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Auranofin

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https://www.readbyqxmd.com/read/29444979/irreversible-inhibition-of-cytosolic-thioredoxin-reductase-1-as-a-mechanistic-basis-for-anticancer-therapy
#1
William C Stafford, Xiaoxiao Peng, Maria Hägg Olofsson, Xiaonan Zhang, Diane K Luci, Li Lu, Qing Cheng, Lionel Trésaugues, Thomas S Dexheimer, Nathan P Coussens, Martin Augsten, Hanna-Stina Martinsson Ahlzén, Owe Orwar, Arne Östman, Sharon Stone-Elander, David J Maloney, Ajit Jadhav, Anton Simeonov, Stig Linder, Elias S J Arnér
Cancer cells adapt to their inherently increased oxidative stress through activation of the glutathione (GSH) and thioredoxin (TXN) systems. Inhibition of both of these systems effectively kills cancer cells, but such broad inhibition of antioxidant activity also kills normal cells, which is highly unwanted in a clinical setting. We therefore evaluated targeting of the TXN pathway alone and, more specifically, selective inhibition of the cytosolic selenocysteine-containing enzyme TXN reductase 1 (TXNRD1). TXNRD1 inhibitors were discovered in a large screening effort and displayed increased specificity compared to pan-TXNRD inhibitors, such as auranofin, that also inhibit the mitochondrial enzyme TXNRD2 and additional targets...
February 14, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/29399682/the-antioxidant-2-6-di-tert-butylphenol-moiety-attenuates-the-pro-oxidant-properties-of-the-auranofin-analogue
#2
D B Shpakovsky, A A Shtil, E V Kharitonashvili, V Yu Tyurin, T A Antonenko, A A Nazarov, V P Osipova, N T Berberova, L S Foteeva, C Schmidt, I Ott, E R Milaeva
Metal-based drugs are gaining momentum as a rapidly developing area of medicinal inorganic chemistry. Among gold pharmaceuticals, auranofin is a well known antirheumatic drug. The efficacy of gold-organic complexes largely depends on their pro-oxidant properties since auranofin targets the redox enzyme thioredoxin reductase (TrxR). However, an uncontrollable oxygen burst may be harmful for healthy cells; therefore, the search for chemical modifications to attenuate oxidation-related general toxicity of gold containing anti-inflammatory drugs is justified...
February 5, 2018: Metallomics: Integrated Biometal Science
https://www.readbyqxmd.com/read/29396541/tdp-43-self-interaction-is-modulated-by-redox-active-compounds-auranofin-chelerythrine-and-riluzole
#3
Moritz Oberstadt, Jens Stieler, David Larbi Simpong, Ute Römuß, Nicole Urban, Michael Schaefer, Thomas Arendt, Max Holzer
Amyotrophic lateral sclerosis (ALS) represents a fatal neurodegenerative disease, which is characterized by a rapid loss of lower and upper motor neurons. As a major neuropathological hallmark, protein aggregates containing the Transactivating Response Region (TAR) DNA Binding Protein (TDP-43) are detectable in about 95% of sporadic ALS patients. TDP-43 interacts with itself physiologically to form liquid droplets, which may progress to pathological aggregates. In this study, we established the NanoBit luciferase complementation assay to measure TDP-43 self-interaction and found the fusion of the split luciferase subunits to the N-terminus of the protein as the strongest interacting partners...
February 2, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29367724/elimination-of-stem-like-cancer-cell-side-population-by-auranofin-through-modulation-of-ros-and-glycolysis
#4
Guo-Xin Hou, Pan-Pan Liu, Shengyi Zhang, Mengqi Yang, Jianwei Liao, Jing Yang, Yumin Hu, Wen-Qi Jiang, Shijun Wen, Peng Huang
Cancer side-population (SP) represents a sub-population of stem-like cancer cells that have an important role in drug resistance due to their high expression of the ATP-binding cassette transporter ABCG2 involved in drug export. Auranofin (AF), a clinical drug of gold complex that is used in treatment of rheumatoid arthritis, has been reported inducing tumor antiproliferation. However, whether AF can impact SP cells remains unclear. Our study showed that AF caused a depletion of SP cells and a downregulation of stem cell markers, and impaired their ability to form tumor colonies in vitro and incidence to develop tumors in vivo of lung cancer cells...
January 24, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/29320894/biomarkers-of-tumor-redox-status-in-response-to-modulations-of-glutathione-and-thioredoxin-antioxidant-pathways
#5
Julie Kengen, Jean-Philippe Deglasse, Marie-Aline Neveu, Lionel Mignion, Céline Desmet, Florian Gourgue, Jean-Christophe Jonas, Bernard Gallez, Bénédicte F Jordan
The ability of certain cancer cells to maintain a highly reduced intracellular environment is correlated with aggressiveness and drug resistance. Since the gluthathione (GSH) and thioredoxin (TRX) systems cooperate to a tight regulation of ROS in cell physiology, and to a stimulation of tumor initiation and progression, modulation of the GSH and TRX pathways are emerging as new potential targets in cancer. In vivo methods to assess changes in tumor redox status are critically needed to assess the relevance of redox-targeted agents...
January 10, 2018: Free Radical Research
https://www.readbyqxmd.com/read/29277393/the-possible-repositioning-of-an-oral-anti-arthritic-drug-auranofin-for-nrf2-activating-therapy-the-demonstration-of-nrf2-dependent-anti-oxidative-action-using-a-zebrafish-model
#6
Yuji Fuse, Yuka Endo, Sho Araoi, Hiroaki Daitoku, Hiroyuki Suzuki, Mitsuyasu Kato, Makoto Kobayashi
The Nrf2 pathway is a biological defense system against oxidative stress. The pharmacological activation of the Nrf2 pathway is a promising therapy for oxidative stress-related diseases, but it has been challenging to find an Nrf2 activator with acceptable toxicity. To circumvent this problem, we focused on an already approved oral anti-arthritic drug, auranofin that has been reported to have the potential to activate Nrf2. We used a zebrafish model to investigate whether auranofin has protective action against oxidative stress in vivo...
December 19, 2017: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/29223747/an-automated-high-throughput-system-for-phenotypic-screening-of-chemical-libraries-on-c-elegans-and-parasitic-nematodes
#7
Frederick A Partridge, Anwen E Brown, Steven D Buckingham, Nicky J Willis, Graham M Wynne, Ruth Forman, Kathryn J Else, Alison A Morrison, Jacqueline B Matthews, Angela J Russell, David A Lomas, David B Sattelle
Parasitic nematodes infect hundreds of millions of people and farmed livestock. Further, plant parasitic nematodes result in major crop damage. The pipeline of therapeutic compounds is limited and parasite resistance to the existing anthelmintic compounds is a global threat. We have developed an INVertebrate Automated Phenotyping Platform (INVAPP) for high-throughput, plate-based chemical screening, and an algorithm (Paragon) which allows screening for compounds that have an effect on motility and development of parasitic worms...
December 2, 2017: International Journal for Parasitology, Drugs and Drug Resistance
https://www.readbyqxmd.com/read/29221187/selection-and-characterization-of-a-human-ovarian-cancer-cell-line-resistant-to-auranofin
#8
Ida Landini, Andrea Lapucci, Alessandro Pratesi, Lara Massai, Cristina Napoli, Gabriele Perrone, Pamela Pinzani, Luigi Messori, Enrico Mini, Stefania Nobili
The anti-arthritic drug auranofin exerts also potent antitumour activity in in vitro and in vivo models, whose mechanisms are not yet well defined. From an auranofin-sensitive human ovarian cancer cell line A2780, a highly resistant (>20-fold) subline (A2780/AF-R) was developed and characterized. Marked reduction of gold accumulation occurred in auranofin-resistant A2780 cells. Also, moderately higher thioredoxin reductase activity in A2780/AF-R cells was observed while no changes in intracellular glutathione content occurred...
November 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/29194002/auranofin-a-thioredoxin-reductase-inhibitor-causes-platelet-death-through-calcium-overload
#9
Matthew T Harper
Platelets are central to normal hemostasis and must be tightly controlled to prevent thrombosis. However, drug treatments that also affect platelets could lead to unwanted side effects on hemostasis or thrombosis. In this study, the effect of auranofin on platelets was tested. Auranofin, a gold-based thioredoxin reductase (TRXR) inhibitor, has been previously used in arthritis. Recently, auranofin and other inhibitors of the thioredoxin system have been proposed as novel anti-cancer therapies. TRXR is an important part of the antioxidant defenses in many cells that maintain intracellular proteins in their reduced state...
December 1, 2017: Platelets
https://www.readbyqxmd.com/read/29077771/correction-correction-auranofin-inhibits-retinal-pigment-epithelium-cell-survival-through-reactive-oxygen-species-dependent-epidermal-growth-factor-receptor-mitogen-activated-protein-kinase-signaling-pathway
#10
https://www.readbyqxmd.com/read/29065820/recent-advances-in-antabuse-disulfiram-the-importance-of-its-metal-binding-ability-to-its-anticancer-activity
#11
Maricela Viola-Rhenals, Kush Rohit Patel, Laura Jaimes-Santamaria, Guojun Wu, Jinbao Liu, Q Ping Dou
Disulfiram (DSF, also called tetraethylthiuram disulphide), a disulfide derivative of N,N-diethyldithiocarbamate (DEDTC), is an antialcoholism drug that is currently being repurposed as a promising anticancer drug. DSF has been investigated in many studies, including in vitro, in vivo, preclinical and clinical. Various mechanisms have been proposed to be responsible for the cytotoxic effect of DSF on cancer cells. DSF is a pro-drug which is converted to its metabolite DEDTC in human body. A complex of DEDTC with a metal ion [usually Cu(II) or Zn(II)] could be responsible for the anticancer activity of DSF in breast, prostate, glioblastoma, lung, melanoma, cervical, colorectal cancers as well as myeloma and leukemia...
October 23, 2017: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/29057040/auranofin-et3paucl-and-et3paui-are-highly-cytotoxic-on-colorectal-cancer-cells-a-chemical-and-biological-study
#12
Tiziano Marzo, Damiano Cirri, Chiara Gabbiani, Tania Gamberi, Francesca Magherini, Alessandro Pratesi, Annalisa Guerri, Tarita Biver, Francesca Binacchi, Matteo Stefanini, Annarosa Arcangeli, Luigi Messori
The solution behavior of auranofin, Et3PAuCl  and Et3PAuI, as well as their interactions with hen egg white lysozyme, single strand oligonucleotide, and ds-DNA were comparatively analyzed through NMR spectroscopy, ESI-MS, ethidium bromide displacement, DNA melting and viscometric tests. The cytotoxic effects toward representative colorectal cancer cell lines were found to be strong and similar in the three cases and a good correlation could be established between the cytotoxicity and the ability to inhibit thioredoxin reductase; remarkably, in vivo acute toxicity experiments for Et3PAuI confirmed that, similarly to auranofin, this drug is well tolerated in a murine model...
October 12, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29039082/metal-based-proteasomal-deubiquitinase-inhibitors-as-potential-anticancer-agents
#13
Xin Chen, Qianqian Yang, Lu Xiao, Daolin Tang, Q Ping Dou, Jinbao Liu
Deubiquitinases (DUBs) play an important role in protein quality control in eukaryotic cells due to their ability to specifically remove ubiquitin from substrate proteins. Therefore, recent findings have focused on the relevance of DUBs to cancer development, and pharmacological intervention on these enzymes has become a promising strategy for cancer therapy. In particular, several DUBs are physically and/or functionally associated with the proteasome and are attractive targets for the development of novel anticancer drugs...
October 16, 2017: Cancer Metastasis Reviews
https://www.readbyqxmd.com/read/28984321/the-cytotoxicity-and-mechanism-of-action-of-new-multinuclear-scaffold-au-iii-pd-ii-pincer-complexes-containing-a-bis-diphenylphosphino-ferrocene-non-ferrocene-ligand
#14
Leila Tabrizi, Hossein Chiniforoshan
New multinuclear gold(iii), palladium(ii) pincer complexes containing bis(diphenylphosphino) ferrocene/non-ferrocene ligands of formula [(L)Au(μ(2)-η(2)-CS3)Pd(dppf)](PF6)2, 1, and [(L)Au(μ(2)-η(2)-CS3)Pd(dppe)](PF6)2, 2 (HL = 5-methoxy-1,3-bis (1-methyl-1H-benzo[d]imidazol-2-yl)benzene, dppf = 1,1'-bis(diphenylphosphino)ferrocene, and dppe = bis(diphenylphosphino)ethane) have been synthesized and fully characterized. Both complexes are more cytotoxic to a number of human cancer cell lines than cisplatin...
October 24, 2017: Dalton Transactions: An International Journal of Inorganic Chemistry
https://www.readbyqxmd.com/read/28981107/targeting-redox-homeostasis-in-rhabdomyosarcoma-cells-gsh-depleting-agents-enhance-auranofin-induced-cell-death
#15
Karoline Johanna Habermann, Leon Grünewald, Sjoerd van Wijk, Simone Fulda
Rhabdomyosarcoma (RMS) cells have recently been reported to be sensitive to oxidative stress. Therefore, we investigated whether concomitant inhibition of the two main antioxidant defense pathways, that is, the thioredoxin (TRX) and the glutathione (GSH) systems, presents a new strategy to trigger cell death in RMS. In this study, we discover that GSH-depleting agents, i.e. γ-glutamylcysteine synthetase inhibitor, buthionine sulfoximine (BSO) or the cystine/glutamate antiporter inhibitor erastin (ERA), synergize with thioredoxin reductase (TrxR) inhibitor auranofin (AUR) to induce cell death in RMS cells...
October 5, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28947276/selective-inhibition-of-endogenous-antioxidants-with-auranofin-causes-mitochondrial-oxidative-stress-which-can-be-countered-by-selenium-supplementation
#16
Filip Radenkovic, Olivia Holland, Jessica J Vanderlelie, Anthony V Perkins
Auranofin is a thiol-reactive gold (I)-containing compound with potential asa chemotherapeutic. Auranofin has the capacity to selectively inhibit endogenous antioxidant enzymes thioredoxin reductase (TrxR) and glutathione peroxidase (GPx), resulting in oxidative stress and the initiation of a pro-apoptotic cascade. The effect of Auranofin exposure on TrxR and GPx, and the potential for cellular protection through selenium supplementation was examined in the non-cancerous human cell line Swan-71. Auranofin exposure resulted in a concentration dependent differential inhibition of selenoprotein antioxidants...
September 22, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28937773/probing-the-hiv-1-ncp7-nucleocapsid-protein-with-site-specific-gold-i-phosphine-complexes
#17
Raphael E F de Paiva, Zhifeng Du, Erica J Peterson, Pedro P Corbi, Nicholas P Farrell
In this work, we examined a series of thiophilic Au(I) compounds based on [Au(L)(PR3)] (L = Cl(-), 4-dimethylaminopyridine (dmap); R= ethyl (Et), cyclohexyl (Cy)) for chemoselective auration of the C-terminal HIV nucleocapsid protein NCp7 F2 and the "full" HIV NCp7 (NC, zinc finger (ZnF)) as probes of nucleocapsid topography. The choice of phosphine allowed electronic and steric effects to be considered. The use of the heterocycle "leaving group" allowed us to study the effect of possible π-stacking with the essential tryptophan residue of NC on the reactivity and selectivity, mimicking the naturally occurring interaction between the zinc finger and nucleic acids...
September 22, 2017: Inorganic Chemistry
https://www.readbyqxmd.com/read/28913818/a-spectroscopic-study-of-interaction-of-auricyanide-with-n-acetylcysteine
#18
Syed G T Kazimi, Mohammad S Iqbal, C Frank Shaw
Interaction of auricyanide, an important metabolite of anti-arthritic gold-based drug auranofin, was studied in vitro with a pharmacologically active ligand n-acetylcysteine with a view to understand reactivity of gold in vivo. Formation of reduction product aurocyanide occurred through mono- and di-n-acetylcysteine-substituted intermediates. The product and intermediates were identified and monitored spectrophotometrically and by electrospray ionization mass spectrometry. This study suggests successive substitution with n-acetylcysteine through trans effect...
September 14, 2017: Biological Trace Element Research
https://www.readbyqxmd.com/read/28910741/drug-susceptibility-testing-in-microaerophilic-parasites-cysteine-strongly-affects-the-effectivities-of-metronidazole-and-auranofin-a-novel-and-promising-antimicrobial
#19
David Leitsch
The microaerophilic parasites Entamoeba histolytica, Trichomonas vaginalis, and Giardia lamblia annually cause hundreds of millions of human infections which are treated with antiparasitic drugs. Metronidazole is the most often prescribed drug but also other drugs are in use, and novel drugs with improved characteristics are constantly being developed. One of these novel drugs is auranofin, originally an antirheumatic which has been relabelled for the treatment of parasitic infections. Drug effectivity is arguably the most important criterion for its applicability and is commonly assessed in susceptibility assays using in vitro cultures of a given pathogen...
September 5, 2017: International Journal for Parasitology, Drugs and Drug Resistance
https://www.readbyqxmd.com/read/28906491/cystatin-sn-inhibits-auranofin-induced-cell-death-by-autophagic-induction-and-ros-regulation-via-glutathione-reductase-activity-in-colorectal-cancer
#20
Byung Moo Oh, Seon-Jin Lee, Hee Jun Cho, Yun Sun Park, Jong-Tae Kim, Suk Ran Yoon, Sang Chul Lee, Jong-Seok Lim, Bo-Yeon Kim, Yong-Kyung Choe, Hee Gu Lee
This corrects the article DOI: 10.1038/cddis.2017.100.
September 14, 2017: Cell Death & Disease
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