Thioredoxin Reductase Inhibition for Cancer Therapy.
Annu Rev Pharmacol Toxicol
; 62: 177-196, 2022 01 06.
Article
em En
| MEDLINE
| ID: mdl-34449246
ABSTRACT
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.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Tiorredoxina Redutase 1
/
Neoplasias
Limite:
Animals
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Humans
Idioma:
En
Revista:
Annu Rev Pharmacol Toxicol
Ano de publicação:
2022
Tipo de documento:
Article