Recent advances in the development of thioredoxin reductase inhibitors as anticancer agents

Redox homeostasis is crucial for the cellular viability and normal function which balance is maintained by two major cellular antioxidant systems, including glutathione system and thioredoxin system. Thioredoxin system, including thioredoxin (Trx), thioredoxin reductase (TrxR) and NADPH, exhibits a wide range of functions such as regulation of redox state and cell apoptosis. Particularly, Trx functions as a protein disulfide reductase which is essential for the function of Trx system. However, the bioactivity of Trx is closely dependent on its reducing form. According to the information, TrxR is the only cellular enzyme to catalyze the NADPH-dependent reduction of Trx. Besides the reduction of some protein disulfide like Trx, TrxR still has a broad substrate specificity to reduce some small molecules like 5, 5 '-dithiobis-2- nitrobenzoic acid (DTNB). The reduction of Trx or its own direct action towards its various substrates endows TrxR with a wide range of cellular functions. Recent studies have elucidated that TrxR was upregulated in many malignant tumors and inhibition of TrxR could prevent the tumor initiation and progression, suggesting TrxR to be a promising target for cancer therapy and the high nucleophilic and accessible selenocysteine (Sec) active site might be the prime target for drug design. Various kinds of TrxR inhibitors have been developed as anticancer agents for years. In this review, TrxR inhibitors are divided into three classes, including metal-containing inhibitors, naturally occurring products and their derivatives and other newly emerged inhibitors. The last five years reports about TrxR inhibitors of each class will be introduced and their novel inhibiting mechanisms will be discussed.