Effects of redox modulation by inhibition of Thioredoxin reductase on radiosensitivity and gene expression

The thioredoxin system is a promising target when aiming to overcome the problem of clinical radiation resistance. Altered cellular redox-status and redox sensitive thiols contributing to induction of resistance strongly connects the ubiquitous redox enzyme thioredoxin reductase to the cellular response to ionizing radiation. To further investigate possible strategies in combating clinical radiation resistance, human radio-resistant lung cancer cells were subjected to a combination of single fractions of γ-radiation at clinically relevant doses and non-toxic levels of a well-characterized thioredoxin reductase (TrxR) inhibitor, the phosphine gold(I) compound [Au(SCN)(PEt(3) )]. The combination of the TrxR-inhibitor and ionizing radiation reduced the surviving fractions and impaired the ability of the U1810 cells to repopulate by approximately 50%. In addition, inhibition of thioredoxin reductase caused changes in the cell cycle distribution, suggesting a disturbance of the mitotic process. Global gene expression analysis also revealed clustered genetic expression changes connected to several major cellular pathways such as cell cycle, cellular response to stress and DNA-damage. Specific TrxR-inhibition as a factor behind the achieved results was confirmed by correlation of gene expression patterns between gold and siRNA treatment. These results clearly demonstrates TrxR as an important factor conferring resistance to irradiation and the use of [Au(SCN)(PEt(3) )] as a promising radiosensitizing agent.