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Auranofin

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https://www.readbyqxmd.com/read/29619196/dual-targeting-of-the-cancer-antioxidant-network-with-1-4-naphthoquinone-fused-gold-i-n-heterocyclic-carbene-complexes
#1
R McCall, M Miles, P Lascuna, B Burney, Z Patel, K J Sidoran, V Sittaramane, J Kocerha, D A Grossie, J L Sessler, K Arumugam, J F Arambula
To achieve a systems-based approach to targeting the antioxidant pathway, 1,4-naphthoquinone annulated N-heterocyclic carbene (NHC) [bis(1,3-dimesityl-4,5-naphthoquino-imidazol-2-ylidene)-gold(i)] [silver(i) dichloride] ( 1 ), [bis(1,3-dimesityl-4,5-naphthoquino-imidazol-2-ylidene)-gold(i)] chloride ( 2 ), and 1,3-dimesityl-4,5-naphthoquino-imidazol-2-ylidene)-gold(i) chloride ( 3 )) were designed, synthesized, and tested for biological activity in a series of human cancer cell lines. The solution phase of complexes 1-3 were assigned using several spectroscopy techniques, including NMR spectroscopic analysis...
September 1, 2017: Chemical Science
https://www.readbyqxmd.com/read/29599910/developing-a-genetic-signature-to-predict-drug-response-in-ovarian-cancer
#2
Stephen Hyter, Jeff Hirst, Harsh Pathak, Ziyan Y Pessetto, Devin C Koestler, Rama Raghavan, Dong Pei, Andrew K Godwin
There is a lack of personalized treatment options for women with recurrent platinum-resistant ovarian cancer. Outside of bevacizumab and a group of poly ADP-ribose polymerase inhibitors, few options are available to women that relapse. We propose that efficacious drug combinations can be determined via molecular characterization of ovarian tumors along with pre-established pharmacogenomic profiles of repurposed compounds. To that end, we selectively performed multiple two-drug combination treatments in ovarian cancer cell lines that included reactive oxygen species inducers and HSP90 inhibitors...
March 13, 2018: Oncotarget
https://www.readbyqxmd.com/read/29579058/comparative-oncology-approach-to-drug-repurposing-in-osteosarcoma
#3
Alejandro Parrales, Peter McDonald, Megan Ottomeyer, Anuradha Roy, Frank J Shoenen, Melinda Broward, Tyce Bruns, Douglas H Thamm, Scott J Weir, Kathleen A Neville, Tomoo Iwakuma, Joy M Fulbright
BACKGROUND: Osteosarcoma is an orphan disease for which little improvement in survival has been made since the late 1980s. New drug discovery for orphan diseases is limited by the cost and time it takes to develop new drugs. Repurposing already approved FDA-drugs can help overcome this limitation. Another limitation of cancer drug discovery is the lack of preclinical models that accurately recapitulate what occurs in humans. For OS using dogs as a model can minimize this limitation as OS in canines develops spontaneously, is locally invasive and metastasizes to the lungs as it does in humans...
2018: PloS One
https://www.readbyqxmd.com/read/29556223/repurposing-auranofin-ebselen-and-px-12-as-antimicrobial-agents-targeting-the-thioredoxin-system
#4
REVIEW
Holly C May, Jieh-Juen Yu, M N Guentzel, James P Chambers, Andrew P Cap, Bernard P Arulanandam
As microbial resistance to drugs continues to rise at an alarming rate, finding new ways to combat pathogens is an issue of utmost importance. Development of novel and specific antimicrobial drugs is a time-consuming and expensive process. However, the re-purposing of previously tested and/or approved drugs could be a feasible way to circumvent this long and costly process. In this review, we evaluate the U.S. Food and Drug Administration tested drugs auranofin, ebselen, and PX-12 as antimicrobial agents targeting the thioredoxin system...
2018: Frontiers in Microbiology
https://www.readbyqxmd.com/read/29554646/deubiquitinase-inhibitor-auranofin-attenuated-cardiac-hypertrophy-by-blocking-nf-%C3%AE%C2%BAb-activation
#5
Ming Hu, Zhenhui Zhang, Bin Liu, Shuangwei Zhang, Renjie Chai, Xiaohua Chen, Tianyu Kong, Fangcheng Zhang, Jingzhi Zhang, Shiming Liu, Ningning Liu
BACKGROUND/AIMS: Cardiac hypertrophy is a major outcome and compensatory response of the cardiovascular system to hemodynamic and additional stress responses that ultimately lead to heart failure. Auranofin (Aur) has been used for treating rheumatic arthritis for several decades. Aur is a 19S proteasome-associated deubiquitinase inhibitor, and inhibition of the proteasome is speculated to reverse cardiac hypertrophy. However, the role of the deubiquitinases, especially 19S proteasome-associated deubiquitinases, in the regulation of cardiac remodeling remains poorly understood...
March 15, 2018: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/29550336/endothelium-derived-hyperpolarizing-factor-and-protein-kinase-g-i%C3%AE-activation-h-2-o-2-versus-s-nitrosothiols
#6
Paula K Bautista-Niño, Marien van der Stel, Wendy W Batenburg, René de Vries, Anton J M Roks, A H Jan Danser
Protein kinase G (PKG) Iα mediates the cyclic guanosine monophosphate-mediated vasodilatory effects induced by NO. Endothelium-derived hyperpolarizing factors (EDHFs), like H2 O2 can activate PKGIα in a cyclic guanosine monophosphate-independent manner, but whether this is true for all EDHFs (e.g., S-nitrosothiols) is unknown. Here, we investigated the contribution of PKGIα to bradykinin-, H2 O2 -, L-S-nitrosocysteine-, and light-induced relaxation in porcine coronary arteries, making use of the fact that thioredoxin reductase inhibition with auranofin or 1-chloro-2,4-dinitrobenzene potentiates PKGIα...
March 14, 2018: European Journal of Pharmacology
https://www.readbyqxmd.com/read/29526505/biochemical-and-thermodynamic-comparison-of-the-selenocysteine-containing-and-non-containing-thioredoxin-glutathione-reductase-of-fasciola-gigantica
#7
Parismita Kalita, Harish Shukla, Rohit Shukla, Timir Tripathi
The thiol-disulfide redox metabolism in platyhelminth parasites depends entirely on a single selenocysteine (Sec) containing flavoenzyme, thioredoxin glutathione reductase (TGR) that links the classical thioredoxin (Trx) and glutathione (GSH) systems. In the present study, we investigated the catalytic and structural properties of different variants of Fasciola gigantica TGR to understand the role of Sec. The recombinant full-length Sec containing TGR (FgTGRsec), TGR without Sec (FgTGR) and TGRsec without the N-terminal glutaredoxin (Grx) domain (∆NTD-FgTGRsec) were purified to homogeneity...
March 8, 2018: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/29508136/a-heterometallic-ruthenium-gold-complex-displays-antiproliferative-antimigratory-and-antiangiogenic-properties-and-inhibits-metastasis-and-angiogenesis-associated-proteases-in-renal-cancer
#8
Benelita T Elie, Yuriy Pechenyy, Fathema Uddin, María Contel
Heterobimetallic compounds are designed to harness chemotherapeutic traits of distinct metal species into a single molecule. The ruthenium-gold (Ru-Au) family of compounds based on Au-N-heterocyclic carbene (NHC) fragments [Cl2 (p-cymene)Ru(μ-dppm)Au(NHC)]ClO4 was conceived to combine the known antiproliferative and cytotoxic properties of Au-NHC-based compounds and the antimigratory, antimetastatic, and antiangiogenic characteristic of specific Ru-based compounds. Following recent studies of the anticancer efficacies of these Ru-Au-NHC complexes with promising potential as chemotherapeutics against colorectal, and renal cancers in vitro, we report here on the mechanism of a selected compound, [Cl2 (p-cymene)Ru(μ-dppm)Au(IMes)]ClO4 (RANCE-1, 1)...
March 5, 2018: Journal of Biological Inorganic Chemistry: JBIC
https://www.readbyqxmd.com/read/29465117/gold-i-phosphine-compounds-as-parasite-attenuating-agents-for-malaria-vaccine-and-drug-development
#9
Aloysious Ssemaganda, Leanne M Low, Krista R Verhoeft, Mathias Wambuzi, Barbarah Kawoozo, Sharon B Nabasumba, Juliet Mpendo, Bernard S Bagaya, Noah Kiwanuka, Danielle I Stanisic, Susan J Berners-Price, Michael F Good
Here, the anti-malarial activity of two gold(i) phosphine compounds auranofin and [Au(d2pype)2 ]Cl (where d2pype is 1,2-bis(di-2-pyridylphosphino)ethane), were examined to inform their use as potential drugs and malaria parasite-attenuating agents. In vitro, the gold compounds were active against Plasmodium falciparum and P. knowlesi as well as the rodent parasite P. chabaudi AS. Attenuation of the parasite was observed when mice were inoculated with P. chabaudi AS infected red blood cells treated in vitro with [Au(d2pype)2 ]Cl (1 or 2 μM) or auranofin (2 μM) for 2 or 3 h...
February 21, 2018: Metallomics: Integrated Biometal Science
https://www.readbyqxmd.com/read/29444979/irreversible-inhibition-of-cytosolic-thioredoxin-reductase-1-as-a-mechanistic-basis-for-anticancer-therapy
#10
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
#11
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
#12
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
#13
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-tumour-redox-status-in-response-to-modulations-of-glutathione-and-thioredoxin-antioxidant-pathways
#14
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 glutathione (GSH) and thioredoxin (TRX) systems cooperate to a tight regulation of ROS in cell physiology, and to a stimulation of tumour 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 tumour redox status are critically needed to assess the relevance of redox-targeted agents...
February 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
#15
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...
February 1, 2018: 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
#16
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
#17
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
#18
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
#19
https://www.readbyqxmd.com/read/29065820/recent-advances-in-antabuse-disulfiram-the-importance-of-its-metal-binding-ability-to-its-anticancer-activity
#20
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
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