Chemoprevention of Pancreatic Cancer by EGCG

EGCG 化学预防胰腺癌

基本信息

批准号：
8305084
负责人：
ANIMESH DHAR
金额：
$ 28.07万
依托单位：
UNIVERSITY OF KANSAS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-15 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8305084
关键词：
Apoptosis Biological Cancer Etiology Cell Cycle Cell Cycle Arrest Cell Cycle Regulation Cell Nucleus Chemoprevention Chemopreventive Agent Clinical Cyclin D1 Data Development Disease Outbreaks Dominant-Negative Mutation Ductal Epithelial Cell Epidemiologic Studies Epidemiology Epigallocatechin Gallate Event Exclusion FOXO1A gene Gene Targeting Genes Genetic Transcription Green tea Growth Human Implant In Vitro Incidence Knowledge MAP Kinase Gene MAPK3 gene Malignant Neoplasms Malignant neoplasm of pancreas Mediating Mitochondria Mitogen-Activated Protein Kinases Modeling Molecular Mus Mutation Neoplasm Metastasis Nuclear Nude Mice Operative Surgical Procedures Oral Administration PTEN gene Pancreas Pathogenesis Pathway interactions Patients Phosphorylation Play Population Preclinical Testing Prevention Prevention strategy Preventive Proteins Proto-Oncogene Proteins c-akt Radiation Radiation therapy Ras/Raf Recurrence Regulation Reporting Resistance Role Signal Pathway Signal Transduction Solid Staging Survival Rate Testing Time Transgenic Mice Work Xenograft procedure base cancer prevention cancer risk carcinogenesis cell growth chemotherapy efficacy evaluation gallocatechol in vivo inhibitor/antagonist interest mortality mouse model oncoprotein p21 operation outcome forecast pancreatic cancer cells pancreatic neoplasm preclinical evaluation prevent transcription factor tumor growth tumor initiation

项目摘要

DESCRIPTION (provided by applicant): Pancreatic cancer ranks as the fourth leading cause of cancer mortality in the US. It has the worst prognosis of all cancers, with a 5-year survival rate of < 3%. Pancreatic cancer is often detected too late for surgery to be helpful and is highly resistant to current chemotherapy and radiation treatment. Currently, the only curative treatment for pancreatic cancer is surgery, but only 15% of patients are candidates for surgery at the time of presentation, and only 20% patients who undergo a curative operation are alive after 5 years. Therefore, new options for prevention and treatment are needed. This proposal is based on the use of green tea polyphenol, epigallocatechin-3-gallate (EGCG), which exerts significant inhibitory effects on diverse cellular events associated with tumor initiation, promotion and progression. Besides these advances, the intracellular mechanisms by which EGCG inhibits proliferation and induces apoptosis in pancreatic cancer cells are not well understood. Since EGCG is non-toxic, its worldwide interest as a cancer preventive agent has increased. Rationale for preclinical evaluation of EGCG against pancreatic cancer comes from our preliminary studies, which led us to hypothesize that EGCG will inhibit ras-dependent PI3K/Akt and MAP kinase activities, and these two pathways will converge to regulate FOXO transcription factors, cell growth and apoptosis in pancreatic cancer cells. EGCG will be highly effective in suppressing growth of human pancreatic cancer cells due to its ability to induce cell cycle arrest and apoptosis through regulation of FOXO transcription factors. The specific aims of the project are: (1) To examine the molecular mechanisms by which EGCG induces cell cycle arrest and apoptosis in pancreatic cancer cells, (2) To determine the effects of oral administration of EGCG on growth and regression of human pancreatic cancer cells implanted in nude mice, and (3) To determine in vivo efficacy of EGCG administration on pancreatic carcinogenesis using KrasG12D transgenic mouse model. This transgenic mouse model faithfully reproduces the histological features of human pancreatic cancer. Since EGCG is non-toxic, its worldwide interest as a cancer preventive agent has increased. Rationale for preclinical evaluation of EGCG against pancreatic cancer comes from our preliminary studies, which led us to hypothesize that EGCG will inhibit ras-dependent PI3K/Akt and MAP kinase activities, and these two pathways will converge to regulate FOXO transcription factors, cell growth and apoptosis in pancreatic cancer cells. EGCG will be highly effective in suppressing growth of human pancreatic cancer cells due to its ability to induce cell cycle arrest and apoptosis through regulation of FOXO transcription factors. The specific aims of the project are: (1) To examine the molecular mechanisms by which EGCG induces cell cycle arrest and apoptosis in pancreatic cancer cells, (2) To determine the effects of oral administration of EGCG on growth and regression of human pancreatic cancer cells implanted in nude mice, and (3) To determine in vivo efficacy of EGCG administration on pancreatic carcinogenesis using KrasG12D transgenic mouse model. This transgenic mouse model faithfully reproduces the histological features of human pancreatic cancer. Studies outlined in this proposal are highly significant because they will validate Kras transgenic mouse model for pancreatic cancer prevention and establish a clinical potential of EGCG that can delay the onset and/or progression of human pancreatic cancer.

描述（由申请人提供）：胰腺癌是美国第四大癌症死亡原因。它是所有癌症中预后最差的，5年生存率<3%。胰腺癌常常发现得太晚，手术无济于事，并且对当前的化疗和放疗具有高度抵抗力。目前，胰腺癌唯一的治愈方法是手术，但只有 15% 的患者在就诊时适合手术，并且只有 20% 接受根治性手术的患者 5 年后仍存活。因此，需要新的预防和治疗选择。该提案基于绿茶多酚、表没食子儿茶素-3-没食子酸酯 (EGCG) 的使用，它对与肿瘤发生、促进和进展相关的多种细胞事件具有显着的抑制作用。除了这些进展之外，EGCG 抑制胰腺癌细胞增殖和诱导细胞凋亡的细胞内机制尚不清楚。由于 EGCG 无毒，其作为癌症预防剂的全球兴趣日益浓厚。 EGCG 抗胰腺癌临床前评估的基本原理来自我们的初步研究，这使我们假设 EGCG 会抑制 ras 依赖性 PI3K/Akt 和 MAP 激酶活性，并且这两条途径将汇聚来调节 FOXO 转录因子、细胞生长和胰腺癌细胞的凋亡。 EGCG 通过调节 FOXO 转录因子诱导细胞周期停滞和细胞凋亡，因此能够非常有效地抑制人胰腺癌细胞的生长。该项目的具体目标是：（1）研究EGCG诱导胰腺癌细胞细胞周期停滞和凋亡的分子机制，（2）确定口服EGCG对人胰腺癌生长和消退的影响(3)使用KrasG12D转基因小鼠模型确定EGCG施用对胰腺癌发生的体内功效。这种转基因小鼠模型忠实地再现了人类胰腺癌的组织学特征。由于 EGCG 无毒，其作为癌症预防剂的全球兴趣日益浓厚。 EGCG 抗胰腺癌临床前评估的基本原理来自我们的初步研究，这使我们假设 EGCG 会抑制 ras 依赖性 PI3K/Akt 和 MAP 激酶活性，并且这两条途径将汇聚来调节 FOXO 转录因子、细胞生长和胰腺癌细胞的凋亡。 EGCG 通过调节 FOXO 转录因子诱导细胞周期停滞和细胞凋亡，因此能够非常有效地抑制人胰腺癌细胞的生长。该项目的具体目标是：（1）研究EGCG诱导胰腺癌细胞细胞周期停滞和凋亡的分子机制，（2）确定口服EGCG对人胰腺癌生长和消退的影响(3)使用KrasG12D转基因小鼠模型确定EGCG施用对胰腺癌发生的体内功效。这种转基因小鼠模型忠实地再现了人类胰腺癌的组织学特征。该提案中概述的研究非常重要，因为它们将验证 Kras 转基因小鼠模型用于预防胰腺癌，并确定 EGCG 延缓人类胰腺癌发病和/或进展的临床潜力。