Thioredoxin reductase: An emerging pharmacologic target for radiosensitization of cancer

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Highlights

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Thioredoxin reductase (TrxR), a seleno enzyme, regulates cellular redox.
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Several human cancers are known to overexpress TrxR.
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Inhibitors of TrxR have enhanced radiation induced cytotoxicity in multiple cancers.
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TrxR could be a potential target during radiotherapy of cancer patients.

Abstract

Novel agents are required to increase the radiosensitivity of cancer and improve the outcome of radiotherapy. Thioredoxin (Trx) and thioredoxin reductase (TrxR) reduce the oxidized cysteine thiols in several proteins, which regulate cellular redox, survival, proliferation, DNA synthesis, transcription factor activity and apoptosis. TrxR is essential for maintaining a conducive redox state for tumor growth, survival and resistance to therapy. Therefore, it is an appealing pharmacological target for the radiosensitization of tumors. Ionizing radiation (IR) is known to cause cytotoxicity through ROS, oxidative stress and DNA damage. Inhibition of thioredoxin system augments IR induced oxidative stress and potentiates cytotoxic effects. However, TrxR also regulates several critical cellular processes in normal cells. Here, we highlight the pre-clinical research and pharmacological studies to surmise possible utility of different TrxR inhibitors for radiosensitization. This review provides a succinct perspective on the role of TrxR inhibitors during the radiotherapy of cancer.

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Most cited references 47

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The tumour microenvironment after radiotherapy: mechanisms of resistance and recurrence.

Holly Barker, James T-E H Paget, Aadil A Khan … (2015)

Radiotherapy plays a central part in curing cancer. For decades, most research on improving treatment outcomes has focused on modulating radiation-induced biological effects on cancer cells. Recently, we have better understood that components within the tumour microenvironment have pivotal roles in determining treatment outcomes. In this Review, we describe vascular, stromal and immunological changes that are induced in the tumour microenvironment by irradiation and discuss how these changes may promote radioresistance and tumour recurrence. We also highlight how this knowledge is guiding the development of new treatment paradigms in which biologically targeted agents will be combined with radiotherapy.

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Cancer Radiosensitizers.

Hua HE, Xiao-Dong Zhang, Hao Wang … (2018)

Radiotherapy (RT) is a mainstay treatment for many types of cancer, although it is still a large challenge to enhance radiation damage to tumor tissue and reduce side effects to healthy tissue. Radiosensitizers are promising agents that enhance injury to tumor tissue by accelerating DNA damage and producing free radicals. Several strategies have been exploited to develop highly effective and low-toxicity radiosensitizers. In this review, we highlight recent progress on radiosensitizers, including small molecules, macromolecules, and nanomaterials. First, small molecules are reviewed based on free radicals, pseudosubstrates, and other mechanisms. Second, nanomaterials, such as nanometallic materials, especially gold-based materials that have flexible surface engineering and favorable kinetic properties, have emerged as promising radiosensitizers. Finally, emerging macromolecules have shown significant advantages in RT because these molecules can be combined with biological therapy as well as drug delivery. Further research on the mechanisms of radioresistance and multidisciplinary approaches will accelerate the development of radiosensitizers.

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Thioredoxins, glutaredoxins, and peroxiredoxins--molecular mechanisms and health significance: from cofactors to antioxidants to redox signaling.

Christopher H. Lillig, J Godoy-Navajas, Christoph Hudemann … (2013)

Thioredoxins (Trxs), glutaredoxins (Grxs), and peroxiredoxins (Prxs) have been characterized as electron donors, guards of the intracellular redox state, and "antioxidants". Today, these redox catalysts are increasingly recognized for their specific role in redox signaling. The number of publications published on the functions of these proteins continues to increase exponentially. The field is experiencing an exciting transformation, from looking at a general redox homeostasis and the pathological oxidative stress model to realizing redox changes as a part of localized, rapid, specific, and reversible redox-regulated signaling events. This review summarizes the almost 50 years of research on these proteins, focusing primarily on data from vertebrates and mammals. The role of Trx fold proteins in redox signaling is discussed by looking at reaction mechanisms, reversible oxidative post-translational modifications of proteins, and characterized interaction partners. On the basis of this analysis, the specific regulatory functions are exemplified for the cellular processes of apoptosis, proliferation, and iron metabolism. The importance of Trxs, Grxs, and Prxs for human health is addressed in the second part of this review, that is, their potential impact and functions in different cell types, tissues, and various pathological conditions.

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Author and article information

Contributors

Deepak Sharma

Santosh K. Sandur

Journal

Journal ID (nlm-ta): Transl Oncol

Journal ID (iso-abbrev): Transl Oncol

Title: Translational Oncology

Publisher: Neoplasia Press

ISSN (Electronic): 1936-5233

Publication date PMC-release: 23 January 2022

Publication date Collection: March 2022

Publication date (Electronic): 23 January 2022

Volume: 17

Electronic Location Identifier: 101341

Affiliations

[a ]Radiation Biology and Health Sciences Division, Bio-Science Group, Bhabha Atomic Research Centre, Trombay, Mumbai 400085, India

[b ]Homi Bhabha National Institute, Anushaktinagar, Mumbai 400094, India

Author notes

[* ]Corresponding authors at: Radiation Biology and Health Sciences Division, Bio-Science Group, Bhabha Atomic Research Centre, Trombay, Mumbai 400085, India. dsharma@ 123456barc.gov.in sskumar@ 123456barc.gov.in

Article

Publisher Item ID: S1936-5233(22)00003-1 Publisher ID: 101341

DOI: 10.1016/j.tranon.2022.101341

PMC ID: 8790659

PubMed ID: 35078017

SO-VID: fa37f5cd-0247-4064-a6f5-82b8380c7551

License:

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

History

Date received : 5 January 2022

Date accepted : 6 January 2022

Categories

Subject: Review

Keywords: thioredoxin reductase,thioredoxin,redox homeostasis,radiation,aif, apoptosis inducing factor,ape1, apurinic/apyrimidinic endonuclease 1,are, antioxidant response element,ask1, apoptosis signaling kinase,bso, buthionine sulfoximine,con a, concanavalin a,cypd, cyclophilin d,fad, flavine adenine dinucleotide,g.r., glutathione reductase,grx2, glutaredoxin 2,gnp, gold nanoparticle,hif1α, hypoxia inducible factor 1 α,hnscc, head & neck squamous cell carcinoma,iq9, indolequinone 9,ir, ionizing radiation,llc, lewis lung carcinoma,lps, lipopolysaccharide,msr, methionine sulfoxide reductase,mnsod, manganese superoxide dismutase,nadph, nicotinamide adenine dinucleotide phosphate,n.f.-κb, nuclear factor kappa b,nrf2, nuclear factor erythroid 2 related factor 2,nsclc, non-small cell lung cancer,pdi, protein disulfide isomerase,prx, peroxiredoxin,pten, phosphatase and tensin homolog,pma, phorbol-12-myristic acid,peg, polyethylene glycol,ros, reactive oxygen species,ref-1, redox factor 1,rnr, ribonucleotide reductase,sapk, stress activated protein kinase,sec, selenocysteine,slnb, solid lipid nanoparticles of baicalein,trx, thioredoxin,trxr, thioredoxin reductase,tnf, tumor necrosis factor

Data availability:

Keywords: thioredoxin reductase, thioredoxin, redox homeostasis, radiation, aif, apoptosis inducing factor, ape1, apurinic/apyrimidinic endonuclease 1, are, antioxidant response element, ask1, apoptosis signaling kinase, bso, buthionine sulfoximine, con a, concanavalin a, cypd, cyclophilin d, fad, flavine adenine dinucleotide, g.r., glutathione reductase, grx2, glutaredoxin 2, gnp, gold nanoparticle, hif1α, hypoxia inducible factor 1 α, hnscc, head & neck squamous cell carcinoma, iq9, indolequinone 9, ir, ionizing radiation, llc, lewis lung carcinoma, lps, lipopolysaccharide, msr, methionine sulfoxide reductase, mnsod, manganese superoxide dismutase, nadph, nicotinamide adenine dinucleotide phosphate, n.f.-κb, nuclear factor kappa b, nrf2, nuclear factor erythroid 2 related factor 2, nsclc, non-small cell lung cancer, pdi, protein disulfide isomerase, prx, peroxiredoxin, pten, phosphatase and tensin homolog, pma, phorbol-12-myristic acid, peg, polyethylene glycol, ros, reactive oxygen species, ref-1, redox factor 1, rnr, ribonucleotide reductase, sapk, stress activated protein kinase, sec, selenocysteine, slnb, solid lipid nanoparticles of baicalein, trx, thioredoxin, trxr, thioredoxin reductase, tnf, tumor necrosis factor

Thioredoxin reductase: An emerging pharmacologic target for radiosensitization of cancer

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Abstract

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Cancer Metabolism

Most cited references 47

The tumour microenvironment after radiotherapy: mechanisms of resistance and recurrence.

Cancer Radiosensitizers.

Thioredoxins, glutaredoxins, and peroxiredoxins--molecular mechanisms and health significance: from cofactors to antioxidants to redox signaling.

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