NQO1 Inhibitors and Pancreatic Cancer Therapy

NQO1 抑制剂和胰腺癌治疗

• 批准号: 7038446
• 负责人: DAVID ROSS
• 金额: $ 27.37万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-30 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7038446
• 关键词: NAD(P)H dehydrogenase; antineoplastics; apoptosis; athymic mouse; cell line; confocal scanning microscopy; cytotoxicity; drug screening /evaluation; flow cytometry; neoplasm /cancer chemotherapy; neoplastic cell; neoplastic growth; oxidoreductase inhibitor; pancreas neoplasms; pharmacokinetics; phenotype; small interfering RNA; superoxide dismutase; xenotransplantation

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（申请人提供）：使用非特异性抑制剂双香豆素抑制胰腺肿瘤细胞中的酶NQO1导致细胞内超氧化物增加，抑制细胞生长并抑制细胞的体外恶性表型。提出的假设是，抑制 NQO1 会导致超氧化物水平升高，从而抑制胰腺癌细胞的生长和体外恶性表型。我们最近证明，NQO1 可以直接清除超氧化物，为 NQO1 抑制剂治疗胰腺癌提供了潜在的方法和作用机制。在本提案中，我们将测试以下假设：基于特定机制的 NQO1 抑制剂是体外和体内治疗胰腺肿瘤的有效化合物。其中一种抑制剂吲哚醌 ES936 是胰腺癌细胞生长和体外恶性表型的有效抑制剂。因此，我们将测试 ES936 可用作胰腺癌有效治疗剂的假设，并将体外数据扩展到体内异种移植和原位胰腺肿瘤模型。我们将定义 ES936 的作用机制，并尝试使用化学/药理学和遗传学方法将 NQO1 抑制与对胰腺癌细胞生长和体外恶性表型的影响分开。将确定 ES936 的作用是否是由于 NQO1 抑制导致的超氧化物水平增加所致，并将在体外和体内确定 ES936 对细胞周期和细胞凋亡调节的下游影响。 这种方法代表了一种治疗胰腺癌的新颖治疗策略，这种疾病的治疗选择非常有限，而且化疗的效果也很小。