Combined Targeting of the Glutathione and Thioredoxin Antioxidant Systems in Pancreatic Cancer

Pancreatic ductal adenocarcinoma is characterized by increased generation of reactive oxygen species that can cause lethal oxidative stress. Here, we evaluated the combined inhibition of the glutathione and thioredoxin antioxidant systems in preclinical models of pancreatic ductal adenocarcinoma, using buthionine sulfoximine (BSO) that targets glutathione synthesis, and auranofin that targets thioredoxin recycling. BSO potentiated the cytotoxicity of auranofin and induced lethal oxidative stress in primary pancreatic cancer cells. As assessed by the cellular thermal shift assay, auranofin engaged with thioredoxin reductase 1 in primary cells at concentrations known to induce cell death. Moreover, we used imaging mass cytometry to map the biodistribution of atomic gold in patient-derived xenografts treated with auranofin, and the drug was readily detectable throughout the epithelial and stromal compartments after treatment with a clinically relevant dose. In conclusion, combinatorial treatment with BSO and auranofin could serve as a potential therapeutic strategy in pancreatic ductal adenocarcinoma.