Journal
ANNUAL REVIEW OF PHARMACOLOGY AND TOXICOLOGY
Volume 62, Issue -, Pages 177-196Publisher
ANNUAL REVIEWS
DOI: 10.1146/annurev-pharmtox-052220-102509
Keywords
thioredoxin reductase; redox; oxidative stress; cancer; chemotherapy; Nrf2; TXNRD1
Categories
Funding
- Karolinska Institutet
- Knut and Alice Wallenberg Foundation
- Swedish Cancer Society
- Hungarian Thematic Excellence Program [TKP2020-NKA-26]
- CABRI
- Swedish Research Council
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Cytosolic selenoprotein thioredoxin reductase 1 (TrxR1) and mitochondrial TrxR2 (TXNRD2) can be inhibited by a wide range of electrophilic compounds, which may have important implications for cancer therapy.
The cytosolic selenoprotein thioredoxin reductase 1 (TrxR1, TXNRD1), and to some extent mitochondrial TrxR2 (TXNRD2), can be inhibited by a wide range of electrophilic compounds. Many such compounds also yield cytotoxicity toward cancer cells in culture or in mouse models, and most compounds are likely to irreversibly modify the easily accessible selenocysteine residue in TrxR1, thereby inhibiting its normal activity to reduce cytosolic thioredoxin (Trx1, TXN) and other substrates of the enzyme. This leads to an oxidative challenge. In some cases, the inhibited forms of TrxR1 are not catalytically inert and are instead converted to prooxidant NADPH oxidases, named SecTRAPs, thus further aggravating the oxidative stress, particularly in cells expressing higher levels of the enzyme. In this review, the possible molecular and cellular consequences of these effects are discussed in relation to cancer therapy, with a focus on outstanding questions that should be addressed if targeted TrxR1 inhibition is to be further developed for therapeutic use.
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