Prostate Cancer Prevention by Procyanidins in Grape Seed

葡萄籽中的原花青素预防前列腺癌

基本信息

批准号：
7174782
负责人：
CHAPLA AGARWAL
金额：
$ 32.25万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-02-14 至 2008-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7174782
关键词：
Androgens Apoptosis Apoptosis Regulator Apoptotic Biological CDK2 gene CDK4 gene Cancer Cell Growth Cancer Etiology Cancer Model Cancer Patient Caspase Cell Cycle Cell Cycle Progression Cell Survival Cells Cessation of life Chemical Structure Clinical Trials Cultured Tumor Cells Cytochromes DU145 Depth Diagnosis Disease regression Dose Epithelial Event Family member G1 Arrest G2/M Arrest Genetic Grant Growth Individual Invasive LNCaP Lead M cell MAPK8 gene Malignant Neoplasms Malignant neoplasm of prostate Mediating Methods Mitochondria Molecular NF-kappa B Nude Mice Outcome Pathway interactions Plasma Prevention Preventive Procyanidins Prostate Repression Sampling Second Primary Neoplasms Signal Transduction Therapeutic Intervention Treatment Efficacy United States Xenograft procedure base cancer cell cell growth cyclin-dependent kinase inhibitor 1B feeding grape seed grape seed extract indexing men pre-clinical procyanidin B3 prostate cancer prevention response translational approach tumor tumor progression tumor xenograft

项目摘要

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.

在最近的研究中，我们发现葡萄籽提取物（GSE）显着抑制 DU145 异种移植物的生长裸鼠。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，这些事件与人类相关前列腺癌 (PCA) DU145 细胞生长抑制、G1 期停滞和细胞凋亡。试图进行通过对 GSE 中活性化合物的详细机制研究，我们能够分离出原花青素 B3，显示出更强的 DU145 细胞生长抑制、S 期和/或 G2-M 期停滞以及诱导细胞凋亡在 DU145 细胞中的功效优于 GSE。在这笔资助中，我们提出了深入的机制以及肿瘤疗效在细胞培养物和肿瘤异种移植物中进行原花青素 B3 的研究。核心假设是原花青素 B3 抑制 a) 促有丝分裂和细胞存活信号传导，b) 通过细胞周期调节因子的改变，根据其浓度诱导 S 和/或 G2-M 停滞， c) 通过抑制生存信号、线粒体损伤和半胱天冬酶引起细胞凋亡激活。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，将利用正常人前列腺上皮和 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，并表征个体其中存在的化合物。作为一种实用和转化的方法，拟议研究的结果将构成以下研究的基础：在临床前 PCA 模型中进行其他研究，然后在 PCA 患者中进行临床试验，以进一步定义并确定从 GSE 中分离出的原花青素 B3 的预防和治疗功效。