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.
