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Computers in Biology and Medicine Jan 2023Auranofin is a thioredoxin reductase-1 inhibitor originally approved for the treatment of rheumatoid arthritis. Recently, auranofin has been repurposed as an anticancer...
Auranofin is a thioredoxin reductase-1 inhibitor originally approved for the treatment of rheumatoid arthritis. Recently, auranofin has been repurposed as an anticancer drug, with pharmacological activity reported in multiple cancer types. In this study, we characterized transcriptional and genetic alterations associated with auranofin response in cancer. By integrating data from an auranofin cytotoxicity screen with transcriptome profiling of lung cancer cell lines, we identified an auranofin resistance signature comprising 29 genes, most of which are classical targets of the transcription factor NRF2, such as genes involved in glutathione metabolism (GCLC, GSR, SLC7A11) and thioredoxin system (TXN, TXNRD1). Pan-cancer analysis revealed that mutations in NRF2 pathway genes, namely KEAP1 and NFE2L2, are strongly associated with overexpression of the auranofin resistance gene set. By clustering cancer types based on auranofin resistance signature expression, hepatocellular carcinoma, and a subset of non-small cell lung cancer, head-neck squamous cell carcinoma, and esophageal cancer carrying NFE2L2/KEAP1 mutations were predicted resistant, whereas leukemia, lymphoma, and multiple myeloma were predicted sensitive to auranofin. Cell viability assays in a panel of 20 cancer cell lines confirmed the augmented sensitivity of hematological cancers to auranofin; an effect associated with dependence upon glutathione and decreased expression of NRF2 target genes involved in GSH synthesis and recycling (GCLC, GCLM and GSR) in these cancer types. In summary, the omics-based identification of sensitive/resistant cancers and genetic alterations associated with these phenotypes may guide an appropriate repurposing of auranofin in cancer therapy.
Topics: Humans; Auranofin; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Drug Repositioning; Kelch-Like ECH-Associated Protein 1; NF-E2-Related Factor 2; Glutathione
PubMed: 36493734
DOI: 10.1016/j.compbiomed.2022.106347 -
International Journal of Molecular... Nov 2022Auranofin (AF), a gold(I) compound that is currently used for the treatment of rheumatoid arthritis and is in clinical trials for its promising anticancer activity, was...
Auranofin (AF), a gold(I) compound that is currently used for the treatment of rheumatoid arthritis and is in clinical trials for its promising anticancer activity, was encapsulated within the human H-chain and the horse spleen ferritin nanocages using the alkaline disassembly/reassembly protocol. The aim of the work was to highlight possible differences in their drug loading capacity and efficacy. The drug-loaded ferritins were characterized via UV-vis absorption spectroscopy and inductively coupled plasma-atomic emission spectroscopy to assess AF encapsulation and to define the exact amount of gold atoms trapped in the Ft cavity. The crystal structures allowed us to define the nature of AF interaction with both ferritins and to identify the gold binding sites. Moreover, the biological characterization let us to obtain preliminary information on the cytotoxic effect of AF when bound to the human H-chain.
Topics: Animals; Humans; Antineoplastic Agents; Auranofin; Binding Sites; Ferritins; Gold; Horses; Nanoparticle Drug Delivery System
PubMed: 36430642
DOI: 10.3390/ijms232214162 -
Biomolecules Nov 2022Gold compounds have a long tradition in medicine and offer many opportunities for new therapeutic applications. Herein, we evaluated the lead compound Auranofin and five...
Gold compounds have a long tradition in medicine and offer many opportunities for new therapeutic applications. Herein, we evaluated the lead compound Auranofin and five related gold(I) complexes as possible inhibitors of SARS-CoV-2 Main Protease (SARS-CoV-2 M), a validated drug target for the COVID-19 disease. The investigational panel of gold compounds included Auranofin; three halido analogues, i.e., Au(PEt)Cl, Au(PEt)Br, and Au(PEt)I; and two gold carbene complexes, i.e., Au(NHC)Cl and [Au(NHC)]PF. Notably, all these gold compounds, with the only exception of [Au(NHC)]PF, turned out to be potent inhibitors of the catalytic activity of SARS-CoV-2 M: the measured K values were in the range 2.1-0.4 μM. The reactions of the various gold compounds with SARS-CoV-2 M were subsequently investigated through electrospray ionization (ESI) mass spectrometry (MS) upon a careful optimization of the experimental conditions; the ESI MS spectra provided clear evidence for the formation of tight metallodrug-protein adducts and for the coordination of well defined gold-containing fragments to the SARS-CoV-2 M, again with the only exception of [Au(NHC)]PF, The metal-protein stoichiometry was unambiguously determined for the resulting species. The crystal structures of the metallodrug- M adducts were solved in the case of Au(PEt)Br and Au(NHC)Cl. These crystal structures show that gold coordination occurs at the level of catalytic Cys 145 in the case of Au(NHC)Cl and at the level of both Cys 145 and Cys 156 for Au(PEt)Br. Tight coordination of gold atoms to functionally relevant cysteine residues is believed to represent the true molecular basis of strong enzyme inhibition.
Topics: Humans; Auranofin; Viral Proteins; SARS-CoV-2; Gold Compounds; Cysteine; Gold; COVID-19 Drug Treatment
PubMed: 36421689
DOI: 10.3390/biom12111675 -
Chemico-biological Interactions Jan 2023Programmed cell death protein-1 (PD-1)/programmed cell death ligand-1 (PD-L1) interaction exerts a vital role in tumor-associated immune evasion. While strategies...
Programmed cell death protein-1 (PD-1)/programmed cell death ligand-1 (PD-L1) interaction exerts a vital role in tumor-associated immune evasion. While strategies disrupting PD-1/PD-L1 axis have shown clinical benefits in various cancers, the limited response rate prompts us to investigate the complex mechanisms underlying the molecular regulation of PD-L1. Here, we identify the RNA binding protein RBMS3 as a crucial PD-L1 regulator in triple-negative breast cancer (TNBC). Correlation analysis shows that Rbms3 significantly correlates with immunosuppressive CD274, Rbms1, NT5E and ENTPD1. RBMS3 protein binds to CD274 mRNA specifically in TNBC cells to increase PD-L1 levels. Mechanistically, RBMS3 stabilizes CD274 mRNA by interacting with its 3'UTR, which represents as an intrinsic cancer cell mechanism for driving PL-D1 upregulation in TNBC. RBMS3 depletion not only destabilizes the mRNA stability and protein expression of PD-L1, but also suppresses the migratory abilities of TNBC MDA-MB-231 cells. Importantly, combination of RBMS3 ablation with auranofin (AUF), an FDA-approved thioredoxin reductase inhibitor, facilitates anti-tumor T-cell immunity in vivo and improves AUF-mediated anti-cancer effect. Taken together, our findings reveal RBMS3 as a key post-transcriptional regulator of PD-L1 and how they contribute to immune escape in TNBC, which could lead to novel combinatorial therapeutic strategies to enhance the efficacy of cancer immunotherapy.
Topics: Humans; Triple Negative Breast Neoplasms; Auranofin; Programmed Cell Death 1 Receptor; B7-H1 Antigen; Antibodies; RNA, Messenger; Cell Line, Tumor; DNA-Binding Proteins; RNA-Binding Proteins; Trans-Activators
PubMed: 36414028
DOI: 10.1016/j.cbi.2022.110260 -
Clinical and Molecular Hepatology Jan 2023
Topics: Humans; Auranofin; Fibrosis; Liver; Liver Cirrhosis; NF-E2-Related Factor 2; NF-kappa B; Non-alcoholic Fatty Liver Disease; Signal Transduction
PubMed: 36353765
DOI: 10.3350/cmh.2022.0381 -
Microbiology Spectrum Dec 2022Alternative antimicrobial therapies are urgently required for the multidrug-resistant bacterial pathogen Neisseria gonorrhoeae, for which currently ceftriaxone is the...
Alternative antimicrobial therapies are urgently required for the multidrug-resistant bacterial pathogen Neisseria gonorrhoeae, for which currently ceftriaxone is the only remaining recommended first-line therapy. Repurposing of drugs that are approved for other clinical applications offers an efficient approach for development of alternative antimicrobial therapies. Auranofin, cannabidivarin, and tolfenamic acid were recently identified to display antimicrobial activity against N. gonorrhoeae. Here, we investigated their activity against a collection of 575 multidrug-resistant clinical isolates. All three compounds displayed consistent antimicrobial activity against all isolates, including against strains associated with the high-level ceftriaxone-resistant FC428 clone, with both the mode and MIC for auranofin of 0.5 mg/L, while both the mode and MIC for cannabidivarin and tolfenamic acid were 8 mg/L. Correlations between MICs of ceftriaxone and auranofin, cannabidivarin or tolfenamic acid were low, indicating that development of cross-resistance is unlikely. Furthermore, antimicrobial synergy analysis between ceftriaxone and auranofin, cannabidivarin, or tolfenamic acid by determination of the fractional inhibitory concentration index (FICI) resulted in an interpretation of indifference. Finally, time-kill analyses showed that all three compounds are bactericidal against both the N. gonorrhoeae ATCC 49226 reference strain and an FC428-associated clinical isolate, with particularly cannabidivarin displaying rapid bactericidal activity. Overall, auranofin, cannabidivarin, and tolfenamic acid displayed consistent antimicrobial activity against multidrug-resistant N. gonorrhoeae, warranting further exploration of their suitability as alternative antimicrobials for treatment of gonococcal infections. Neisseria gonorrhoeae is a major public health concern because of the high incidence of gonorrhea and the increasingly limited options for antimicrobial therapy. Strains associated with the FC428 clone are a particular concern because they have shown global dissemination and they display high-level resistance against the currently recommended ceftriaxone therapy. Therefore, development of alternative antimicrobial therapies is urgently required to ensure treatment of gonorrhea remains available in the future. Repurposing of clinically approved drugs could be a rapid approach for the development of such alternative antimicrobials. In this study, we showed that repurposing of auranofin, cannabidivarin, and tolfenamic acid for antimicrobial therapy of gonorrhea deserves further clinical explorations because these compounds displayed consistent antimicrobial activity against a large collection of contemporary multidrug-resistant gonococcal isolates that included strains associated with the FC428 clone.
Topics: Humans; Neisseria gonorrhoeae; Gonorrhea; Ceftriaxone; Auranofin; Anti-Bacterial Agents; Anti-Infective Agents; Microbial Sensitivity Tests; Drug Resistance, Bacterial
PubMed: 36350125
DOI: 10.1128/spectrum.03952-22 -
Biochemical and Biophysical Research... Dec 2022Osteoarthritis, a prevalent orthopedic disease, can affect the elderly and causes impairment. The degradation and aberrant homeostasis of cartilage extracellular matrix...
Osteoarthritis, a prevalent orthopedic disease, can affect the elderly and causes impairment. The degradation and aberrant homeostasis of cartilage extracellular matrix figure pivotally in the progression of osteoarthritis. Thioredoxin systems plays a role in a wide range of biological processes, including cell proliferation, apoptosis, and oxidative stress. The present study aimed to investigate the unique function and underlying pathophysiological mechanism of TXNRD1 in chondrocytes. An upregulated expression of TXNRD1 was observed in the articular cartilage of osteoarthritis patients compared with normal articular cartilage. Furthermore, in vitro experiments showed that the expression of TXNRD1 was also abnormally increased in IL-1β-induced primary mouse chondrocytes. Silencing TXNRD1 using siRNA in chondrocytes could effectively inhibit the expression of ADAMTS5 and MMP13, and enhance the expression of COL2A1 and SOX9. The same was true for auranofin, an inhibitor of TXNRD1. This phenomenon indicated that inhibition of TXNRD1 attenuated il-1β-induced metabolic imbalance of extracellular matrix (ECM) and the progression of chondrocyte osteoarthritis. Further mechanism analysis revealed that the activation of Nrf2 signaling pathway and the expression of heme oxygenase-1 (HO-1) were increased upon TXNRD1 inhibition. Furthermore, auranofin was found to attenuate DMM-induced osteoarthritis progression in vivo. Therefore, the pharmacological downregulation of TXNRD1 may provide an effective novel therapy for OA.
Topics: Animals; Mice; Auranofin; Cartilage, Articular; Chondrocytes; Extracellular Matrix; Interleukin-1beta; NF-E2-Related Factor 2; Osteoarthritis; Thioredoxin Reductase 1
PubMed: 36308906
DOI: 10.1016/j.bbrc.2022.10.059 -
Clinical and Molecular Hepatology Jan 2023
Topics: Humans; Auranofin; Fibrosis; Liver; Liver Cirrhosis; NF-E2-Related Factor 2; NF-kappa B; Non-alcoholic Fatty Liver Disease; Signal Transduction
PubMed: 36300328
DOI: 10.3350/cmh.2022.0326 -
International Journal of Molecular... Oct 2022Reactive oxygen species (ROS) homeostasis and mitochondrial metabolism are critical for the survival of cancer cells, including cancer stem cells (CSCs), which often...
Reactive oxygen species (ROS) homeostasis and mitochondrial metabolism are critical for the survival of cancer cells, including cancer stem cells (CSCs), which often cause drug resistance and cancer relapse. Auranofin is a mono-gold anti-rheumatic drug, and it has been repurposed as an anticancer agent working by the induction of both ROS increase and mitochondrial dysfunction. Hypothetically, increasing auranofin's positive charges via incorporating more gold atoms to enhance its mitochondria-targeting capacity could enhance its anti-cancer efficacy. Hence, in this work, both mono-gold and bi-gold compounds were designed and evaluated to test our hypothesis. The results showed that bi-gold compounds generally suppressed cancer cells proliferation better than their mono-gold counterparts. The most potent compound, BGC2a, substantially inhibited the antioxidant enzyme TrxR and increased the cellular ROS. BGC2a induced cell apoptosis, which could not be reversed by the antioxidant agent vitamin C, implying that the ROS induced by TrxR inhibition might not be the decisive cause of cell death. As expected, a significant proportion of BGC2a accumulated within mitochondria, likely contributing to mitochondrial dysfunction, which was further confirmed by measuring oxygen consumption rate, mitochondrial membrane potential, and ATP production. Moreover, BGC2a inhibited colony formation and reduced stem-like side population (SP) cells of A549. Finally, the compound effectively suppressed the tumor growth of both A549 and PANC-1 xenografts. Our study showed that mitochondrial disturbance may be gold-based compounds' major lethal factor in eradicating cancer cells, providing a new approach to developing potent gold-based anti-cancer drugs by increasing mitochondria-targeting capacity.
Topics: Humans; Reactive Oxygen Species; Auranofin; Antioxidants; Mitochondria; Apoptosis; Gold Compounds; Ascorbic Acid; Antirheumatic Agents; Adenosine Triphosphate; Cell Proliferation; Cell Line, Tumor; Neoplasms
PubMed: 36293028
DOI: 10.3390/ijms232012169 -
Journal of Medicinal Chemistry Nov 2022A new series of seven gold(I) complexes (-) containing 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene (IPr) and phosphane ligands (L1-L7) were synthesized and...
A new series of seven gold(I) complexes (-) containing 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene (IPr) and phosphane ligands (L1-L7) were synthesized and evaluated for antitumor activity in ovarian cancer (OvCa) models. The synthesized complexes were characterized by IR, mass spectrometry and NMR spectroscopy, and complex was characterized by XRD crystallography. The antiproliferative effect of the new complexes (-) was found to be higher than cisplatin and auranofin in OvCa cells sensitive and resistant to cisplatin. The anticancer activity of the most active complex was investigated using OvCa models, including three-dimensional (3D) multicellular tumor spheroids and tumor xenografts. Both cisplatin and auranofin were used for comparative purposes. Complex induced apoptosis, mitochondrial reactive oxygen species, and DNA damage; caused a G1 phase cell cycle arrest, inhibited proteasome activity, and cell migration; modified actin polymerization; and significantly inhibited OvCa murine xenografts. These promising results suggest further preclinical testing of these complexes for future applications.
Topics: Humans; Female; Mice; Animals; Cisplatin; Auranofin; Antineoplastic Agents; Ovarian Neoplasms; Cell Line, Tumor; Coordination Complexes
PubMed: 36278959
DOI: 10.1021/acs.jmedchem.2c00737