B3的预防和治疗功效。性能现场=

EXCEED THE SPACE PROVIDED. 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. PERFORMANCE SITE ========================================Section End===========================================