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

• 批准号: 8206642
• 负责人: CHING-SHIH CHEN
• 金额: $ 28.56万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 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/8206642
• 关键词: 2,4-thiazolidinedione; 5' -AMP-activated protein kinase; Adenocarcinoma; Animal Model; Apoptotic; 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 prevention; prostate carcinogenesis; public health relevance; response; scaffold; sensor; small molecule; tumor; tumor growth; tumor progression; tumorigenesis

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. PUBLIC HEALTH RELEVANCE: In men, prostate cancer is the most frequently diagnosed cancer and the second leading cause of cancer death. Our overall research goal is to develop novel agents that target the specific molecular and cellular defects in prostate cancer cells that make the clinical management and development of preventive strategies for this disease so challenging. We expect that this project will ultimately yield new drugs that will block or delay the development and/or the progression of prostate cancer.

描述(申请人提供)：癌细胞通过将细胞代谢转移到有氧糖酵解，即所谓的华宝效应，在微环境中获得生长优势。通过利用肿瘤细胞和正常细胞对糖酵解抑制的不同敏感性，靶向有氧糖酵解用于癌症治疗的兴趣日益增长，这一概念的验证是由饮食热量限制和天然产物能量限制模拟剂(ERMA)的体内有效性提供的，如白藜芦醇和2-脱氧葡萄糖(2-DG)在抑制实验动物模型的癌变方面。然而，白藜芦醇和2-DG的效价较低，阻碍了它们的临床应用。我们的研究发现，噻唑烷二酮(TZD)是一类新的ERMA，因为它们可以引起具有能量限制特征的标志性细胞反应，包括瞬时诱导沉默信息调节因子(SIRT)1的表达，激活细胞内燃料传感器AMP激活的蛋白激酶(AMPK)，以及内质网(ER)应激，它们之间的相互作用最终导致自噬和细胞凋亡。这些结果为进行TZDS的先导优化提供了分子基础，TZDS使OSU-CG12(CG12)在通过阻止葡萄糖摄取而限制肿瘤代谢方面表现出比白藜芦醇高一个数量级的效力。因此，这一相互竞争的更新建议旨在测试CG12靶向能量代谢的独特能力在前列腺癌预防中具有翻译潜力的假设。提出了三个具体目标。目的1是对CG12在调节能量限制中的作用模式进行机制表征。我们将确定CG12抑制葡萄糖利用的机制，研究p53在CG12诱导的细胞凋亡和自噬细胞死亡中的作用，并探讨CG12介导的抑制HIF-1a的机制，HIF-1a通过代谢转换到糖酵解和对2-DG的耐药性而发挥关键作用，调节细胞代谢。目标2是继续对CG12进行领先优化，以开发有效的ERMA。目的3是评估优化的ERMA在TRAMP和PTEN缺陷小鼠模型中阻断前列腺癌发生的体内效果。总之，拟议的研究将有效地将我们的新发现TZDS独特地针对肿瘤代谢转化为具有显著化学预防潜力的新型ERMA的临床前开发。 与公共卫生相关：在男性中，前列腺癌是最常见的诊断癌症，也是癌症死亡的第二大原因。我们的总体研究目标是开发针对前列腺癌细胞中特定分子和细胞缺陷的新型药物，这使得这种疾病的临床管理和预防策略的制定具有挑战性。我们预计，该项目最终将产生阻止或延缓前列腺癌发展和/或进展的新药。