NQO1 Inhibitors and Pancreatic Cancer Therapy

NQO1 抑制剂和胰腺癌治疗

基本信息

批准号：
7477717
负责人：
DAVID ROSS
金额：
$ 25.96万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-09-30 至 2010-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7477717
关键词：
Agar Apoptosis Biochemical Biochemical Markers Biological Assay Cancer Cell Growth Cancer cell line Cell Cycle Cell Cycle Arrest Cell Line Cells Characteristics Chemicals Coupled Data Dicoumarol Disease Dose Drug Kinetics Electrons End Point Enzyme Inhibition Enzymes Event Exhibits Flow Cytometry Fluorescence Genetic Growth Human In Vitro Indolequinones Induction of Apoptosis Laboratories Laser Scanning Confocal Microscopy Left Malignant Neoplasms Malignant neoplasm of pancreas Mass Spectrum Analysis Measures Metabolism Methods Modeling NAD(P)H dehydrogenase (quinone) 1, human NQO1 gene Nude Mice Numbers Oxidoreductase Pancreas Pharmacodynamics Phenotype Plasma Principal Investigator Rate Relative (related person)Reporting Role Small Interfering RNA Suicide Superoxide Dismutase Superoxides Techniques Testing Therapeutic Therapeutic Agents Tissues Transfection Tumor Volume X ray spectrometry X-Ray Crystallography Xenograft procedure analog antitumor agent base cancer cell cancer therapy cell growth chemotherapy cytotoxicity enzyme substrate hydroethidine in vivo inhibitor/antagonist knock-down malignant phenotype neoplastic cell novel therapeutics pancreatic neoplasm programs research study symposium tissue culture tumor

项目摘要

DESCRIPTION (provided by applicant): Inhibition of the enzyme NQO1 in pancreatic tumor cells using the non-specific inhibitor dicoumarol resulted in increased intracellular superoxide, inhibition of cell growth and inhibition of the in-vitro malignant phenotype of cells. The hypothesis proposed was that inhibition of NQO1 led to increased superoxide levels which inhibited pancreatic cancer cell growth and the in-vitro malignant phenotype. We have recently shown that NQO1 can directly scavenge superoxide providing both a potential approach and a mechanism of action for the use of NQO1 inhibitors in the therapy of pancreatic cancer. In this proposal, we will test the hypothesis that specific mechanism-based inhibitors of NQO1 are effective compounds for the therapy of pancreatic tumors both in-vitro and in-vivo. One of these inhibitors, the indolequinone ES936, is a potent inhibitor of pancreatic cancer cell growth and the in-vitro malignant phenotype. We will therefore test the hypothesis that ES936 can be employed as an effective therapeutic agent in pancreatic cancer and extend in-vitro data to in-vivo xenograft and orthotopic pancreatic tumor models. We will define the mechanism of action of ES936 and will attempt to dissociate NQO1 inhibition from effects on pancreatic cancer cell growth and the in-vitro malignant phenotype using both chemical/pharmacological and genetic approaches. Whether the effect of ES936 is due to increased levels of superoxide as a result of NQO1 inhibition will be characterized and downstream effects of ES936 on modulation of the cell cycle and apoptosis will be determined both in-vitro and in-vivo. This approach represents a novel therapeutic strategy for the treatment of pancreatic cancer, a disease where therapeutic options are very limited and where chemotherapy has made minimal impact.

描述（由申请人提供）：使用非特异性抑制剂DICOUMAROL抑制酶NQO1在胰腺肿瘤细胞中的抑制作用导致细胞内超氧化物增加，抑制细胞生长和抑制细胞内恶性表型。提出的假设是，NQO1的抑制导致了超氧化物水平升高，抑制了胰腺癌细胞生长和体外恶性表型。我们最近表明，NQO1可以直接清除超氧化物，从而提供潜在的方法和一种在胰腺癌治疗中使用NQO1抑制剂的作用机理。在此提案中，我们将检验以下假设：NQO1的基于特定机制的抑制剂是用于治疗胰腺肿瘤的有效化合物。这些抑制剂之一是吲哚酮ES936，是胰腺癌细胞生长和体外恶性表型的有效抑制剂。因此，我们将检验以下假设：ES936可以用作胰腺癌的有效治疗剂，并将视频内数据扩展到体内异种移植物和原位胰腺肿瘤模型。我们将定义ES936的作用机理，并将尝试使用化学/药理和遗传学方法将NQO1抑制与对胰腺癌细胞生长和体外恶性表型的影响分离。 ES936的作用是否是由于NQO1抑制作用的升高而引起的，并且将确定ES936对细胞周期和凋亡调节的下游影响，并将确定视野内和体内。这种方法代表了治疗胰腺癌的一种新型治疗策略，胰腺癌是一种疾病，在该疾病中，治疗疗法非常有限，并且化学疗法的影响很小。