Targeting Antioxidant Systems to Treat Pancreatic Cancer

Pancreatic cancer has the worst prognosis of all cancers. Pancreatic tumours are characterized by excessive oxidative stress that may provide a unique vulnerability to target in the development of new therapeutic strategies. I investigated a novel combination therapy targeting the two main intracellular antioxidant systems, glutathione and thioredoxin. Buthionine sulfoximine (BSO) targets glutathione synthesis and auranofin targets thioredoxin recycling. These drugs have been tested in human clinical trials and are strong candidates for repurposing in cancer therapy. I found that BSO potentiated auranofin’s cytotoxic effects in vitro. Furthermore, the combination augmented oxidative stress in cells. Auranofin engaged its target TrxR in vitro at concentrations causing cell death. I also assessed the biodistribution of auranofin in vivo and observed a preferential accumulation in the stroma 24 hours after treatment. Overall, I conclude that this treatment strategy can be effective against pancreatic cancer and deserves attention for future development.M.Sc