NQO1 Inhibitors and Pancreatic Cancer Therapy

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NQO1酶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导致超氧化物水平增加，从而抑制胰腺癌细胞的生长和体外恶性表型。我们最近发现NQO1可以直接清除超氧化物，为NQO1抑制剂在胰腺癌治疗中的应用提供了一种潜在的途径和作用机制。在这项提案中，我们将检验基于特定机制的NQO1抑制剂是体内和体外治疗胰腺肿瘤的有效化合物的假设。其中一种抑制剂吲哚喹酮ES936是一种有效的胰腺癌细胞生长和体外恶性表型的抑制剂。因此，我们将验证ES936可以作为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。我们将确定ES936的作用机制，并试图利用化学/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。ES936的作用是否归因于NQO1抑制导致超氧化物水平增加，将在体外和体内确定ES936对细胞周期和细胞凋亡的调节作用。 这种方法代表了治疗胰腺癌的一种新的治疗策略，这种疾病的治疗选择非常有限，化疗的影响也很小。

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.