Thioredoxin Reductase 1 as an Anticancer Drug Target
Several genetic, biochemical and pharmacological studies suggest that the cytosolic selenoprotein thioredoxin reductase 1 (TrxR1, TXNRD1) can serve as a promising anticancer drug target. This notion is in part based upon potent and selective targeting of
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Thioredoxin Reductase 1 as an Anticancer Drug Target Edward E. Schmidt and Elias S.J. Arnér
Abstract Several genetic, biochemical and pharmacological studies suggest that the cytosolic selenoprotein thioredoxin reductase 1 (TrxR1, TXNRD1) can serve as a promising anticancer drug target. This notion is in part based upon potent and selective targeting of the selenocysteine residue in TrxR1 by electrophilic anticancer agents. Whereas normal somatic cells typically can survive without TrxR1, the metabolic and proliferative realignments associated with cancer increase the oxidative stress and thus an increased reliance upon reducing pathways in cancer cells, thereby increasing their dependence upon TrxR1 activity. Intricate functional links between TrxR1 and transcription factors such as Nrf2, NF-kB and p53, and interaction with other growth-promoting signaling pathways, further underpin anticancer therapies involving TrxR1 targeting. However, caveats exist, as some effects of TrxR1 inhibition may promote cancer rather than counteract its progression. Although encouraging advances are being made, the field is clearly not yet ready for clinical trials evaluating novel specific TrxR1 inhibitors in anticancer treatments. In this chapter we present and discuss the major aspects of this topic. Keywords Cancer • Therapy • Thioredoxin reductase
16.1
Introduction
The thioredoxin (Trx) system is an important reductive enzyme system that acts in conjunction with enzymes of the glutathione (GSH) system [1–4]. The Trx system involves isoenzymes of Trx and thioredoxin reductase (TrxR), the latter using E.E. Schmidt Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 77 Stockholm, Sweden Microbiology and Immunology, Montana State University, Bozeman, MT 59715, USA e-mail: [email protected] E.S.J. Arnér (*) Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 77 Stockholm, Sweden e-mail: [email protected] © Springer Science+Business Media, LLC 2016 D.L. Hatfield et al. (eds.), Selenium, DOI 10.1007/978-3-319-41283-2_16
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NADPH to reduce the active site disulfide of Trxs, which subsequently act upon a wide range of downstream targets that are required for reductive pathways and regulate cellular function. In mammals, the Trx system is selenium-dependent due to the fact that the three mammalian TrxR isoenzymes are among the approximately 25 selenoproteins that exist in mammals. The reader is referred to other literature for detailed information on the wide physiological roles and biochemical features of the enzymes that constitute the Trx system [1, 2, 4–7]. Here we shall instead focus upon the role of this system in cancer and the potential therapeutic effects of inhibiting the cytosolic TrxR1 enzyme for anticancer therapy.
16.2
The Multiple Roles of the Thioredoxin System in Cancer
Many studies have indicated that the Trx system should be considered an important player in carcinogenesis
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