Repurposing of auranofin: Thioredoxin reductase remains a primary target of the drug

Zhang, Xiaonan; Selvaraju, Karthik; Saei, Amir Ata; D’Arcy, Pádraig; Zubarev, Roman A.; Arnér, Elias S.J.; Linder, Stig

doi:10.1016/j.biochi.2019.03.015

Cited by 135 publications

(100 citation statements)

References 43 publications

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“…The exception for the latter is AUR, the clinically approved drug primarily used in rheumatology and suggested in numerous other indications [46]. AUR is known to inhibit, among others, selenoprotein thioredoxin reductase (TXNR) [47], the inhibition of which blocks PRDX1 reduction and hydrogen peroxide removal. Accordingly, AUR has been shown to hamper the functionality of TXN-dependent PRDX1 and PRDX3 enzymes in MDA-MB-231 cells [35].…”

Section: Discussionmentioning

confidence: 99%

Triple Combination of Ascorbate, Menadione and the Inhibition of Peroxiredoxin-1 Produces Synergistic Cytotoxic Effects in Triple-Negative Breast Cancer Cells

et al. 2020

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Triple-negative breast cancer (TNBC) is an aggressive form of mammary malignancy currently without satisfactory systemic treatment options. Agents generating reactive oxygen species (ROS), such as ascorbate (Asc) and menadione (Men), especially applied in combination, have been proposed as an alternative anticancer modality. However, their effectiveness can be hampered by the cytoprotective effects of elevated antioxidant enzymes (e.g., peroxiredoxins, PRDX) in cancer. In this study, PRDX1 mRNA and protein expression were assessed in TNBC tissues by analysis of the online RNA-seq datasets and immunohistochemical staining of tissue microarray, respectively. We demonstrated that PRDX1 mRNA expression was markedly elevated in primary TNBC tumors as compared to non-malignant controls, with PRDX1 protein staining intensity correlating with favorable survival parameters. Subsequently, PRDX1 functionality in TNBC cell lines or non-malignant mammary cells was targeted by genetic silencing or chemically by auranofin (AUR). The PRDX1-knockdown or AUR treatment resulted in inhibition of the growth of TNBC cells in vitro. These cytotoxic effects were further synergistically potentiated by the incubation with a combination of the prooxidant agents, Asc and Men. In conclusion, we report that the PRDX1-related antioxidant system is essential for maintaining redox homeostasis in TNBC cells and can be an attractive therapeutic target in combination with ROS-generating agents.

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Section: Discussionmentioning

confidence: 99%

Triple Combination of Ascorbate, Menadione and the Inhibition of Peroxiredoxin-1 Produces Synergistic Cytotoxic Effects in Triple-Negative Breast Cancer Cells

et al. 2020

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“…Auranofin has been shown to induce cellular proteotoxicity as well as inhibition of USP14 and UCHL5, resulting in proteasome-blockage and toxicity to cancer cells. However, USP14 inhibition only occurs at concentrations exceeding IC 50 [316]. It has been suggested that an intermediate form of the compound allows the chelated gold ion (Au+)…”

Section: Auranofinmentioning

confidence: 99%

Proteasome inhibitor b-AP15 induces enhanced proteotoxicity by inhibiting cytoprotective aggresome formation

et al. 2019

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“…Gold-based medicines have been widely studied and used as anti-inflammatory, anti-cancer, and anti-microbial agents to treat various pathologies [[23], [24], [25], [26], [70]]. Gold compounds have a high affinity for thiol and selenol groups, which makes the Trx system vulnerable to these compounds [27], since TrxR contains a selenocysteine residue in its C-terminal active site [28].…”

Section: Introductionmentioning

confidence: 99%

“…Gold compounds have a high affinity for thiol and selenol groups, which makes the Trx system vulnerable to these compounds [27], since TrxR contains a selenocysteine residue in its C-terminal active site [28]. Auranofin, an FDA-approved gold-based drug for treating arthritis [25,29], is currently being tested in clinical trials for various cancers including chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL) (NCT01419691) and ovarian cancer (NCT01747798). However, there are concerns that auranofin may react non-discriminately with protein thiols (including serum proteins), which may render this drug ineffective and potentially introduce negative side effects in patients [26,30,31].…”

Section: Introductionmentioning

confidence: 99%

Anticancer activity of a Gold(I) phosphine thioredoxin reductase inhibitor in multiple myeloma

et al. 2020

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Multiple myeloma (MM), the second most common haematological malignancy, is a clonal plasma B-cell neoplasm that forms within the bone marrow. Despite recent advancements in treatment, MM remains an incurable disease. Auranofin, a linear gold(I) phosphine compound, has previously been shown to exert a significant anti-myeloma activity by inhibiting thioredoxin reductase (TrxR) activity. A bis-chelated tetrahedral gold(I) phosphine complex [Au(d2pype)2]Cl (where d2pype is 1,2-bis(di-2-pyridylphosphino)ethane) was previously designed to improve the gold(I) compound selectivity towards selenol- and thiol-containing proteins, such as TrxR. In this study, we show that [Au(d2pype)2]Cl significantly inhibited TrxR activity in both bortezomib-sensitive and resistant myeloma cells, which led to a significant reduction in cell proliferation and induction of apoptosis, both of which were dependent on ROS. In clonogenic assays, treatment with [Au(d2pype)2]Cl completely abrogated the tumourigenic capacity of MM cells, whereas auranofin was less effective. We also show that [Au(d2pype)2]Cl exerted a significant anti-myeloma activity in vivo in human RPMI8226 xenograft model in immunocompromised NOD/SCID mice. The MYC oncogene, known to drive myeloma progression, was downregulated in both in vitro and in vivo models when treated with [Au(d2pype)2]Cl. This study highlights the “proof of concept” that improved gold(I)-based compounds could potentially be used to not only treat MM but as an alternative tool to understand the role of the Trx system in the pathogenesis of this blood disease.

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Repurposing of auranofin: Thioredoxin reductase remains a primary target of the drug

Cited by 135 publications

References 43 publications

Triple Combination of Ascorbate, Menadione and the Inhibition of Peroxiredoxin-1 Produces Synergistic Cytotoxic Effects in Triple-Negative Breast Cancer Cells

Triple Combination of Ascorbate, Menadione and the Inhibition of Peroxiredoxin-1 Produces Synergistic Cytotoxic Effects in Triple-Negative Breast Cancer Cells

Proteasome inhibitor b-AP15 induces enhanced proteotoxicity by inhibiting cytoprotective aggresome formation

Anticancer activity of a Gold(I) phosphine thioredoxin reductase inhibitor in multiple myeloma

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