Research and Development - Iowa City VA Health Care System
Research in Progress
Principal Investigator:
- Joseph J. Cullen, M.D.
Project Title:
Role of Antioxidant Enzymes in Pancreatic Cancer
Summary:
Pancreatic cancer is the 4th most common cause of cancer death in the U.S. and increasing in incidence. NAD(P)H:quinone oxidoreductase (NQO1), which detoxifies quinone xenobiotics, serves as a protective mechanism against reactive oxygen species (ROS), and is elevated 12-fold in pancreatic cancer. Using NAD(P)H, NQO1 directly reduces the quinone form to the hydroquinone form, thus bypassing the reactive semiquinone intermediate. Dicumarol inhibits NQO1, causing ROS production when reactive semiquinones generate a redox cycle, resulting in superoxide formation. The objective of this application is to determine if NQO1 can be used as a specific target for therapeutic purposes in pancreatic cancer. The central hypothesis of the application is that dicumarol, a drug that selectively inhibits the two-electron reductase NQO1, will be an effective agent for use against pancreatic cancer cells that specifically overexpress this bioactivating enzyme. Our hypothesis has been formulated on the basis of strong preliminary data demonstrating that dicumarol induces cytotoxicity and oxidative stress in pancreatic cancer cells that overexpress NQO1. The rationale for the proposed research is that if dicumarol induces cytotoxicity in pancreatic cancer cells that overexpress NQO1, this would represent a new and innovative approach to the treatment of pancreatic cancer. We plan to test our hypothesis and accomplish the objective of this application by pursuing the following three specific aims:
- Determine if dicumarol selectively induces cell death in human pancreatic cancer cells that are known to overexpress NQO1.
- Determine if superoxide and/or hydrogen peroxide mediate the cytotoxicity and metabolic oxidative stress seen with dicumarol treatment in pancreatic cancer cells.
- Determine if the therapeutic efficacy of dicumarol can be enhanced by increasing levels of superoxide and/or hydrogen peroxide.
The proposed work is innovative because it investigates if dicumarol inhibition of NQO1 can be used for therapeutic purposes in pancreatic cancer. Additionally, it takes advantage of techniques in free radical biology, which are readily available in our laboratory. These results will be significant because the proposed experiments will provide evidence supporting the rational design of combined modality therapy for pancreatic cancer. It is our expectation that the results will advance the field of free radical biology and facilitate the discovery and development of targeted therapeutics, while developing and validating preclinical models of human pancreatic cancer
MeSH Terms: pancreatic cancer, reactive oxygen species dicumarol, NAD(P) H: quinone
