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[PMID]:28461071
[Au] Autor:Langsjoen RM; Auguste AJ; Rossi SL; Roundy CM; Penate HN; Kastis M; Schnizlein MK; Le KC; Haller SL; Chen R; Watowich SJ; Weaver SC
[Ad] Endereço:Institute for Translational Science, University of Texas Medical Branch, Galveston, TX, USA; Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX, USA.
[Ti] Título:Host oxidative folding pathways offer novel anti-chikungunya virus drug targets with broad spectrum potential.
[So] Source:Antiviral Res;143:246-251, 2017 07.
[Is] ISSN:1872-9096
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Alphaviruses require conserved cysteine residues for proper folding and assembly of the E1 and E2 envelope glycoproteins, and likely depend on host protein disulfide isomerase-family enzymes (PDI) to aid in facilitating disulfide bond formation and isomerization in these proteins. Here, we show that in human HEK293 cells, commercially available inhibitors of PDI or modulators thereof (thioredoxin reductase, TRX-R; endoplasmic reticulum oxidoreductin-1, ERO-1) inhibit the replication of CHIKV chikungunya virus (CHIKV) in vitro in a dose-dependent manner. Further, the TRX-R inhibitor auranofin inhibited Venezuelan equine encephalitis virus and the flavivirus Zika virus replication in vitro, while PDI inhibitor 16F16 reduced replication but demonstrated notable toxicity. 16F16 significantly altered the viral genome: plaque-forming unit (PFU) ratio of CHIKV in vitro without affecting relative intracellular viral RNA quantities and inhibited CHIKV E1-induced cell-cell fusion, suggesting that PDI inhibitors alter progeny virion infectivity through altered envelope function. Auranofin also increased the extracellular genome:PFU ratio but decreased the amount of intracellular CHIKV RNA, suggesting an alternative mechanism of action. Finally, auranofin reduced footpad swelling and viremia in the C57BL/6 murine model of CHIKV infection. Our results suggest that targeting oxidative folding pathways represents a potential new anti-alphavirus therapeutic strategy.
[Mh] Termos MeSH primário: Antivirais/farmacologia
Febre de Chikungunya/virologia
Vírus Chikungunya/efeitos dos fármacos
Vírus Chikungunya/fisiologia
Interações Hospedeiro-Patógeno/fisiologia
[Mh] Termos MeSH secundário: Infecções por Alphavirus/virologia
Animais
Auranofina/antagonistas & inibidores
Febre de Chikungunya/mortalidade
Vírus Chikungunya/patogenicidade
Modelos Animais de Doenças
Vírus da Encefalite Equina Venezuelana/efeitos dos fármacos
Flavivirus/efeitos dos fármacos
Células HEK293
Seres Humanos
Glicoproteínas de Membrana
Camundongos
Camundongos Endogâmicos C57BL
Isomerases de Dissulfetos de Proteínas/farmacologia
Dobramento de Proteína
Tiorredoxina Dissulfeto Redutase/farmacologia
Proteínas do Envelope Viral/metabolismo
Replicação Viral/efeitos dos fármacos
Zika virus/efeitos dos fármacos
Infecção pelo Zika virus/virologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antiviral Agents); 0 (Membrane Glycoproteins); 0 (Viral Envelope Proteins); 3H04W2810V (Auranofin); EC 1.8.1.9 (Thioredoxin-Disulfide Reductase); EC 5.3.4.1 (Protein Disulfide-Isomerases)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:180213
[Lr] Data última revisão:
180213
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170503
[St] Status:MEDLINE


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[PMID]:28684416
[Au] Autor:Dagnell M; Pace PE; Cheng Q; Frijhoff J; Östman A; Arnér ESJ; Hampton MB; Winterbourn CC
[Ad] Endereço:From the Centre for Free Radical Research, Department of Pathology, University of Otago, Christchurch 8041, New Zealand.
[Ti] Título:Thioredoxin reductase 1 and NADPH directly protect protein tyrosine phosphatase 1B from inactivation during H O exposure.
[So] Source:J Biol Chem;292(35):14371-14380, 2017 Sep 01.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Regulation of growth factor signaling involves reversible inactivation of protein tyrosine phosphatases (PTPs) through the oxidation and reduction of their active site cysteine. However, there is limited mechanistic understanding of these redox events and their co-ordination in the presence of cellular antioxidant networks. Here we investigated interactions between PTP1B and the peroxiredoxin 2 (Prx2)/thioredoxin 1 (Trx1)/thioredoxin reductase 1 (TrxR1) network. We found that Prx2 becomes oxidized in PDGF-treated fibroblasts, but only when TrxR1 has first been inhibited. Using purified proteins, we also found that PTP1B is relatively insensitive to inactivation by H O but found no evidence for a relay mechanism in which Prx2 or Trx1 facilitates PTP1B oxidation. Instead, these proteins prevented PTP1B inactivation by H O Intriguingly, we discovered that TrxR1/NADPH directly protects PTP1B from inactivation when present during the H O exposure. This protection was dependent on the concentration of TrxR1 and independent of Trx1 and Prx2. The protection was blocked by auranofin and required an intact selenocysteine residue in TrxR1. This activity likely involves reduction of the sulfenic acid intermediate form of PTP1B by TrxR1 and is therefore distinct from the previously described reactivation of end-point oxidized PTP1B, which requires both Trx1 and TrxR1. The ability of TrxR1 to directly reduce an oxidized phosphatase is a novel activity that can help explain previously observed increases in PTP1B oxidation and PDGF receptor phosphorylation in TrxR1 knockout cells. The activity of TrxR1 is therefore of potential relevance for understanding the mechanisms of redox regulation of growth factor signaling pathways.
[Mh] Termos MeSH primário: NADP/metabolismo
Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo
Proteínas Tirosina Fosfatases Classe 3 Semelhantes a Receptores/metabolismo
Tiorredoxina Redutase 1/metabolismo
[Mh] Termos MeSH secundário: Animais
Auranofina/farmacologia
Domínio Catalítico
Células Cultivadas
Dimerização
Embrião de Mamíferos/citologia
Proteínas de Homeodomínio/química
Proteínas de Homeodomínio/genética
Proteínas de Homeodomínio/metabolismo
Seres Humanos
Peróxido de Hidrogênio/farmacologia
Camundongos
Oxidantes/farmacologia
Oxirredução
Fragmentos de Peptídeos/química
Fragmentos de Peptídeos/genética
Fragmentos de Peptídeos/metabolismo
Domínios e Motivos de Interação entre Proteínas
Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores
Proteína Tirosina Fosfatase não Receptora Tipo 1/genética
Ratos
Proteínas Tirosina Fosfatases Classe 3 Semelhantes a Receptores/química
Proteínas Tirosina Fosfatases Classe 3 Semelhantes a Receptores/genética
Proteínas Recombinantes de Fusão/química
Proteínas Recombinantes de Fusão/metabolismo
Selenocisteína/química
Selenocisteína/metabolismo
Tiorredoxina Redutase 1/antagonistas & inibidores
Tiorredoxina Redutase 1/química
Tiorredoxina Redutase 1/genética
Tiorredoxinas/química
Tiorredoxinas/genética
Tiorredoxinas/metabolismo
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Homeodomain Proteins); 0 (Oxidants); 0 (PRRX2 protein, human); 0 (Peptide Fragments); 0 (Recombinant Fusion Proteins); 0 (TXN protein, human); 0CH9049VIS (Selenocysteine); 3H04W2810V (Auranofin); 52500-60-4 (Thioredoxins); 53-59-8 (NADP); BBX060AN9V (Hydrogen Peroxide); EC 1.8.1.9 (Thioredoxin Reductase 1); EC 1.8.1.9 (Txnrd1 protein, rat); EC 3.1.3.48 (PTPN1 protein, human); EC 3.1.3.48 (Protein Tyrosine Phosphatase, Non-Receptor Type 1); EC 3.1.3.48 (Receptor-Like Protein Tyrosine Phosphatases, Class 3)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170926
[Lr] Data última revisão:
170926
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170708
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M117.793745


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[PMID]:28300829
[Au] Autor:Oh BM; Lee SJ; Cho HJ; Park YS; Kim JT; Yoon SR; Lee SC; Lim JS; Kim BY; Choe YK; Lee HG
[Ad] Endereço:Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.
[Ti] Título:Cystatin SN inhibits auranofin-induced cell death by autophagic induction and ROS regulation via glutathione reductase activity in colorectal cancer.
[So] Source:Cell Death Dis;8(3):e2682, 2017 Mar 16.
[Is] ISSN:2041-4889
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Cystatin SN (CST1) is a specific inhibitor belonging to the cystatin superfamily that controls the proteolytic activities of cysteine proteases such as cathepsins. Our previous study showed that high CST1 expression enhances tumor metastasis and invasiveness in colorectal cancer. Recently, auranofin (AF), a gold(I)-containing thioredoxin reductase 1 (TrxR1) inhibitor, has been used clinically to treat rheumatoid arthritis. AF is a proteasome-associated deubiquitinase inhibitor and can act as an anti-tumor agent. In this study, we investigated whether CST1 expression induces autophagy and tumor cell survival. We also investigated the therapeutic effects of AF as an anti-tumor agent in colorectal cancer (CRC) cells. We found that CRC cells expressing high levels of CST1 undergo increased autophagy and exhibit chemotherapeutic resistance to AF-induced cell death, while those expressing low levels of CST1 are sensitive to AF. We also observed that knockdown of CST1 in high-CST1 CRC cells using CST1-specific small interfering RNAs attenuated autophagic activation and restored AF-induced cell mortality. Conversely, the overexpression of CST1 increased autophagy and viability in cells expressing low levels of CST1. Interestingly, high expression of CST1 attenuates AF-induced cell death by inhibiting intracellular reactive oxygen species (ROS) generation, as demonstrated by the fact that the blockage of ROS production reversed AF-induced cell death in CRC cells. In addition, upregulation of CST1 expression increased cellular glutathione reductase (GR) activity, reducing the cellular redox state and inducing autophagy in AF-treated CRC cells. These results suggest that high CST1 expression may be involved in autophagic induction and protects from AF-induced cell death by inhibition of ROS generation through the regulation of GR activity.
[Mh] Termos MeSH primário: Auranofina/farmacologia
Autofagia/efeitos dos fármacos
Morte Celular/efeitos dos fármacos
Neoplasias Colorretais/metabolismo
Glutationa Redutase/metabolismo
Espécies Reativas de Oxigênio/metabolismo
Cistatinas Salivares/farmacologia
[Mh] Termos MeSH secundário: Catepsinas/farmacologia
Linhagem Celular Tumoral
Sobrevivência Celular/efeitos dos fármacos
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos
Células HCT116
Células HT29
Seres Humanos
Oxirredução/efeitos dos fármacos
Complexo de Endopeptidases do Proteassoma/metabolismo
Inibidores de Proteassoma/farmacologia
Cistatinas Salivares/metabolismo
Tiorredoxina Redutase 1/metabolismo
Regulação para Cima/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (CST1 protein, human); 0 (Proteasome Inhibitors); 0 (Reactive Oxygen Species); 0 (Salivary Cystatins); 3H04W2810V (Auranofin); EC 1.8.1.7 (Glutathione Reductase); EC 1.8.1.9 (Thioredoxin Reductase 1); EC 3.4.- (Cathepsins); EC 3.4.25.1 (Proteasome Endopeptidase Complex)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171027
[Lr] Data última revisão:
171027
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170317
[St] Status:MEDLINE
[do] DOI:10.1038/cddis.2017.100


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[PMID]:28218611
[Au] Autor:Hwang-Bo H; Jeong JW; Han MH; Park C; Hong SH; Kim GY; Moon SK; Cheong J; Kim WJ; Yoo YH; Choi YH
[Ad] Endereço:Department of Biochemistry, Dongeui University College of Korean Medicine, Busan 614-052, Republic of Korea.choiyh@deu.ac.kr.
[Ti] Título:Auranofin, an inhibitor of thioredoxin reductase, induces apoptosis in hepatocellular carcinoma Hep3B cells by generation of reactive oxygen species.
[So] Source:Gen Physiol Biophys;36(2):117-128, 2017 Apr.
[Is] ISSN:0231-5882
[Cp] País de publicação:Slovakia
[La] Idioma:eng
[Ab] Resumo:Mammalian thioredoxin reductase (TrxR) plays a vital role in restoring cellular redox balance disrupted by reactive oxygen species (ROS) generation and oxidative damage. Here, we evaluated whether auranofin, a selective inhibitor of TrxR, could serve as a potential anti-cancer agent through its selective targeting of TrxR activity in Hep3B hepatocellular carcinoma cells. Auranofin treatment reduced the TrxR activity of these cells and induced apoptosis, which were accompanied by up-regulation of death receptors (DRs) and activation of caspases, as well as promotion of proteolytic degradation of poly(ADP-ribose)-polymerase. Treatment with a pan-caspase inhibitor reversed the auranofin-induced apoptosis and growth suppression, indicating that auranofin may induce apoptosis through a caspase-dependent mechanism involving both the intrinsic and extrinsic apoptotic pathways. Auranofin also significantly altered mitochondrial function, promoting mitochondrial membrane permeabilization and cytochrome c release by regulating Bcl-2 family proteins; these events were accompanied by an accumulation of ROS. Inhibition of ROS generation with the ROS quencher significantly attenuated the inactivation of TrxR in auranofin-treated cells and almost completely suppressed the auranofin-induced up-regulation of DRs and activation of caspases, thereby preventing auranofin-induced apoptosis and loss of cell viability. Taken together, these findings indicate that auranofin inhibition of TrxR activity in Hep3B cells activates ROS- and caspase-dependent apoptotic signaling pathways and triggers cancer cell death.
[Mh] Termos MeSH primário: Apoptose/efeitos dos fármacos
Auranofina/administração & dosagem
Carcinoma Hepatocelular/tratamento farmacológico
Carcinoma Hepatocelular/metabolismo
Espécies Reativas de Oxigênio/metabolismo
Tiorredoxina Dissulfeto Redutase/antagonistas & inibidores
[Mh] Termos MeSH secundário: Carcinoma Hepatocelular/patologia
Linhagem Celular Tumoral
Relação Dose-Resposta a Droga
Seres Humanos
Neoplasias Hepáticas/tratamento farmacológico
Neoplasias Hepáticas/metabolismo
Neoplasias Hepáticas/patologia
Tiorredoxina Dissulfeto Redutase/metabolismo
Resultado do Tratamento
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Reactive Oxygen Species); 3H04W2810V (Auranofin); EC 1.8.1.9 (Thioredoxin-Disulfide Reductase)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170619
[Lr] Data última revisão:
170619
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170221
[St] Status:MEDLINE
[do] DOI:10.4149/gpb_2016043


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[PMID]:28149831
[Au] Autor:Thangamani S; Maland M; Mohammad H; Pascuzzi PE; Avramova L; Koehler CM; Hazbun TR; Seleem MN
[Ad] Endereço:Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University West Lafayette, IN, USA.
[Ti] Título:Repurposing Approach Identifies Auranofin with Broad Spectrum Antifungal Activity That Targets Mia40-Erv1 Pathway.
[So] Source:Front Cell Infect Microbiol;7:4, 2017.
[Is] ISSN:2235-2988
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:Current antifungal therapies have limited effectiveness in treating invasive fungal infections. Furthermore, the development of new antifungal is currently unable to keep pace with the urgent demand for safe and effective new drugs. Auranofin, an FDA-approved drug for the treatment of rheumatoid arthritis, inhibits growth of a diverse array of clinical isolates of fungi and represents a new antifungal agent with a previously unexploited mechanism of action. In addition to auranofin's potent antifungal activity against planktonic fungi, this drug significantly reduces the metabolic activity of cells encased in a biofilm. Unbiased chemogenomic profiling, using heterozygous deletion strains, combined with growth assays revealed three probable targets for auranofin's antifungal activity- , and . Mia40 is of particular interest given its essential role in oxidation of cysteine rich proteins imported into the mitochondria. Biochemical analysis confirmed auranofin targets the Mia40-Erv1 pathway as the drug inhibited Mia40 from interacting with its substrate, Cmc1, in a dose-dependent manner similar to the control, MB-7. Furthermore, yeast mitochondria overexpressing Erv1 were shown to exhibit resistance to auranofin as an increase in Cmc1 import was observed compared to wild-type yeast. Further antifungal activity of auranofin was examined in a animal model of infection. Auranofin significantly reduced the fungal load in infected . Collectively, the present study provides valuable evidence that auranofin has significant promise to be repurposed as a novel antifungal agent and may offer a safe, effective, and quick supplement to current approaches for treating fungal infections.
[Mh] Termos MeSH primário: Antifúngicos/farmacologia
Auranofina/farmacologia
Proteínas de Transporte da Membrana Mitocondrial/metabolismo
Proteínas Mitocondriais/metabolismo
Oxirredutases atuantes sobre Doadores de Grupo Enxofre/metabolismo
Proteínas de Saccharomyces cerevisiae/metabolismo
Transdução de Sinais/efeitos dos fármacos
[Mh] Termos MeSH secundário: Biofilmes/efeitos dos fármacos
Reposicionamento de Medicamentos
Deleção de Genes
Perfilação da Expressão Gênica
Regulação Fúngica da Expressão Gênica
Haploinsuficiência
Seres Humanos
Potenciais da Membrana
Testes de Sensibilidade Microbiana
Mitocôndrias/efeitos dos fármacos
Mitocôndrias/metabolismo
Proteínas Mitocondriais/genética
Oxirredutases atuantes sobre Doadores de Grupo Enxofre/genética
Consumo de Oxigênio
Espécies Reativas de Oxigênio/metabolismo
Proteínas de Saccharomyces cerevisiae/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antifungal Agents); 0 (MIA40 protein, S cerevisiae); 0 (Mitochondrial Membrane Transport Proteins); 0 (Mitochondrial Proteins); 0 (Reactive Oxygen Species); 0 (Saccharomyces cerevisiae Proteins); 3H04W2810V (Auranofin); EC 1.8.- (Oxidoreductases Acting on Sulfur Group Donors); EC 1.8.3.2 (ERV1 protein, S cerevisiae)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:171104
[Lr] Data última revisão:
171104
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170203
[St] Status:MEDLINE
[do] DOI:10.3389/fcimb.2017.00004


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[PMID]:28110998
[Au] Autor:Justilien V; Ali SA; Jamieson L; Yin N; Cox AD; Der CJ; Murray NR; Fields AP
[Ad] Endereço:Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Griffin Cancer Research Building, Room 212, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
[Ti] Título:Ect2-Dependent rRNA Synthesis Is Required for KRAS-TRP53-Driven Lung Adenocarcinoma.
[So] Source:Cancer Cell;31(2):256-269, 2017 Feb 13.
[Is] ISSN:1878-3686
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The guanine nucleotide exchange factor (GEF) epithelial cell transforming sequence 2 (Ect2) has been implicated in cancer. However, it is not clear how Ect2 causes transformation and whether Ect2 is necessary for tumorigenesis in vivo. Here, we demonstrate that nuclear Ect2 GEF activity is required for Kras-Trp53 lung tumorigenesis in vivo and that Ect2-mediated transformation requires Ect2-dependent rDNA transcription. Ect2 activates rRNA synthesis by binding the nucleolar transcription factor upstream binding factor 1 (UBF1) on rDNA promoters and recruiting Rac1 and its downstream effector nucleophosmin (NPM) to rDNA. Protein kinase Cι (PKCι)-mediated Ect2 phosphorylation stimulates Ect2-dependent rDNA transcription. Thus, Ect2 regulates rRNA synthesis through a PKCι-Ect2-Rac1-NPM signaling axis that is required for lung tumorigenesis.
[Mh] Termos MeSH primário: Adenocarcinoma/etiologia
Neoplasias Pulmonares/etiologia
Proteínas Proto-Oncogênicas p21(ras)/fisiologia
Proteínas Proto-Oncogênicas/fisiologia
RNA Ribossômico/biossíntese
Proteína Supressora de Tumor p53/fisiologia
[Mh] Termos MeSH secundário: Animais
Auranofina/farmacologia
Linhagem Celular Tumoral
Nucléolo Celular/metabolismo
Citocinese
Seres Humanos
Isoenzimas/fisiologia
Camundongos
Proteínas Nucleares/fisiologia
Proteína Quinase C/fisiologia
Transdução de Sinais/fisiologia
Proteínas rac1 de Ligação ao GTP/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ECT2 protein, human); 0 (Isoenzymes); 0 (KRAS protein, human); 0 (Nuclear Proteins); 0 (Proto-Oncogene Proteins); 0 (RAC1 protein, human); 0 (RNA, Ribosomal); 0 (TP53 protein, human); 0 (Tumor Suppressor Protein p53); 117896-08-9 (nucleophosmin); 3H04W2810V (Auranofin); EC 2.7.11.13 (Protein Kinase C); EC 2.7.11.13 (protein kinase C lambda); EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras)); EC 3.6.5.2 (rac1 GTP-Binding Protein)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170629
[Lr] Data última revisão:
170629
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170124
[St] Status:MEDLINE


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[PMID]:28098782
[Au] Autor:Carle S; Brink T; Orth JH; Aktories K; Barth H
[Ad] Endereço:Institute of Pharmacology and Toxicology, University of Ulm Medical Center, Albert-Einstein-Allee 11, Ulm 89081, Germany. stefan.carle@uni-ulm.de.
[Ti] Título:Auranofin Inhibits the Enzyme Activity of Pasteurella multocida Toxin PMT in Human Cells and Protects Cells from Intoxication.
[So] Source:Toxins (Basel);9(1), 2017 Jan 13.
[Is] ISSN:2072-6651
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:The AB-type protein toxin from (PMT) contains a functionally important disulfide bond within its catalytic domain, which must be cleaved in the host cell cytosol to render the catalytic domain of PMT into its active conformation. Here, we found that the reductive potential of the cytosol of target cells, and more specifically, the activity of the thioredoxin reductase (TrxR) is crucial for this process. This was demonstrated by the strong inhibitory effect of the pharmacological TrxR inhibitor auranofin, which inhibited the intoxication of target cells with PMT, as determined by analyzing the PMT-catalyzed deamidation of GTP-binding proteins (G-proteins) in the cytosol of cells. The amount of endogenous substrate levels modified by PMT in cells pretreated with auranofin was reduced compared to cells treated with PMT alone. Auranofin had no inhibitory effect on the activity of the catalytic domain of constitutively active PMT in vitro, demonstrating that auranofin did not directly inhibit PMT activity, but interferes with the mode of action of PMT in cells. In conclusion, the results show that TrxR is crucial for the mode of action of PMT in mammalian cells, and that the drug auranofin can serve as an efficient inhibitor, which might be a starting point for novel therapeutic options against toxin-associated diseases.
[Mh] Termos MeSH primário: Auranofina/farmacologia
Proteínas de Bactérias/antagonistas & inibidores
Toxinas Bacterianas/antagonistas & inibidores
Pasteurella multocida/enzimologia
Tiorredoxina Dissulfeto Redutase/antagonistas & inibidores
[Mh] Termos MeSH secundário: Proteínas de Bactérias/genética
Toxinas Bacterianas/genética
Domínio Catalítico
Técnicas de Cultura de Células
Citosol/metabolismo
Células HeLa
Proteínas Heterotriméricas de Ligação ao GTP/metabolismo
Interações Hospedeiro-Patógeno
Seres Humanos
Pasteurella multocida/patogenicidade
Virulência
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Bacterial Proteins); 0 (Bacterial Toxins); 0 (Pasteurella multocida toxin); 3H04W2810V (Auranofin); EC 1.8.1.9 (Thioredoxin-Disulfide Reductase); EC 3.6.5.1 (Heterotrimeric GTP-Binding Proteins)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171110
[Lr] Data última revisão:
171110
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170119
[St] Status:MEDLINE


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[PMID]:27838777
[Au] Autor:Jatoi A; Grudem ME; Dockter TJ; Block MS; Villasboas JC; Tan A; Deering E; Kasi PM; Mansfield AS; Botero JP; Okuno SH; Smith DR; Fields AP
[Ad] Endereço:Department of Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA. jatoi.aminah@mayo.edu.
[Ti] Título:A proof-of-concept trial of protein kinase C iota inhibition with auranofin for the paclitaxel-induced acute pain syndrome.
[So] Source:Support Care Cancer;25(3):833-838, 2017 Mar.
[Is] ISSN:1433-7339
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:PURPOSE: Paclitaxel causes the paclitaxel-induced acute pain (PIAP) syndrome. Based on preclinical data, we hypothesized that the protein kinase C (PKC) iota inhibitor, auranofin (a gold salt used for other pain conditions), palliates this pain. METHODS: In a randomized, double-blinded manner, patients who had suffered this syndrome were assigned a one-time dose of auranofin 6 mg orally on day #2 of the chemotherapy cycle (post-paclitaxel) versus placebo. Patients completed the Brief Pain Inventory and a pain diary on days 2 through 8 and at the end of the cycle. The primary endpoint was pain scores, as calculated by area under the curve, in response to "Please rate your pain by circling the one number that best describes your pain at its worse in the last 24 hours." RESULTS: Thirty patients were enrolled. For the primary endpoint, mean area under the curve of 55 units (standard deviation 19) and 61 units (standard deviation 22) were observed in auranofin-treated and placebo-exposed patients, respectively (p = 0.44). On day 8 and at the end of the cycle, pain scores in auranofin-treated patients were more favorable, although differences were not statistically significant. CONCLUSIONS: In the dose schedule studied, auranofin did not palliate the PIAP syndrome, but delayed beneficial trends suggest further study for this indication.
[Mh] Termos MeSH primário: Dor Aguda/induzido quimicamente
Dor Aguda/tratamento farmacológico
Auranofina/administração & dosagem
Isoenzimas/antagonistas & inibidores
Paclitaxel/efeitos adversos
Proteína Quinase C/antagonistas & inibidores
Inibidores de Proteínas Quinases/administração & dosagem
[Mh] Termos MeSH secundário: Dor Aguda/enzimologia
Administração Oral
Antineoplásicos Fitogênicos/efeitos adversos
Antineoplásicos Fitogênicos/uso terapêutico
Método Duplo-Cego
Feminino
Seres Humanos
Masculino
Meia-Idade
Paclitaxel/uso terapêutico
Doenças do Sistema Nervoso Periférico/induzido quimicamente
Doenças do Sistema Nervoso Periférico/tratamento farmacológico
Síndrome
[Pt] Tipo de publicação:JOURNAL ARTICLE; RANDOMIZED CONTROLLED TRIAL
[Nm] Nome de substância:
0 (Antineoplastic Agents, Phytogenic); 0 (Isoenzymes); 0 (Protein Kinase Inhibitors); 3H04W2810V (Auranofin); EC 2.7.11.13 (Protein Kinase C); EC 2.7.11.13 (protein kinase C lambda); P88XT4IS4D (Paclitaxel)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171011
[Lr] Data última revisão:
171011
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161114
[St] Status:MEDLINE
[do] DOI:10.1007/s00520-016-3467-9


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[PMID]:27821451
[Au] Autor:Capparelli EV; Bricker-Ford R; Rogers MJ; McKerrow JH; Reed SL
[Ad] Endereço:Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California, USA.
[Ti] Título:Phase I Clinical Trial Results of Auranofin, a Novel Antiparasitic Agent.
[So] Source:Antimicrob Agents Chemother;61(1), 2017 Jan.
[Is] ISSN:1098-6596
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Under an NIH priority to identify new drugs to treat class B parasitic agents, we performed high-throughput screens, which identified the activity of auranofin (Ridaura) against Entamoeba histolytica and Giardia intestinalis, major causes of water- and foodborne outbreaks. Auranofin, an orally administered, gold (Au)-containing compound that was approved by the FDA in 1985 for treatment of rheumatoid arthritis, was effective in vitro and in vivo against E. histolytica and both metronidazole-sensitive and -resistant strains of Giardia We now report the results of an NIH-sponsored phase I trial to characterize the pharmacokinetics (PK) and safety of auranofin in healthy volunteers using modern techniques to measure gold levels. Subjects received orally 6 mg (p.o.) of auranofin daily, the recommended dose for rheumatoid arthritis, for 7 days and were followed for 126 days. Treatment-associated adverse events were reported by 47% of the subjects, but all were mild and resolved without treatment. The mean gold maximum concentration in plasma (C ) at day 7 was 0.312 µg/ml and the half-life (t ) 35 days, so steady-state blood levels would not be reached in short-term therapy. The highest concentration of gold, 13 µM (auranofin equivalent), or more than 25× the 50% inhibitory concentration (IC ) for E. histolytica and 4× that for Giardia, was in feces at 7 days. Modeling of higher doses (9 and 21 mg/day) was performed for systemic parasitic infections, and plasma gold levels of 0.4 to 1.0 µg/ml were reached after 14 days of treatment at 21 mg/day. This phase I trial supports the idea of the safety of auranofin and provides important PK data to support its potential use as a broad-spectrum antiparasitic drug. (This study has been registered at ClinicalTrials.gov under identifier NCT02089048.).
[Mh] Termos MeSH primário: Antiparasitários/farmacocinética
Antirreumáticos/farmacocinética
Auranofina/farmacocinética
Entamoeba histolytica/efeitos dos fármacos
Giardia lamblia/efeitos dos fármacos
Modelos Estatísticos
[Mh] Termos MeSH secundário: Administração Oral
Adulto
Antiparasitários/sangue
Antirreumáticos/sangue
Auranofina/sangue
Simulação por Computador
Esquema de Medicação
Cálculos da Dosagem de Medicamento
Reposicionamento de Medicamentos
Entamoeba histolytica/crescimento & desenvolvimento
Feminino
Giardia lamblia/crescimento & desenvolvimento
Ouro/sangue
Meia-Vida
Voluntários Saudáveis
Ensaios de Triagem em Larga Escala
Seres Humanos
Concentração Inibidora 50
Masculino
Metronidazol/farmacologia
Distribuição Tecidual
[Pt] Tipo de publicação:CLINICAL TRIAL, PHASE I; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antiparasitic Agents); 0 (Antirheumatic Agents); 140QMO216E (Metronidazole); 3H04W2810V (Auranofin); 7440-57-5 (Gold)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170918
[Lr] Data última revisão:
170918
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161109
[Cl] Clinical Trial:ClinicalTrial
[St] Status:MEDLINE


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[PMID]:27268469
[Au] Autor:Wiederhold NP; Patterson TF; Srinivasan A; Chaturvedi AK; Fothergill AW; Wormley FL; Ramasubramanian AK; Lopez-Ribot JL
[Ad] Endereço:a Department of Pathology , The University of Texas Health Science Center at San Antonio , San Antonio , TX , USA.
[Ti] Título:Repurposing auranofin as an antifungal: In vitro activity against a variety of medically important fungi.
[So] Source:Virulence;8(2):138-142, 2017 Feb 17.
[Is] ISSN:2150-5608
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Repositioning old drugs can significantly decrease the time and effort that it takes to develop novel antifungal therapeutics, which represents a pressing and unmet clinical need due to the devastating nature of fungal infections. We have previously described the activity of auranofin, a gold thiol compound used to treat rheumatoid arthritis, against Candida albicans biofilms. Here we evaluate its antifungal spectrum of action and describe its activity against a variety of medically important fungi.
[Mh] Termos MeSH primário: Antifúngicos/farmacologia
Antirreumáticos/farmacologia
Auranofina/farmacologia
Candida albicans/efeitos dos fármacos
Reposicionamento de Medicamentos
[Mh] Termos MeSH secundário: Aspergillus fumigatus/efeitos dos fármacos
Candidíase/microbiologia
Fungos/efeitos dos fármacos
Seres Humanos
Testes de Sensibilidade Microbiana
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antifungal Agents); 0 (Antirheumatic Agents); 3H04W2810V (Auranofin)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170726
[Lr] Data última revisão:
170726
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160609
[St] Status:MEDLINE
[do] DOI:10.1080/21505594.2016.1196301



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