Prostate Cancer Prevention by Procyanidins in Grape Seed

葡萄籽中的原花青素预防前列腺癌

• 批准号: 6697450
• 负责人: CHAPLA AGARWAL
• 金额: $ 34.15万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-02-14 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6697450
• 关键词: Prostate; Cancer; Prevention; Procyanidins; Grape

DESCRIPTION (provided by applicant): 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 xenografts. 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.

描述（申请人提供）：在最近的研究中，我们发现葡萄籽提取物（GSE）显着抑制裸鼠体内DU145异种移植物的生长。机制研究表明，GSE 抑制 erbB1-ERKI/2-AP1 和 NF-kB 激活，b) 改变细胞周期调节因子，c) 激活半胱天冬酶，并且这些事件与人前列腺癌 (PCA) DU145 细胞生长抑制、G1 相关逮捕和凋亡性死亡。在尝试用 GSE 中的活性化合物进行详细的机制研究时，我们能够分离出原花青素 B3，它在 DU145 细胞中表现出比 GSE 更强的 DU145 细胞生长抑制、S 和/或 G2-M 期阻滞以及细胞凋亡诱导功效。在这笔资助中，我们提出了深入的机理研究，然后是原花青素 B3 在细胞培养物和肿瘤异种移植物中的肿瘤功效研究。中心假设是原花青素 B3 抑制 a) 有丝分裂和细胞生存信号，b) 通过改变细胞周期调节因子，根据其浓度诱导 S 和/或 G2-M 停滞，c) 通过抑制生存信号、线粒体引起细胞凋亡损伤和半胱天冬酶激活。总的来说，这些作用导致了其对 PCA 的预防和治疗功效。提出以下具体目标，即利用正常人前列腺上皮细胞和 PCA LNCaP 和 DU145 细胞。 1) 评估和定义原花青素 B3 对促有丝分裂和细胞存活信号传导的影响。 2) 评估和定义原花青素 B3 对 S 和 G2-M 细胞周期调节剂的影响。 3) 评估和定义原花青素B3对细胞凋亡调节因子的作用。 4) 评估和建立原花青素B3在裸鼠异种移植瘤中的功效。 5) 继续鉴定 GSE 中的生物活性组分，并表征其中存在的各个化合物。作为一种实用和转化方法，拟议研究的结果将为临床前 PCA 模型的进一步研究奠定基础，随后在 PCA 患者中进行临床试验，以进一步确定和确定从 GSE 中分离出的原花青素 B3 的预防和治疗功效。