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

Abstract

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