Regulation of the thioredoxin-dependent system as an element of pharmacotherapy in redox-impaired diseases

Abstract

The action of many exogenous factors as well as disturbed metabolic processes of cells contribute to the increased production of oxidants, which leads to redox imbalance and, as a consequence, metabolic changes, including death or tumor transformation of cells. However, each cell is equipped with antioxidants to prevent this type of situation.One of the antioxidant systems functioning in cells is the thioredoxin dependent system, which includes thioredoxin (Trx), thioredoxin reductase (TrxR) and thioredoxin peroxidase (TPx), which have the ability to reduce oxidized forms of cell components at the expense of nicotinamidoadenine dinucleotide phosphate (NADPH). This effect results from the spatial structure of Trx and TrxR, which allows the formation of an intramolecular disulfide bridge within the thioredoxin molecule and two intermolecular selenesulfide bridges within the thioredoxin reductase dimer. Another, equally important function of the thioredoxin-dependent system is to regulate the expression of many proteins through factors such as NFκB transcription factor and apoptosis regulating kinase (ASK-1), which trigger cascades of metabolic transformations ultimately leading to cell proliferation or apoptosis. The increase in expression /activity of Trx-dependent system components is observed in the development of many cancers. Therefore, the search for selective thioredoxin or thioredoxin reductase inhibitors is currently one of the main research directions in cancer pharmacotherapy. It has been shown that many naturally occurring polyphenolic compounds of natural origin with antioxidant activity (e.g. quercetin or curcumin) inactivate the Trx-dependent system. At the same time, a number of synthetic compounds, including complex compounds, that are used in cancer therapy (e.g. cisplatin, auranofin, gadolinium motexafin) also inhibit the action of the thioredoxin system.