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

Abstract

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.

ROS and radiotherapy: more we care

“…[5] in this issue of Oncotarget constitutes a particularly good example of how cancer cells can exploit their metabolic activities to resist to radiotherapy, and of what can be done therapeutically to counteract such intrinsic radioresistance. As metabolic entities, cancer cells are deemed to reach three objectives: the production of enough energy for cell proliferation and repair (bioenergetics), the generation of building blocks for the same purposes (biosynthesis), and the maintenance of a pool of reductive molecules that protect against redox stress [6].…”

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“…The study by Wang H et al [5] in this issue of Oncotarget constitutes a particularly good example of how cancer cells can exploit their metabolic activities to resist to radiotherapy, and of what can be done therapeutically to counteract such intrinsic radioresistance. As metabolic entities, cancer cells are deemed to reach three objectives: the production of enough energy for cell proliferation and repair (bioenergetics), the generation of building blocks for the same purposes (biosynthesis), and the maintenance of a pool of reductive molecules that protect against redox stress [6].…”

“…In the context of X-ray radiotherapy, Wang H et al [5] demonstrate experimentally that Auranofin, an antirheumatic agent, could be repurposed as a radiosensitizer in cancer. Auronafin is indeed a potent ThxR inhibitor that acts by forming a three-coordinate intermediate gold(I)-selenolate complex, thus blocking the activity of the selenoenzyme [8].…”

“…Auronafin is indeed a potent ThxR inhibitor that acts by forming a three-coordinate intermediate gold(I)-selenolate complex, thus blocking the activity of the selenoenzyme [8]. Using mouse mammary carcinoma cells as model, Wang H et al [5] report that low micromolar doses of Auronafin that are not cytotoxic per se disarm cancer cells against redox insults, which the authors exploited with radiotherapy. The combination strategy was effective in both hypoxic and normoxic cancer cells, demonstrating that a high ThxR activity is an essential component supporting intrinsic radioresistance.…”

“…The importance of the findings of Wang H et al [5] is that the radiosensitizing strategy that they identified is expected to be rapidly implemented in clinical practice with the repurposing of FDA-approved drug Auranofin from an antirheumatic to a radiosensitizing agent.…”