Chemoprevention of Pancreatic Cancer by EGCG

EGCG 化学预防胰腺癌

• 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
• 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

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）： 胰腺癌是美国癌症死亡率的第四个主要原因。它具有所有癌症的最差预后，5年的存活率<3％。通常发现胰腺癌为时已晚，无法提供帮助，并且对当前的化学疗法和放射治疗高度抗性。目前，胰腺癌的唯一治疗方法是手术，但在出现时只有15％的患者是候选手术，只有20％接受治疗手术的患者在5年后还活着。因此，需要新的预防和治疗选择。该提案基于使用绿茶多酚，表瓜蛋白-3-gallate（EGCG），它对与肿瘤起始，促进和进展相关的各种细胞事件产生了重大抑制作用。除了这些进展外，尚不清楚EGCG抑制增殖并诱导胰腺癌细胞凋亡的细胞内机制。由于EGCG无毒，因此作为癌症预防剂的全球兴趣增加了。 EGCG对胰腺癌的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将抑制依赖RAS的PI3K/AKT和MAP激酶活性，并且这两种途径将融合以调节FOX FOX转录因子的转录因子，细胞生长和细胞中的细胞，细胞中的细胞，蛋白癌细胞中的细胞。 EGCG由于通过调节FOXO转录因子诱导细胞周期停滞和凋亡的能力，在抑制人类胰腺癌细胞的生长方面非常有效。该项目的具体目的是：（1）检查EGCG在胰腺癌细胞中诱导细胞周期停滞和凋亡的分子机制，（2）确定EGCG口服施用EGCG对人类胰腺的生长和消退的影响，以确定在裸小鼠中植入的人类胰腺癌细胞的作用。 KRASG12D转基因小鼠模型。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，因此作为癌症预防剂的全球兴趣增加了。 EGCG对胰腺癌的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将抑制依赖RAS的PI3K/AKT和MAP激酶活性，并且这两种途径将融合以调节FOX FOX转录因子的转录因子，细胞生长和细胞中的细胞，细胞中的细胞，蛋白癌细胞中的细胞。 EGCG由于通过调节FOXO转录因子诱导细胞周期停滞和凋亡的能力，在抑制人类胰腺癌细胞的生长方面非常有效。该项目的具体目的是：（1）检查EGCG在胰腺癌细胞中诱导细胞周期停滞和凋亡的分子机制，（2）确定EGCG口服施用EGCG对人类胰腺的生长和消退的影响，以确定在裸小鼠中植入的人类胰腺癌细胞的作用。 KRASG12D转基因小鼠模型。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转基因小鼠模型进行胰腺癌预防，并建立EGCG的临床潜力，以延迟人类胰腺癌的发作和/或进展。