Auranofin radiosensitizes tumor cells through targeting thioredoxin reductase and resulting overproduction of reactive oxygen species

Hui Wang, Soumaya Bouzakoura, Sven de Mey, Heng Jiang, Kalun Law, Inès Dufait, Cyril Corbet, Valeri Verovski, Thierry Gevaert, Olivier Feron, Dirk Van den Berge, Guy Storme, Mark De Ridder

Onderzoeksoutput: Article

37 Citaten (Scopus)

Samenvatting

Auranofin (AF) is an anti-arthritic drug considered for combined chemotherapy due to its ability to impair the redox homeostasis in tumor cells. In this study, we asked whether AF may in addition radiosensitize tumor cells by targeting thioredoxin reductase (TrxR), a critical enzyme in the antioxidant defense system operating through the reductive protein thioredoxin. Our principal findings in murine 4T1 and EMT6 tumor cells are that AF at 3-10 μM is a potent radiosensitizer in vitro, and that at least two mechanisms are involved in TrxR-mediated radiosensitization. The first one is linked to an oxidative stress, as scavenging of reactive oxygen species (ROS) by N-acetyl cysteine counteracted radiosensitization. We also observed a decrease in mitochondrial oxygen consumption with spared oxygen acting as a radiosensitizer under hypoxic conditions. Overall, radiosensitization was accompanied by ROS overproduction, mitochondrial dysfunction, DNA damage and apoptosis, a common mechanism underlying both cytotoxic and antitumor effects of AF. In tumor-bearing mice, a simultaneous disruption of the thioredoxin and glutathione systems by the combination of AF and buthionine sulfoximine was shown to significantly improve tumor radioresponse. In conclusion, our findings illuminate TrxR in cancer cells as an exploitable radiobiological target and warrant further validation of AF in combination with radiotherapy.

Originele taal-2English
Pagina's (van-tot)35728-35742
Aantal pagina's15
TijdschriftOncotarget
Volume8
Nummer van het tijdschrift22
DOI's
StatusPublished - mei 2017

Vingerafdruk

Duik in de onderzoeksthema's van 'Auranofin radiosensitizes tumor cells through targeting thioredoxin reductase and resulting overproduction of reactive oxygen species'. Samen vormen ze een unieke vingerafdruk.

Citeer dit