Novel Energy Restriction-Mimetic Agents for Prostate Cancer Prevention

用于预防前列腺癌的新型能量限制模拟剂

基本信息

批准号：
8387783
负责人：
CHING-SHIH CHEN
金额：
$ 26.84万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-06-01 至 2015-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8387783
关键词：
2,4-thiazolidinedione 5&apos -AMP-activated protein kinase Adenocarcinoma Animal Model Apoptotic BCL2 gene Biological Factors Caloric Restriction Cancer Etiology Cell Death Cells Cessation of life Characteristics Chemopreventive Agent Chronic Clinical Management Combinatorial Synthesis Data Defect Deoxyglucose Development Diet Disease Effectiveness Energy Metabolism Enzymes Epigenetic Process Epithelial Cells Exhibits Experimental Animal Model Funding Genetic Glucose Glucose Transporter Glycolysis Goals Growth Heterogeneity Histone Deacetylase Inhibitor Hypoxia Incidence Indole-3-Carbinol Inhibitory Concentration 50 LNCaP Laboratories Lead Malignant - descriptor Malignant neoplasm of prostate Mediating Metabolic Metabolism Modeling Modification Molecular Mus Non-Malignant Normal Cell Oral PTEN gene Pathway interactions Peroxisome Proliferator-Activated Receptors Pharmaceutical Preparations Phase Phase I Clinical Trials Play Predisposition Prevention strategy Prostate Prostatic Proteins Research Resistance development Resources Resveratrol Role Safety Second Primary Cancers Series Signal Transduction Solid Starvation Testing Thiazolidinediones TimeLine Toxic effect Transgenic Organisms Translating Validation Warburg Effect Wild Type Mouse Xenograft Model Xenograft procedure aerobic glycolysis base cancer cell cancer chemoprevention cancer diagnosis cancer therapy carcinogenesis ciglitazone clinical application cytotoxicity deprivation design endoplasmic reticulum stress gene induction glucose uptake in vivo inhibitor/antagonist interest men mimetics mouse model novel pre-clinical prostate cancer cell prostate cancer prevention prostate carcinogenesis public health relevance response scaffold sensor small molecule tumor tumor growth tumor metabolism tumor progression

项目摘要

DESCRIPTION (provided by applicant): Cancer cells gain growth advantages in the microenvironment by shifting cellular metabolism to aerobic glycolysis, the so-called Warburg effect. There is a growing interest in targeting aerobic glycolysis for cancer therapy by exploiting the differential susceptibility of malignant versus normal cells to glycolytic inhibition, of which the proof-of-concept is provided by the in vivo efficacy of dietary caloric restriction and natural product-based energy restriction-mimetic agents (ERMAs) such as resveratrol and 2-deoxyglucose (2-DG) in suppressing carcinogenesis in experimental animal models. The clinical applications of resveratrol and 2-DG, however, are hampered by their weak potencies. Our studies have identified thiazolidinediones (TZDs) as a novel class of ERMAs in that they elicited hallmark cellular responses characteristic of energy restriction, including transient induction of silent information regulator (Sirt)1 expression, activation of the intracellular fuel sensor AMP-activated protein kinase (AMPK), and endoplasmic reticulum (ER) stress, the interplay among which culminated in autophagic and apoptotic cell death. These results provided a molecular basis to conduct lead optimization of TZDs, which netted OSU-CG12 (CG12) exhibiting an-order-of-magnitude higher potency than resveratrol in restricting tumor metabolism by blocking glucose uptake. Thus, this competing renewal proposal is aimed at testing the hypothesis that the unique ability of CG12 to target energy metabolism has translational potential in prostate cancer prevention. Three Specific Aims are proposed. Aim 1 is to conduct the mechanistic characterization of the mode of action of CG12 in mediating energy restriction. We will identify the mechanism underlying the suppressive effects of CG12 on glucose utilization, examine the role of p53 in CG12-induced apoptotic and autophagic cell death, and investigate the mechanism underlying CG12-mediated suppression of HIF-1a, which plays a critical role in regulating cell metabolism through the metabolic switch to glycolysis and the development of resistance to 2-DG. Aim 2 is to continue the lead optimization of CG12 to develop potent ERMAs. Aim 3 is to assess the in vivo efficacy of an optimized ERMA to block prostate tumorigenesis in the TRAMP and PTEN-deficient mouse models. Together, the proposed studies will effectively translate our novel finding that TZDs uniquely target tumor metabolism to preclinical development of a novel class of ERMAs with significant chemopreventive potential.

描述（由申请人提供）：癌细胞通过将细胞代谢转移到有氧糖酵解（所谓的Warburg效应）中，从而在微环境中获得了生长优势。通过利用恶性和正常细胞对糖酵解抑制的差异敏感性来靶向有氧糖酵解进行癌症治疗的兴趣越来越大，概念证明是由饮食热量限制和基于自然产物的能量限制性抑制剂（ERMAS）和2-DECRICTING和2-DECING的体内功效提供的。实验动物模型中的致癌作用。但是，白藜芦醇和2-DG的临床应用受到其弱势效果的阻碍。 Our studies have identified thiazolidinediones (TZDs) as a novel class of ERMAs in that they elicited hallmark cellular responses characteristic of energy restriction, including transient induction of silent information regulator (Sirt)1 expression, activation of the intracellular fuel sensor AMP-activated protein kinase (AMPK), and endoplasmic reticulum (ER) stress, the interplay among which culminated in自噬和凋亡细胞死亡。这些结果为进行TZD的铅优化提供了一个分子基础，TZD的铅优化，在限制葡萄糖摄取来限制肿瘤代谢方面，其净化OSU-CG12（CG12）表现出比白藜芦醇高的效力。因此，该竞争性更新提案旨在检验以下假设：CG12靶向能量代谢的独特能力在预防前列腺癌中具有转化潜力。提出了三个具体目标。目的1是进行CG12在介导能量限制中的作用方式的机械表征。我们将确定CG12对葡萄糖利用的抑制作用的基础机制，检查p53在CG12诱导的凋亡和自噬细胞死亡中的作用，并研究CG12介导的HIF-1A抑制的基本机制，该机制在调节细胞代谢中的重要作用在抑制细胞代理方面与GGLYCOLISS的调节和GGLYCLISS相关。目标2是继续对CG12进行铅优化，以发展有效的ERMA。 AIM 3是评估优化ERMA的体内功效，以阻止缺乏小鼠和PTEN缺乏小鼠模型中的前列腺肿瘤发生。共同提出的研究将有效地转化我们的新发现，即TZD独特地将肿瘤代谢靶向具有明显的化学预防潜力的新型ERMA类别的临床前发展。