Elsevier

Pharmacological Research

Volume 174, December 2021, 105854
Pharmacological Research

Review
Thioredoxin reductase as a pharmacological target

https://doi.org/10.1016/j.phrs.2021.105854Get rights and content

Highlights

  • Thioredoxin Reductases (TrxRs) play roles in physiological and pathological conditions.

  • TrxRs are increasingly recognized as one of the most critical clinical targets.

  • TrxRs inhibition has great relevance in pharmacology.

  • TrxRs inhibition by metal ions and chemicals is discussed.

Abstract

Thioredoxin reductases (TrxRs) belong to the pyridine nucleotide disulfide oxidoreductase family enzymes that reduce thioredoxin (Trx). The couple TrxR and Trx is one of the major antioxidant systems that control the redox homeostasis in cells. The thioredoxin system, comprised of TrxR, Trx and NADPH, exerts its activities via a disulfide-dithiol exchange reaction. Inhibition of TrxR is an important clinical goal in all conditions in which the redox state is perturbed. The present review focuses on the most critical aspects of the cellular functions of TrxRs and their inhibition mechanisms by metal ions or chemicals, through direct targeting of TrxRs or their substrates or protein interactors. To update the involvement of overactivation/dysfunction of TrxRs in various pathological conditions, human diseases associated with TrxRs genes were critically summarized by publicly available genome-wide association study (GWAS) catalogs and literature. The pieces of evidence presented here justify why TrxR is recognized as one of the most critical clinical targets and the growing current interest in developing molecules capable of interfering with the functions of TrxR enzymes.

Introduction

The cytosolic and mitochondrial thioredoxin reductase (TrxR) and thioredoxins (Trx1 and Trx2) are critical components of the mammalian thioredoxin system [1]. Trx and TrxR provide a coupled redox system required for redox reactions in biosynthetic pathways involved in controlling redox homeostasis in cells [2], [3].

TrxRs are FAD-containing pyridine nucleotide disulfide oxidoreductases that utilize NADPH for reduction of active-site disulfide of Trxs. TrxR is necessary to all biochemical pathways in which Trx is involved as a reducing substrate [4].

Crucial redox-sensitive biological processes, including cell survival, growth, migration, and inhibition of apoptosis is mediated by thioredoxin system. However, the overexpression of TrxR and Trxs, as a defense response against oxidative stress, are also associated to several type of cancers through an unknown mechanism [4]. Moreover, TrxR plays also an important role in diverse physiological and pathological conditions such as parasitoses, chronic inflammatory, autoimmune diseases, and neurodegenerative disorders [5], [6], [7], [8], [9], [10], [11], [12], [13].

Rapid proliferation of cancer cells requires high metabolic activity, including increased glycolysis and other metabolic reactions [14]. Due to this increased metabolic rate, cancer cells, particularly those in advanced stages, are subject to high oxidative stress caused by abundant reactive oxygen species (ROS) production, which are considered to originate mainly from the electronic leakage of mitochondrial respiratory complexes [14], [15], [16].

Trx, a redox active protein, can be oxidized by ROS, which leads to the formation of a disulfide bridge (vide infra). The reduction by TrxR re-activates Trx providing a circuit for sequential turnover in multiple oxidation/reduction cycles [2], [17]. In its reduced form, Trx inhibits apoptosis signal-regulating kinase 1 (ASK1) and the downstream mitogen-activated protein kinase p38 (p38-MAPK). Upon accumulating ROS, Trx is oxidized, and ASK1 is activated, leading to apoptotic cell death [18], [19]. In several cancer cells, over-expression of Trx increases the capacity for ROS, which leads to increased drug resistance and promotes tumor progression [20]. Therefore, several small molecules targeting the Trx-TrxR system have been developed to preferentially induce cell death in malignant cells due to the increased dependence of these cells on the anti-oxidative activity of the Trx-TrxR system [21], [22].

Recently published reviews are mainly focused on the overactivation/dysfunction of TrxRs linked to the onset and development of cancer. These researchers also indicated that a number of effective natural and synthetic inhibitors of mammalian TrxRs could be used as potential anticancer agents [5], [23], [24], [25], [26], [27], [28], [29].

This review focuses on the most critical aspects of the cellular functions of TrxRs and their inhibition mechanisms through direct targeting to them or their substrates or protein interactors by metal ions or other chemicals. To update the involvement of overactivation/dysfunction of TrxRs in various pathological conditions, human diseases associated with TrxRs genes were critically summarized by publicly available genome-wide association study (GWAS) catalogs and literature. The evidence presented here justifies why TrxR is increasingly recognized as one of the most critical clinical targets, as well as the growing interest in developing molecules capable of interfering with the functions of TrxR enzymes.

Section snippets

Cellular functions of thioredoxin reductase (TrxRs) and thioredoxins (Trxs)

TrxR is a selenoprotein with three isozymes (TrxR1, TrxR2, and TrxR3, Table 1), vulnerable to low dietary selenium (Se) intakes, though less so than glutathione peroxidase-1 (Gpx-1), another crucial antioxidant enzyme in humans [30], [31], [32], [33], [34]. TrxR activity in the liver, kidneys, and lungs is decreased by Se deficiency and enhanced by high Se intake, while the activity of the enzyme in animal brains is much less affected by low Se intake because its concentrations in the brain are

Functions of reduced thioredoxin

Reduced Trx (which is regenerated by TrxR) has several different important roles [68]. It functions as one of the two alternatives reducing substrates for ribonucleotide reductase and is therefore important for DNA synthesis and repair [69]. Reduced glutaredoxin, which depends on GSH as a reducing cofactor for regeneration, is used by ribonucleotide reductase as a secondary alternative reducing substrate [70]. Therefore, it is especially unfavorable if both of the two parallel electron

Thioredoxin reductase inhibition by metals

TrxR is very sensitive to inhibition by several metals including gold, palladium, and platinum, as well as by silver, zinc, mercury, cadmium and gadolinium (Fig. 3) [86], [87], [88], [89], [90], [91].

While TrxR strongly binds particularly toxic metals, its substrate Trx is also a heavy metal-binding protein. This probably means that the substrate can help protect the enzyme itself from inhibition by the metal ion, when the total concentration of the latter is substantially lower than the

Thioredoxin reductase inhibition by other chemicals

A series of other chemicals can form covalent adducts to selenocysteine and cysteine residues of TrxR and Trx causing irreversible effects on their activity [145].

4-Hydroxynonenal and acrolein are formed as secondary products of peroxidation of polyunsaturated fatty acids. The peroxidation rate in vivo depends on the ratio of polyunsaturated to monounsaturated fatty acids in the diet [146], with dietary stearic acid having a similar but not equally strong effect as dietary linoleic acid because

TrxR protein interactors

TrxR may regulate signaling and metabolic pathways though its interaction with proteins, receptors and enzymes respectively. From this perspective, all the interactors of TrxR1, TrxR2 and TrxR3 deposited in the publicly available bioGRID protein-protein interaction (PPI) database (https://thebiogrid.org) [178] and reported in the literature were mined and presented in the Table 2. Interestingly, according to the recent reported human heavy metal proteome [179], 25% of the interactors of TrxR1

Association of thioredoxin reductase 1, 2, and 3 genes with human diseases

There are many reported associations between the TrxR genes and their variants with human diseases in GWAS (Genome-Wide Association Studies) catalogs and literature. TrxR1 (TXNRD1) gene is associated with nervous system diseases, including epilepsy [187], aura [188], cryptogenic and awakening epilepsy [187]), neoplasms (adenoma [189], mesothelioma [190], pancreatic cancer [191], trabecular, papillary, monomorphic, microcystic, basal cell and follicular thyroid adenomas [189]), skin and

Conclusion

The present review aims to carry out a critical reappraisal of the literature on the rationale of targeting TrxR for pharmaceutical purposes. TrxR is necessary to all biochemical pathways in which Trx is involved as a reducing substrate; those have been suggested to play roles in such diverse physiological and pathological conditions. There are two redox sites of TrxR: the first is constituted by the FAD and a couple of Cys residues that receives electrons from NADPH, and the second in the

CRediT authorship contribution statement

Geir Bjørklund: Conceptualization, Writing – original draft, Data curation, Visualization, Investigation, Writing – review & editing, Supervision, Project administration. Lili Zou: Data curation, Visualization, Investigation, Writing – review & editing Jun Wang: Data curation, Visualization, Investigation, Writing – review & editing. Christos T. Chasapis: Data curation, Visualization, Investigation, Writing – review & editing. Massimiliano Peana: Conceptualization, Writing – original draft,

Author contributions

All authors confirmed they have contributed to the intellectual content of this paper and have met the following three requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; and (c) final approval of the published article.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

LZ and JW thank the National Natural Science Foundation of China (32170191) for the financial support.

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