Targeting the Thioredoxin System for Cancer Therapy

The Trx system is increasingly recognized as an essential player in maintaining cellular redox homeostasis and regulating diverse cellular signaling pathways. Malfunction of TrxR/Trx enzymes has been linked to multiple pathological conditions, including cancer, inflammation, and neurodegenerative disorders, making the enzymes promising therapeutic targets. Although a significant number of TrxR/Trx inhibitors have been disclosed as potential anticancer agents, and some are currently in clinical trials, finding highly selective inhibitors of the enzymes is urgently needed but challenging. Based on the inhibition mechanisms and the structure profiles of mammalian TrxRs, novel strategies that might lead to specific targeting of TrxR/Trx are proposed. Thioredoxin (Trx) and thioredoxin reductase (TrxR) are essential components of the Trx system which plays pivotal roles in regulating multiple cellular redox signaling pathways. In recent years TrxR/Trx have been increasingly recognized as an important modulator of tumor development, and hence targeting TrxR/Trx is a promising strategy for cancer treatment. In this review we first discuss the structural details of TrxR, the functions of the Trx system, and the rational of targeting TrxR/Trx for cancer treatment. We also highlight small-molecule TrxR/Trx inhibitors that have potential anticancer activity and review their mechanisms of action. Finally, we examine the challenges of developing TrxR/Trx inhibitors as anticancer agents and perspectives for selectively targeting TrxR/Trx. Thioredoxin (Trx) and thioredoxin reductase (TrxR) are essential components of the Trx system which plays pivotal roles in regulating multiple cellular redox signaling pathways. In recent years TrxR/Trx have been increasingly recognized as an important modulator of tumor development, and hence targeting TrxR/Trx is a promising strategy for cancer treatment. In this review we first discuss the structural details of TrxR, the functions of the Trx system, and the rational of targeting TrxR/Trx for cancer treatment. We also highlight small-molecule TrxR/Trx inhibitors that have potential anticancer activity and review their mechanisms of action. Finally, we examine the challenges of developing TrxR/Trx inhibitors as anticancer agents and perspectives for selectively targeting TrxR/Trx.