Oxidation of structural cysteine residues in thioredoxin 1 by aromatic arsenicals enhances cancer cell cytotoxicity caused by the inhibition of thioredoxin reductase 1

Zhang, Xu; Lu, Jun; Ren, Xiaoyuan; Du, Yu‐Cang; Zheng, Yi; Ioannou, Panayiotis V.; Holmgren, Arne

doi:10.1016/j.freeradbiomed.2015.07.010

Cited by 29 publications

(7 citation statements)

References 59 publications

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“…The result indicated that the ability of inhibition of Trx1/TrxR1 by these arsenic molecules were consistent with their observed cytotoxicity in vitro, and these compounds exhibited strong inhibitory activity on TrxR1 with IC 50 values around 1.0 μM. Similar results were also observed in SH‐SH5Y cells . Sun and co‐workers found that the TrxR activity was decreased significantly in pancreatic INS‐1 cells after treatment with low‐level (0.25–1.00 μM) of sodium arsenite ( 299 , Figure ) for 96 hr …”

Section: Thioredoxin Reductase Inhibitorssupporting

confidence: 75%

Small molecule inhibitors of mammalian thioredoxin reductase as potential anticancer agents: An update

Zhang

et al. 2018

Medicinal Research Reviews

135

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Mammalian thioredoxin reductase (TrxR) enzymes are homodimeric flavin proteins sharing a unique yet essential selenocysteine residue at their C-terminus. TrxRs, together with their endogenous substrate thioredoxins, play a crucial role in regulating diverse cellular redox events. A wealth of evidence from both clinic observations and bench studies supports that overactivation/dysfunction of TrxRs has a close link to the onset and development of various diseases, such as cancer and neurodegeneration. Thus, an increasing interest has been attracted to find small molecule modulators of TrxRs during the past years. Herein, we briefly discussed the relevance of targeting TrxRs inhibition for cancer treatment, and presented the small molecule inhibitors of mammalian TrxRs published in the nonpatent literatures from 2011 to 2016. The mechanisms of inhibition by different classes of molecules were summarized, and some inhibitors with promising anticancer activity were further discussed. We expect this work would be a comprehensive reference in the medicinal chemistry, and have a broad audience across multiple disciplines.

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Section: Thioredoxin Reductase Inhibitorssupporting

confidence: 75%

Small molecule inhibitors of mammalian thioredoxin reductase as potential anticancer agents: An update

Zhang

et al. 2018

Medicinal Research Reviews

135

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“…Notably, we observed a reduction in Trx1 protein levels upon cambogin treatment. Although oxidative stress-induced Trx1 degradation has already been reported elsewhere [54, 55], the underlying mechanism remains obscure, thereby how cambogin induces the reduction in Trx1 expression also awaits further study. Of note, the pro-apoptotic effect of cambogin was further aggravated when the cells were transiently transfected with siRNA against Trx1, suggesting that Trx1 inhibitors may enhance the effectiveness of cambogin in breast cancer treatment.…”

Section: Discussionmentioning

confidence: 98%

Cambogin exerts anti-proliferative and pro-apoptotic effects on breast adenocarcinoma through the induction of NADPH oxidase 1 and the alteration of mitochondrial morphology and dynamics

Shen

Xie

et al. 2016

Oncotarget

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Cambogin, a bioactive polycyclic polyprenylated acylphoroglucinol (PPAP) derived from the Garcinia genus, possesses proapoptotic effect in medulloblastoma and breast cancer cells. We have previously demonstrated that the proapoptotic effect of cambogin is driven by the production of reactive oxygen species (ROS). Here we have shown that the inhibitory effect of cambogin on cell proliferation is associated with the loss of mitochondrial transmembrane potential (ΔΨm) and mitochondrial fragmentation. Cambogin also promotes the mutual complex formation of the membrane-bound subunit p22phox of NADPH oxidase 1 (NOX1), as well as the phosphorylation of the cytosolic subunit p47phox, subsequently enhancing membrane-bound NOX1 activity, which leads to increases in intracellular and mitochondrial levels of O2.- and H2O2. Pharmacological inhibition of NOX1 using apocynin (pan-NOX inhibitor), ML171 (NOX1 inhibitor) or siRNA against NOX1 prevents the increases in O2.- and H2O2 levels and the anti-proliferative effect of cambogin. Antioxidants, including SOD (superoxide dismutase), CAT (catalase) and EUK-8, are also able to restore cell viability in the presence of cambogin. Besides, cambogin increases the dissociation of thioredoxin-1 (Trx1) from ASK1, switching the inactive form of ASK1 to the active kinase, subsequently leads to the phosphorylation of JNK/SAPK, which is abolished upon ML171 treatment. The proapoptotic effect of cambogin in breast cancer cells is also aggravated upon knocking down Trx1 in MCF-7 cells. Taken in conjunction, these data indicate that the anti-proliferative and pro-apoptotic effect of cambogin is mediated via inducing NOX1-dependent ROS production and the dissociation of ASK1 and Trx1.

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“…[29,35] Our lead compound 1a has already shown good inhibition of AKR1C and glutathione S-transferase, two enzymes involved in cancerp rogression. [18,20] In the literature, arsenic complexes, including one bearing ap yrithione ligand,h ave been reported to show av ery good ability for inhibiting thioredoxin reductase (TrxR), [36] one of the crucial enzymes that regulates redox homeostasisi nc ells. If overexpressed,i tc an also cause cancer progression and the latter thus represents an interesting" druggable"t arget.…”

Section: Thioredoxin Reductase Inhibitionmentioning

confidence: 99%

Towards Identification of Essential Structural Elements of Organoruthenium(II)‐Pyrithionato Complexes for Anticancer Activity

Kladnik

Kljun

Burmeister

et al. 2019

Chemistry A European J

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An organoruthenium(II) complex with pyrithione (2-mercaptopyridine N-oxide) 1a has previously been identified by our group as ac ompound with promising anticancer potential without cytotoxicity towards non-cancerous cells. To expand the rather limited research on compounds of this type, an array of novel chlorido and 1,3,5-triaza-7-phosphaadamantane( pta) organoruthenium(II) complexesw ith methyl-substituted pyrithiones has been prepared. After thorough investigation of the aqueous stability of these complexes, their modeso fa ction have been elucidated at the cellular level.M inor structurala lterations in the rutheni-um-pyrithionato compounds resulted in fine-tuning of their cytotoxicities. The best performing compounds, 1b and 2b, with ac hlorido or pta ligand bound to ruthenium, respectively,and amethyl group at the 3-position of the pyrithione scaffold, have been further investigated. Both compounds trigger early apoptosis, induce the generation of reactive oxygen speciesa nd G1 arrest in A549 cancerc ells, and show no strong interaction with DNA. However,o nly 1b also inhibits thioredoxin reductase.W ound healing assays and mitochondrial function evaluation have revealed differences between these two compounds at the cellular level. Figure 2. Structures of the prepared ligands and reaction path leadingt o the organoruthenium(II) chlorido (1a-e)a nd pta (2a-e)complexes.

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Oxidation of structural cysteine residues in thioredoxin 1 by aromatic arsenicals enhances cancer cell cytotoxicity caused by the inhibition of thioredoxin reductase 1

Cited by 29 publications

References 59 publications

Small molecule inhibitors of mammalian thioredoxin reductase as potential anticancer agents: An update

Small molecule inhibitors of mammalian thioredoxin reductase as potential anticancer agents: An update

Cambogin exerts anti-proliferative and pro-apoptotic effects on breast adenocarcinoma through the induction of NADPH oxidase 1 and the alteration of mitochondrial morphology and dynamics

Towards Identification of Essential Structural Elements of Organoruthenium(II)‐Pyrithionato Complexes for Anticancer Activity

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