Targeting the thioredoxin system as a strategy for cancer therapy

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Targeting the thioredoxin system as a strategy for cancer therapy Mianli Bian, Rong Fan, Sai Zhao, and Wukun Liu J. Med. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jmedchem.8b01595 • Publication Date (Web): 09 Apr 2019 Downloaded from http://pubs.acs.org on April 9, 2019

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Title Targeting the thioredoxin system as a strategy for cancer therapy

Authors and affiliations Mianli Bian1, Rong Fan1, Sai Zhao1, 3 and Wukun Liu1, 2* 1 Institute of Chinese Medicine, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, P.R. China 2 State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, P.R. China 3 Institute of New Medicine Research, Nanjing Hicin Pharmaceutical Co. Ltd., Nanjing 210046, P.R. China

ABSTRACT

Thioredoxin reductase (TrxR) participates in the regulation of redox reactions in organisms. It works mainly via its substrate molecule, thioredoxin, to maintain the redox balance and regulate signal transduction, which controls cell proliferation, differentiation, death and other important physiological processes. In recent years, increasing evidence has shown that the overactivation of TrxR is related to the development of tumors. The exploration of TrxR-targeted anti-tumor drugs has attracted wide attention and is expected to provide new therapies for cancer treatment. In this perspective, we highlight the specific relationship between TrxR and apoptotic


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signaling pathways. The cytoplasm and mitochondria both contain TrxR, resulting in the activation of apoptosis. TrxR activity influences ROS and further regulates the inflammatory signaling pathway. In addition, we discuss representative TrxR inhibitors with anticancer activity and analyze the challenges in developing TrxR inhibitors as anticancer drugs.

Keywords: Thioredoxin reductase; Apoptosis signal; Reactive oxygen species; Protein target; Thioredoxin reductase inhibitors

1. INTRODUCTION

The thioredoxin system, including thioredoxin (Trx), thioredoxin reductase (TrxR) and NADPH, catalyzes a series of physiological and biochemical reactions in organisms and participates in many physiological processes.1 Its main function is to regulate the redox balance, which is closely related to cell proliferation, apoptosis, tumor genesis, metastasis and angiogenesis.2 TrxR, the only known enzyme that reduces the oxidation state of Trx, transmits electrons from NADPH to active site disulfide, and then transmits them to oxidized Trx,3-4 thus playing a significant role in both redox regulation and antioxidant defense (Fig.1).5-7 TrxR indirectly scavenges free radicals and maintains cellular function by reducing the levels of other free radical scavengers.2 As an electron carrier, TrxR is essential for the catalytic cycles of biosynthetic enzymes. It protects cytoplasmic proteins from oxidation, allowing them



to form disulfides and also inhibits its own activity, which can induce apoptosis in tumor cells.8 The rapid growth, diffusion and metastasis of tumor cells are related to an imbalance inapoptosis.9 Therefore, the effective intervention of the apoptotic process may be an important strategy in tumor therapy.10-12 Since the early twenty-first century, TrxR has been widely studied as a potential target for cancer treatment. Many inhibitors have thus been developed based on the various possible mechanisms of TrxR, such as the interaction between selenocysteine and TrxR.13 Other compounds target selenocysteine-containing TrxR active sites,14 including gold compounds, platinum compounds and various natural compounds.15-17 The promising role of TrxR inhibitors in cancer therapy is also discussed in this perspective.

2. TRXR AND THE REGULATION OF APOPTOSIS SIGNALING

2.1. Apoptosis Induced by the Mitochondrial Pathway

The mitochondrial pathway induces apoptosis by adjusting the inhibition of Trx/TrxR.18 Apoptosis signaling kinase 1 (ASK1), a mitogen-activated protein kinase (MAPK), is a crucial transmitter from the cell surface to the inner cell nucleus, responsible for the activation of JNK and p38 MAPK pathways.19,20 Members of the Bcl-2 protein family, which includes Bax proteins that promote apoptosis and Bcl-2 proteins that resist apoptosis, have no fungible action in mitochondrial release-related


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proteins.21 Bax proteins promote the release of cytochrome c into the cytoplasm, where it forms a cytochrome c/Apaf-1/caspase-9 apoptotic complex and activates caspase-3.22 Caspases are cysteine proteases that rely on the presence of thiolate in their active sites.23 Interestingly, metal complexes can bind to the TrxR C-terminal Cys-Sec redox-active center and inhibit its activity, thereby promoting the accumulation of reactive oxygen species (ROS), destroying redox homeostasis, altering the permeability of the mitochondrial membrane, stimulating cytochrome c release and ultimately inducing apoptosis of the tumor cell (Fig.2).24-26 In summary, targeting TrxR inhibition could boost cancer cell apoptosis. Moreover, the most important role of redox regulation is to inhibit the production of ROS by mitochondrial respiration.18,27 The physiological role of ROS is mediated by signal transduction and oxidative stress, which promote cell death through the apoptotic pathway.28 TrxR inhibits apoptosis by inducing Trx, which stimulates downstream pathways.29 Trx inhibits apoptosis by inhibiting ASK1, which is mediated through the p38 and JNK pathways, eventually leading to apoptosis (Fig. 2).20 The reduced form of Trx binds to the N-terminal end of ASK1, inhibiting the function of ASK1 as a signal transfer factor and inducing ASK1 degradation.30 Once the Trx bound to ASK1 is oxidized, it dissociates from ASK1, giving rise to downstream ASK1 signal activation, cytochrome c release and the activation of the cysteine-containing aspartate protein hydrolase caspase-3, ultimately leading to apoptosis.31



2.2. TrxR and the Endoplasmic Reticulum Stress (ERS) Pathway

As a mechanism of apoptosis, ERS plays an important regulatory role in the TrxR system. Protein substrate reduction by TrxR leads to the formation of a disulfide bond between two conserved cysteine residues.32 By altering the formation of protein disulfide bonds, TrxR activity affects protein folding and conformational changes.33 An increase in ROS can disturb intracellular redox homeostasis and render the continuous accumulation of unfolded proteins in the endoplasmic reticulum (ER).34 To maintain this balanced state, the ERS response is subsequently triggered.35 The ERS response is executed by the activation of the following three transmembrane ER sensors: PERK (pancreatic endoplasmic reticulum kinase), IRE1 (inositol requiring enzyme 1) and ATF6 (activating transcription factor 6) (Fig. 3).36 Among these three sensors, IRE1 has the shortest duration of action and its activation occurs late in the ERS response, demonstrating the sensitivity of its regulation.37 In addition, IRE1 is expressed as a monomer on the ER and has both protein kinase and RNA endonuclease activities.38 When the ER is stimulated by pressure, dimerization takes place upon autophosphorylation, followed by the activation of the corresponding nuclease activity. The downstream substrate is cleaved and transformed into an active transcription factor that enters the nucleus and activates downstream transcription factors to relieve ER pressure.37,39 Moreover, ERS-mediated apoptosis is mainly associated with the induction of the high-level expression of CHOP (C/EBP homologous protein), a downstream transcriptional coactivator that is a key player in


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ERS-mediated apoptosis.40 TrxR directly affects the level of ROS and further activates the ERS pathway. The ERS is a cytosolic target, which is an interesting proapoptotic pathway of anticancer agents.35 Studies have also demonstrated that TrxR induced ERS-related signaling to bypass tumor resistance.33 The inhibition of TrxR by auranofin, a gold-containing drug, clinically triggered severe ERS.41 In addition, the death-inducing capacity of anticancer drugs was affiliated with ROS generation as well as their capacity to elicit ERS. ROS and ERS simultaneously stimulated different damage-associated molecular patterns and ultimately lead to cancer cell death though different mechanisms.34 SK053 induced ERS activation in Raji cells and further led to cell apoptosis.42 The treatment of tumor cells with SK053 induced the expression of high levels of CHOP, and an increase in spliced XBP-1 levels preceded the induction of apoptosis. Moreover, CHOP-deficient mouse embryonic fibroblasts were more resistant to SK053-induced apoptosis than normal fibroblasts, suggesting that tumor cell apoptosis relies on the expression of transcription factors.42 Altogether, these results indicated that ERS-associated apoptosis depends on the link between TrxR inhibition and the induction of ERS in tumor cells.

2.3. TrxR Directly Acts on the Death Receptor Pathway

TrxR is a key molecule involved in the intracellular regulation of oxidative stress signaling. TrxR downregulates the activity of NFκB and activated protein 1, which



are sensitive to oxidative stress and inflammation. It regulates mitogen-activated kinase, ASK1 and the transduction of the apoptotic signaling pathway. It also inhibits the expression of inflammatory factors and reduces inflammatory responsiveness.43-46 Following injury, both endogenous TrxR and exogenous recombinant human TrxR expressed antioxidant activity and scavenged oxygen free radicals. They reduced the level of malondialdehyde in tissues, increased the activity of superoxide dismutase, alleviated tissue and organ damage, and improved tissue ischemia, microcirculation disorder, and edema.47 TrxR can bind to binding sites, where it reduces residues and modulates the activity of different transcription factors.48 The expression of many stress-related genes including some genes involved in the regulation of apoptosis is regulated by TrxR.10 For example, TrxR regulated the expression of caspase family members, all of which have apoptotic effects.49 Therefore, the regulation of TrxR binding activity can also regulate the apoptotic pathway. TrxR binding inhibitors not only led to the loss of function but also changed the regulation of intracellular transcription, including a reduction in anti-apoptotic protein expression.50 Another method of TrxR regulation is its control of the expression of apoptotic precursor genes.51 The effect of this pre-apoptotic precursor is directly opposite to that of tumor cells, which use the anti-apoptotic, function inactivated gene.50, 52

3. TRXR AND THE GENERATION OF ROS


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ROS are normal products of cellular metabolism and play an important role in many cellular biological functions.53 Due to metabolic abnormalities, the activation of a carcinogen and mitochondrial dysfunction, the excessive production of ROS in cancer cells leads to severe oxidative damage and eventually the death of the tumor cells.54 TrxR, a vital ROS scavenger enzyme, plays a critical role in many human tumors.55 TrxR regulates the intracellular redox balance to protect cancer cells from the damage caused by large numbers of ROS.54 As a result, TrxR is a promising target for the development of anticancer drugs. Exposure to a high concentration of oxygen produces excessive oxygen free radicals that directly damage cells.56 Recently, ROS detection further confirmed the time-dependent increase in the generation of ROS induced by hyperoxia.57 The cell employs an antioxidant system to scavenge intracellular ROS (Fig.4). However, excessive ROS induces the formation of disulfide bonds in proteins, causing stubborn oxidative stress disorders.58 The regulation of the cellular redox balance relies on the activity of the antioxidant system, with TrxR being a member of these important antioxidant systems.59,60 ROS, the common products of cell metabolism, are oxygen-containing chemically reactive molecules that include hydrogen peroxide (H2O2) and superoxide.61 Under physiological conditions, cells maintain redox homeostasis. The balance of ROS is regulated by the ROS system, the TrxR system, superoxide dismutase (SOD) and catalase.62-64 ROS are essential in many cell functions, e.g., signal transduction, cell proliferation and differentiation, the regulation of the activity of enzymes such as ribonucleotide reductase, mediation of the inflammatory



stimulation of cytokines and the killing of external pathogens.62 In the event of metabolic abnormalities, carcinogenic signal stimulation, mitochondrial dysfunction and the loss of functional p53, various cancer cells show a rise in the levels of ROS.65 An increasing number of reports have shown that ROS play complex and controversial roles.60 On the one hand, a slight increase in ROS may promote tumor progression in tumor cells by regulating the mutation of genomic DNA or inducing the activation of the cancer signaling pathway.66 On the other hand, the production of ROS may produce serious oxidative damage in key cell components such as proteins and lipids.67 To counteract excessive ROS and escape ROS-induced cell death, malignant tumor cells produce high levels of reactive oxygen scavenging enzymes. This enhances their antioxidant capacity and becomes an important mechanism for regulating the levels of ROS, avoiding serious oxidative damage to tumor cells, and allowing their survival in the face of oxidative stress.68 Therefore, the survival of cancer cells depends on the antioxidant system. The design of specific inhibitors of antioxidant enzymes in tumor cells that promote the accumulation of ROS is a promising anticancer strategy to selectively promote cytotoxicity that results in cancer cell death.69,70 TrxR has a wide substrate specificity. In addition to Trx, it can also reduce antioxidants, such as ascorbic acid and protein disulfide bond isomerase.52 The inhibition of the Trx/TrxR system caused redox imbalance and cell death or apoptosis.10 Therefore, an increase in the expression of Trx/TrxR in tumor cells would increase their antioxidant capacity, allowing them to resist oxidative stress damage


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and promoting cell survival.

4. TRXR AND THE MECHANISM OF INFLAMMATION

Under oxidative stress, the expression of TrxR protects tissues and cells from oxidative damage induced by oxidative stress.55 TrxR plays a critical role in inflammatory diseases that mainly depends on its expression at a high level in inflammatory tissues and its antioxidant and anti-apoptotic activity. TrxR influences the activity of chemotactic factors and regulates gene expression and protein nitro-nitrosation.71

4.1. TrxR Acts on Inflammatory Factors and Cytokines

NFκB is a transcription factor sensitive to the redox state of the body.72 It is composed of two subunits, p50 and p65, that can adjust the transcriptional activity of genes involved in immunization, inflammation and apoptosis.73 TrxR plays an important role in of the binding of NFκB and DNA.74 When NFκB is located in the cytoplasm, the inhibitory factor IκB binds and prevents NFκB from entering the nucleus, leading to the failure of NFκB to enter the nucleus and work.75 However, NFκB mainly plays a role in the nucleus, TrxR can restore the binding site of NFκB to DNA and help NFκB combine with DNA. Studies have also shown that TrxR promotes the binding of NFκB to DNA and inhibits cell apoptosis.76 TrxR can



induce the expression of various stimuli, especially oxidative stress, suggesting that TrxR is an important molecule in oxidative stress that ultimately leads to inflammation.77 Antioxidant stress and the expression of high levels of TrxR at the site of inflammatory lesions may be a compensatory response to oxidative stress.78 As the main intracellular transmitter of redox potential, the upregulation of TrxR protects cells from the damage from a variety of ROS, such as H2O2. TrxR is chemotactic to monocytes, polymorphonuclear leukocytes and T lymphocytes, and a change in selenium binding to the C-terminal domain of TrxR, which is the specific binding domain, can lead to the loss of chemotaxis.79 As a special chemokine, TrxR is secreted from cells and can induce other cells to secrete TNF-α, interleukin-1, interleukin-8.80 Locally-secreted TrxR has an inflammatory amplifying effect by attracting white blood cells and inducing cytokine expression, and when the overall level of TrxR increases, it also relieves local inflammation and inhibits leukocyte chemotaxis.81 In different stages of inflammation, TrxR carries out different functions.

4.2. Antioxidation Inhibits Inflammation

The occurrence of acute and chronic inflammatory diseases is accompanied by oxidative stress, which can produce many reactive nitrogen species and ROS or cause oxidative damage to tissues due to a decrease in the endogenous antioxidant capacity of the body.77 ROS attack lipid-rich cell membranes, causing lipid peroxidation, small


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molecule products and free radicals produced by malondialdehyde, causing a variety of cell dysfunctions, cell death, and apoptosis, which are related to a variety of inflammatory diseases.82 The antioxidant effect of TrxR is carried out by either direct oxidation or the scavenging of active oxygen species that act as electron donors for peroxidases, which reduces lipid peroxidation, DNA damage and protein inactivation.83 Under oxidative stress, cells maintain their physiological function by upregulating the expression of TrxR. TrxR is induced by oxidizing agents which illustrates the connection between oxidative stress and inflammation.84 TrxR produces many reactive nitrogen and reactive oxygen species, or endogenous antioxidants of the body.85 A decrease in the defense system causes oxidative damage to tissues. Large doses of ROS can damage DNA, protein and the lipid component of biological macromolecules.66,86,87

5. TRXR AND ITS PROTEIN TARGETS

TrxR is a selenocysteine-containing protein that participates in a wide range of cellular responses. The inhibition of TrxR expression causes cell death.88 Many antioxidative and regulatory roles of cytosolic Trx depend on its cytoplasmic activity, which, together with TrxR, is an increasingly important part of cell redox control and antioxidant defense.89 TrxR can reduce some small molecules and proteins. A recent report also showed that TrxR may help regulate redox balance, the survival of rheumatoid synoviocytes, and celluar responses to different cytotoxic drugs and



protect damaged neurons from oxidative stress.90 TrxR mRNA expression in AEC II was also associated with

exposure to hyperoxia.91 This finding further indicated that

the cytoplasmic Trx system may play a key role in this mechanism. TrxR plays a variety of roles in the cell including the induction of DNA synthesis by ribonucleotide reductase and ROS scavenging through the activity of peroxiredoxins.92,93 The active site Cys of TrxR is located in the FAD domain. NADPH provides electrons to the oxidized Trx disulfide bonds through the isoalloxazine ring of FAD. The C-terminal -Cys-Sec -catalytic site is simultaneously oxidized. When thiol-disulfide exchange occurs, conserved sites are oxidized, the C-terminal -Cys-Sec -site is reduced, and electrons are transferred to the substrate.12 Furthermore, TrxR depressed the transcription factors, involved in the regulation of NF-kB and p53.65 Cytosolic TrxR is expressed at higher levels in carcinomas, and its levels are related to the aggressiveness of the tumor.13 Therefore, there is great interest in TrxR as a potential and attractive target for novel anticancer drugs. However, the seminal work by Arnér et al. indicated that knocking down TrxR had little effect on cell growth, irrespective of concurrent glutathione depletion.94 This is most likely explained by residual TrxR activity that maintained Trx functioning. Diverse chemotherapeutic agents have been produced through inhibiting the expression of TrxR and regulating cytotoxic effects. Mammalian TrxR's and holonomic Trx systems are completely based upon selenium. Increasing selenium levels lead to increased TrxR activity until the selenium levels reached saturation.83 Specific TrxR inhibitors brought about nonessential changes in cell growth, indicating


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that a combined approach is necessary to bypass the inherent redundancy in the Trx system. Targeting antioxidant regulator (TrxR) brings about a greater phenotypic alteration when combined with a network stress inducer. In short, TrxR plays an irreplaceable role in the antioxidant system. It can generate Trx through the NADPH-dependent reduction of the active site disulfide bond (Cys32 and Cys35) present in oxidized Trx. Arambula et al. showed that the robustness of TrxR in cancer makes it a great challenge within the context of network pharmacological drug development.95

6. TRXR AND SUPPRESSION OF TELOMERASE

As a carrier of genetic information, DNA can control the growth and metabolism of organisms through replication and translation, causing changes in cellular behavior and biological function, so DNA is an important target for antitumor drugs and that is closely related to DNA replication (cell proliferation) in tumor cells.96 Telomerase maintains the length of telomeres in DNA. When telomerase is overexpressed, tumor cells proliferate indefinitely.97 Antitumor drugs can be inserted into DNA base pairs, causing DNA helical distortion and elongating the DNA chain, or can bind to DNA or inhibit the activity of DNA topoisomerase, thus exerting their antitumor effects.98 That is, DNA telomeres are the central link of tumor proliferation, in which the cell cycle balance is destroyed.99 The redox system plays a key role in the regulation of multiple cellular processes, such as apoptosis and cell cycle progression.100



Cyclin-dependent protein kinase (CDK) is at the core of cell cycle regulation. Its activity determines whether the cell cycle will be successfully completed.99 TrxR regulates the activation and levels of Trx, and Trx regulates the activity of the transcriptional activator AP-1 by reducing nuclear oxidation-reduction factors to regulate the G1/S transition.101 In addition, TrxR can affect chromosome telomere maintenance and increase the number of cells in G2 /M phase. p53 is an important protein involved in cell cycle regulation. These results indicated that TrxR plays a significant role in inhibiting tumor growth.

7. TRXR INHIBITS HYPOXIA INDUCIBLE FACTOR 1 (HIF1α)

TrxR can stimulate the production of HIF1α, nitric oxide synthase 2, and vascular endothelial growth factor by increasing the protein level of HIF1α in tumor cells, thus promoting tumor angiogenesis. Its active site inhibits the formation of capillary tubules in microvascular endothelial cells and changes the cellular status from morphological differentiation to continuous proliferation, which eventually leads to the formation of an infiltrative monomolecular layer.102,103 In addition, TrxR restores extracellular matrix proteins such as laminin and collagen. The interaction of stromal tumor cells and basement membrane can be an important link in the cancer invasion and metastasis. The combination of cells and collagen through receptors on the cells surface can directly affect their morphology, destroy the tumor microenvironment and finally promote tumor angiogenesis.103 Furthermore, the


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special two disulfide bond structure of TrxR can inhibit the activity of tissue inhibitor of metalloproteinase and promote the activity of matrix metalloproteinase-2 through redox activity. So it plays an important role in promoting tumor invasion and metastasis.104 An adequate blood supply is important to maintain solid tumor growth. Therefore, the growth of tumor requires a large number of new blood vessels to maintain blood transportation.105 The formation of blood vessels involves a complex, multifaceted and well-coordinated network. The Trx system is closely related to this process. Recently, it was shown that after knocking out the mitochondrial TrxR, HIF1α and vascular endothelial growth factor (VEGF) level were reduced, which inhibited tumor growth and tumor-driven angiogenesis and promoted the function of VEGF and angiogenesis.106 In addition, studies have shown that the overexpression of TrxR induced the overexpression of VEGF in human peripheral blood mononuclear cells, thereby promoting vascular growth.

8. TRXR INHIBITORS

Inhibitors targeting the TrxR system have attracted much attention. In the light of description of enzyme structure, the 3D structure of a rat TrxR (Sec→Cys) mutant at a resolution of 3.0 Å was discovered by Schneider et al.11 Many years later, Becker et al. solved the human TrxR structure.12 In a word, the structure of human TrxR is analogous to rat TrxR (GeneBank: AAF32362.1) with 90% identity in


primary


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sequences. The crystal structure of TrxR by Fang and coworkers indicated that the C-terminal redox center (C497/U498) was at the surface of the enzyme. However, the N-terminal redox center (C59/C64) was buried inside, which allows for the selective targeting of the C-terminal redox center by various inhibitors (vide infra).3 In view of the nuique structure of TrxR, a series of inhibitors have been designed over the years, and many review articles have specifically discussed them.3,77,107-110 In addition, the measurement of Trx and TrxR activity has been summarized in detail by Arnér et al.111,112 Here, we only discuss several inhibitors that are regarded as promising

anticancer

drugs.

Representative

inhibitors

are

categorized

as

metal-containing, e.g. gold and platinum complexes, or natural inhibitors, e.g. curcumin and flavonoids.

8.1. Metal-containing TrxR Inhibitors

The cytotoxic effects of various metal complexes that target mammalian TrxR were explored.109 Metal-based anticancer complexes, especially platinum and gold complexes, had a great impact on cancer chemotherapy.113-115 Gold complexes are complexes formed by gold ions with special electronic structures.116 They are very active in redox reactions, interacting with reduced biological macromolecules in cells and then exerting their pharmacological activity. Gold compounds (particularly auranofin and aurothioglucose Fig. 5A) are the most efficacious inhibitors of TrxR enzymes studied to date.117-121


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A major obstacle for the use of gold complexes in the clinic is their severe side effects observed in preclinical studies. They are easy to decompose before they reach the cancerous tissues and have a short half-life. In addition, although the antitumor effects of gold complexes are significant, the exact mechanism of their cytotoxic effects is still not fully understood.117-121 Therefore, modifying the structures of gold complexes to obtain complexes with good efficacy and diminish side effects is an urgent issue that remains to be solved. Within this framework, in the last few years, the TrxR inhibitory properties of a number of gold complexes (Fig. 5A and 5B), both coordination complexes and organometallics and including gold N-heterocyclic carbene (NHC) complexes, have been reported.122,123 The seminal works by Berners-Price et al. have shaped and guided the current understanding of the antitumor properties of gold NHC complexes. Their inhibition of TrxR was reported by Berners-Price and coworkers, which makes gold NHC complexes an interesting direction for anticancer drug design because their mode of action is very different from that of cisplatin.118,122-124 The inhibition of TrxR by the cationic bis-NHC complex was confirmed for the first time in cells. NMR-based experiments on 1Au with cysteine or selenocysteine implied that the mechanism of action included ligand exchange and the formation of [Au(Cys)2]– and [Au(SeCys) 2]– species, respectively. In addition, Ott et al. described a novel series of gold NHC complexes (e.g. 2-5Au, Fig. 5B) containing an NHC ligand derived from benzimidazole showing a strong inhibition of purified TrxR. The inhibition of TrxR by these complexes was



selective when compared to that of the related enzyme glutathione reductase.125-128 A large number of gold(I) NHC complexes were rationally designed by Casini and coworkers as TrxR inhibitors (e.g. 6-7Au, Fig 5B).121,122 For example, gold(I) NHC complex with pyrimidinethiolate 6Au significantly inhibited TrxR, especially the higher activity against cytosolie (TrxR1).129 Gold(I) NHC complexes containing a fluorescent coumarin ligand (e.g. 7Au) inhibited the TrxR selenoenzyme. However, they exhibited poor efficacy towards glutathione reductase and glutathione peroxidase. Interestingly, 7Au also displayed the apparent inhibition of TrxR in cell extracts.130 Cisplatin has been widely used as a chemotherapeutic agent because of its ability to bind to DNA and lead to cell death.

109, 115

This complex has been found to

remarkably inhibit rat and bovine TrxR, and when TrxR was knocked down by siRNA, these complexes were more resistant to cisplatin. 131 Interestingly, researchers also demonstrated strong and selective TrxR inhibition by different kinds of metal complexes such as the platinum complexes 1-5Pt (Fig. 5C) with novel modes of action and improving accumulation in tumor cells. 77,107,108,110 In particular, the special electronic structure of these ions makes them very active in redox reactions and allows them to exert cytotoxic effects.

8.2. Other Natural Molecules and Components

Curcumin is a fat-soluble yellow compound extracted from the roots of the natural turmeric plant. Curcumin increased intracellular oxidative stress levels by


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inhibiting TrxR, thereby inducing ROS production, DNA damage, and loss of TrxR activity, ultimately leading to apoptosis. A series of structurally symmetric and asymmetric curcumin analogues 1-4 have been reported.132-135 Almost all asymmetric curcumin analogs with aromatic or heterocyclic rings were more active than those with of traditional symmetric structures. The β-unsaturated ketone structure was a key functional group, and the introduction of a nitrogen-containing five-membered ring increased its efficiency. Recently, many curcumin derivatives have been developed as a valuable source of therapeutic agents (Fig.6). The activity of TrxR was inhibited by the interaction between the C-terminal redox active site (Cys 497/Sec 498) and curcumin, and the enzyme was converted into a pro-oxidant, that stimulated ROS generation via acquired NADPH oxidase activity. 3,77 Many flavonoids have inhibitory activity against TrxR, and the basic skeletal structure of flavonoids contains three rings with different hydroxyl and hydroxyl -modifying groups. The structure-activity experiments indicated that the hydroxyl group at the third position was necessary for inhibitory activity, and its deletion or modification resulted in the loss of inhibitory activity, but the hydroxyl group at the third position alone was insufficient for the inhibitory activity against TrxR.136 In addition, terpenoid is a representative class of TrxR inhibitors that alkylate TrxR and inhibit its activity. This inhibitory activity exhibits time and concentration-dependent and irreversible properties. Kinetic and spectral data indicated that its chemical mechanism inactivated TrxR.137 At present, only a few natural TrxR inhibitors are in clinical research and most remain in the preliminary research stage.



9. CONCLUSION

TrxR catalyzes the conversion of selenite to selenide, which indirectly inhibits inflammation.71 By removing peroxide, TrxR also inhibits fatty acid oxidation. The activation of enzymes and the production of inflammation by leukotrienes induced the anti-inflammatory response.132 All kinds of stress stimuli, such as hypoxia, viruses, TNFα, nitric oxide, lipopolysaccharides, oxygen, H2O2 and other oxidative stressors, upregulate the expression of TrxR in cells.24 Acute and chronic inflammatory diseases are associated with oxidative stress, which produces many reactive nitrogen and reactive oxygen species, and causes oxidative damage to tissues due to the decrease in the endogenous antioxidant capacity of the body.85 A large dose of ROS can damage DNA, proteins and lipids in biological macromolecules, causing a range of cell functional damage, cell death or apoptosis.138 The change of the active site thiol to an alanine residue led to the loss of chemotaxis. The oxidative/reductive balance of cells is maintained by ROS and antioxidants, which play a synergistic role in inflammation factors and oxidative stress.62 Currently, TrxR inhibitors have gained great deal of and interest as cancer therapeutic agents. However, there are still several challenges for future research in this field. For example, the interaction between TrxR and the other proteins studied is an in-depth question in drug development. This is mainly due to the nature of their interface surfaces and the multiple targets of their traditional binding sites. TrxR is


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frequently overexpressed in tumor cells. Rational design could be used to produce prodrugs that could can be selectively activated by TrxR/Trx.139 The advantage of TrxR/Trx-activating prodrugs is that they would selectively kill cancerous cells with minimal side effects on normal cells. A common question in drug development is how to minimize side effects, maximize the inhibition of tumor cell proliferation and promote the apoptosis of tumor cells. Finally, understanding the function of TrxR inhibitors would ameliorate the safety and efficacy of such treatments. At present, metal complexes and natural compounds that target TrxR are promising anticancer agents with potential for future clinical application. However, there is still a great need for further studies to gain more insight into TrxR inhibitors.

AUTHOR INFORMATION Corresponding Author E-mail address: [email protected], [email protected] Tel: +86-25-85811633 Institute of Chinese Medicine, Nanjing University of Chinese Medicine, 138 Xianlin Road, Nanjing, 210023, China.

Notes The authors declare that they have no conflict of interest. Biographies Mianli Bian received her Bachelor’s and Master’s degrees from Nanjing University of Chinese Medicine in 2015 and 2018, respectively. Currently, she is pursuing her Ph.D. under the supervision of Professor Wukun Liu. Her research mainly focuses on



TrxR-dependent anticancer agents. Rong Fan received her Bachelor’s degree from Jiangsu University in 2017. She is currently a postgraduate student at Nanjing University of Chinese Medicine, under the supervision of Professor Wukun Liu. Her Master’s study mainly focuses on the design, synthesis, and biological evaluation of gold and platinum N-heterocyclic carbine complexes. Sai Zhao obtained his Bachelor’s and Master’s degrees from the School of Pharmacy at China Pharmaceutical University, in 2003 and 2006, respectively. He then received his Ph.D. in medicinal chemistry from Duquesne University in 2014 under the supervision of Professor Aleem Gangjee. Now, he works as a leading research scientist in Nanjing Hicin Pharmaceutical Co. Ltd. His research interests are mainly focused on generic drug studies and lead optimization for some pharmacologically active compounds. Wukun Liu received his Ph. D. from the Free University of Berlin under the guidance of Prof. Ronald Gust in 2012 and conducted postdoctoral studies at the Johns Hopkins University in Prof. Jun O. Liu’s laboratory. He was appointed as a Jiangsu Specially-Appointed Professor of Medicinal Chemistry in 2017 within the Institute of Chinese Medicine at the Nanjing University of Chinese Medicine in China. His current research interests are mainly focused on bioorganometallic and medicinal chemistry.

ACKNOWLEDGEMENTS


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The authors are grateful for the financial support of the National Natural Science Foundation of China (No. 81703337), the Jiangsu Specially-Appointed Professors Program, the Six Talent Peaks Project in the Jiangsu Province of China (No. SWYY-069) and the Open Project of State Key Laboratory of Natural Medicines (No. SKLNMKF201808, SKLNMKF201712).

ABBREVIATIONS USED ASK1, Apoptosis signaling kinase 1; ATF6, activating transcription factor 6; CDKs, Cyclin dependent protein kinase; CHOP, C/EBP homologous protein; ERS, endoplasmic reticulum stress; MAPK, mitogen-activated protein kinase; H2O2, hydrogen peroxide; IRE1, inositol requiring enzyme 1; PERK, pancreatic endoplasmic reticulum kinase; ROS, reactive oxygen species; SOD, superoxide dismutase; TrxR, thioredoxin reductase; VEGF, vascular endothelial growth factor

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Figure legends

Fig. 1 Catalytic cycles and functions of the Trx system. A schematic figure illustrates the many functions of the Trx system in mammalian cells. These diverse functions are likely affected by the regulation of TrxR expression and activity.

Fig. 2 TrxR cellular functions. Some of the most important pathways and substrates regulated by TrxR are shown together with their subcellular localization. Inhibitory interactions are also indicated.

Fig. 3 By inducing ROS levels and oxidative stress. TrxR treatment concomitantly induces the ERS response, which is highlighted by elevated levels of p-eIF2α, ATF4, XBP1 and ATF6, as well as an increase in the levels of the downstream co-activator CHOP. CHOP induction is sensitive to the ERS response, and CHOP is a marker of


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commitment to ERS-induced apoptosis.

Fig. 4 Consequences of TrxR inhibition. The inhibition of TrxR results in increased levels of oxidized Trx and a reduction in levels of reduced Trx. Trx is therefore unable to activate the substrates listed, which results in the inhibition of cellular functions including DNA synthesis, protein repair, transcription factor activity, and peroxidase function. H2O2 and free radicals subsequently accumulate. This leads to oxidative stress conditions that promote cell cycle arrest.

Fig. 5 Metal-containing complexes. (A) Representative anticancer gold-containing complexes. (B) Selected examples of gold N-heterocyclic carbine (NHC) complexes. (C) Selected examples of Pt-containing complexes.

Fig. 6 Structures of the natural compound curcumin and its analogs.

Fig. 1



Fig. 2


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Fig.3

Fig.4



Fig.5


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Fig.6




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Targeting the thioredoxin system as a strategy for cancer therapy

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