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Reactive Oxygen Species pp 289–309Cite as

Effects of Mammalian Thioredoxin Reductase Inhibitors

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Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 264))

Abstract

The mammalian thioredoxin system is driven by NADPH through the activities of isoforms of the selenoprotein thioredoxin reductase (TXNRD, TrxR), which in turn help to keep thioredoxins (TXN, Trx) and further downstream targets reduced. Due to a wide range of functions in antioxidant defense, cell proliferation, and redox signaling, strong cellular aberrations are seen upon the targeting of TrxR enzymes by inhibitors. However, such inhibition can nonetheless have rather unexpected consequences. Accumulating data suggest that inhibition of TrxR in normal cells typically yields a paradoxical effect of increased antioxidant defense, with metabolic pathway reprogramming, increased cellular proliferation, and altered cellular differentiation patterns. Conversely, inhibition of TrxR in cancer cells can yield excessive levels of reactive oxygen species (ROS) resulting in cell death and thus anticancer efficacy. The observed increases in antioxidant capacity upon inhibition of TrxR in normal cells are in part dependent upon activation of the Nrf2 transcription factor, while exaggerated ROS levels in cancer cells can be explained by a non-oncogene addiction of cancer cells to TrxR1 due to their increased endogenous production of ROS. These separate consequences of TrxR inhibition can be utilized therapeutically. Importantly, however, a thorough knowledge of the molecular mechanisms underlying effects triggered by TrxR inhibition is crucial for the understanding of therapy outcomes after use of such inhibitors.

Graphical Abstract

The mammalian thioredoxin system is driven by thioredoxin reductases (TXNRD, TrxR), which keeps thioredoxins (TXN, Trx) and further downstream targets reduced. In normal cells, inhibition of TrxR yields a paradoxical effect of increased antioxidant defense upon activation of the Nrf2 transcription factor. In cancer cells, however, inhibition of TrxR yields excessive reactive oxygen species (ROS) levels resulting in cell death and thus anticancer efficacy, which can be explained by a non-oncogene addiction of cancer cells to TrxR1 due to their increased endogenous production of ROS. These separate consequences of TrxR inhibition can be utilized therapeutically.

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Acknowledgments

The author wishes to thank his many talented group members and collaborators. Funding from Karolinska Institutet, the Swedish Cancer Society, the Swedish Research Council, the Hungarian National Institute of Oncology, the Hungarian Ministry of Human Capacities, and the Knut and Alice Wallenberg Foundations is also thankfully acknowledged.

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Authors and Affiliations

  1. Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden

    Elias S. J. Arnér

  2. Department of Selenoprotein Research, National Institute of Oncology, Budapest, Hungary

    Elias S. J. Arnér

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  1. Elias S. J. Arnér
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Correspondence to Elias S. J. Arnér .

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  1. Department of Pharmacology and Personalised Medicine, Maastricht University, Maastricht, The Netherlands

    Harald H. H. W. Schmidt

  2. Brighton and Sussex Medical School, Brighton, UK

    Pietro Ghezzi

  3. Department of Biochemistry, Faculty of Medicine, Autonomous University of Madrid, Madrid, Spain

    Antonio Cuadrado

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Arnér, E.S.J. (2020). Effects of Mammalian Thioredoxin Reductase Inhibitors. In: Schmidt, H.H.H.W., Ghezzi, P., Cuadrado, A. (eds) Reactive Oxygen Species . Handbook of Experimental Pharmacology, vol 264. Springer, Cham. https://doi.org/10.1007/164_2020_393

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