Synergy between auranofin and celecoxib against colon cancer in vitro and in vivo through a novel redox-mediated mechanism

Recent study suggests that auranofin (AF), a US Food and Drug Administration (FDA)-approved drug for treatment of rheumatoid arthritis, has selective anticancer activity in various experimental models. Its clinical applications in cancer treatment, however, have been hampered due in part to its relatively moderate activity as a single agent. In this study, we performed a high-throughput screening of the FDA-approved drug library for clinical compounds that potentiate the anticancer activity auranofin, and unexpectedly identified an anti-inflammatory drug celecoxib (CE) that potently enhanced the therapeutic activity of AF in vitro and in vivo. Mechanistically, AF/CE combination induced severe oxidative stress that caused ROS-mediated inhibition of hexokinase (HK) and a disturbance of mitochondrial redox homeostasis, resulting in a significant decrease of ATP generation. The CE-induced ROS increase together with AF-medicated inhibition of thioredoxin reductase cause a shift of Trx2 to an oxidized state, leading to degradation of MTCO2 and dysfunction of the electron transport chain. Our study has identified a novel drug combination that effectively eliminates cancer cells in vivo. Since AF and CE are FDA-approved drugs that are currently used in the clinic, it is feasible to translate the findings of this study into clinical applications for cancer treatment.