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

Tijdschriftbijdrage - Tijdschriftartikel

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.

Tijdschrift: Oncotarget
ISSN: 1949-2553
Issue: 22
Volume: 8
Pagina's: 35728-35742
Jaar van publicatie:2017
Trefwoorden:Animals, Apoptosis/drug effects, Auranofin/pharmacology, Cell Line, Tumor, DNA Damage/drug effects, Disease Models, Animal, Glutathione/metabolism, Hypoxia/metabolism, Membrane Potential, Mitochondrial/drug effects, Mice, Mitochondria/drug effects, Oxidation-Reduction/drug effects, Oxygen Consumption/drug effects, Radiation Tolerance/drug effects, Radiation-Sensitizing Agents/pharmacology, Reactive Oxygen Species/metabolism, Thioredoxin-Disulfide Reductase/antagonists & inhibitors
  • DOI: https://doi.org/10.18632/oncotarget.16113
  • WoS Id: 000403230000025
  • ORCID: /0000-0002-9945-4357/work/61830130
  • ORCID: /0000-0002-4712-3214/work/62062910
  • Scopus Id: 85047201115
  • ORCID: /0000-0001-8444-0836/work/75810359
  • ORCID: /0000-0003-2447-0202/work/104770244
  • PubMed Central Id: PMC5482612
CSS-citation score:2
Auteurs:International
Toegankelijkheid:Open