Specific irreversible targeting of the selenoprotein thioredoxin reductase 1 in cancer therapy

Abstract

The cytosolic selenoprotein thioredoxin reductase 1 (TrxR1, TXNRD1) is a key enzyme for redox control of cell function and antioxidant capacity. Many cancer cells have high levels of TrxR1 as a means of surviving their increased endogenous oxidative stress. This in turn has led to the hypothesis that TrxR1 may be an anticancer drug target, especially as the enzyme is dispensable for normal adult cells. Interestingly TrxR1 is also inhibited by several anticancer drugs in clinical use, including cisplatin, chlorambucil, nitrosoureas and melphalan. It is also a well-known target of gold compounds such as auranofin, currently in clinical trials for anticancer treatment. It has not been known, however, whether inhibition of TrxR1 is a mechanism leading to some of the anticancer effects seen upon use of some of these compounds, or whether this enzyme inhibition is merely a correlative event due to a high inherent reactivity of TrxR1. Novel findings with more specific inhibitors however suggest that TrxR1 can indeed be an authentic anticancer drug target, the inhibition of which yields anticancer efficacy in mouse models without overt toxicity to normal cells and tissues.