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Auranofin

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https://www.readbyqxmd.com/read/28415723/auranofin-radiosensitizes-tumor-cells-through-targeting-thioredoxin-reductase-and-resulting-overproduction-of-reactive-oxygen-species
#1
Hui Wang, Soumaya Bouzakoura, Sven de Mey, Heng Jiang, Kalun Law, Inès Dufait, Cyril Corbet, Valeri Verovski, Thierry Gevaert, Olivier Feron, Dirk Van den Berge, Guy Storme, Mark De Ridder
Auranofin (AF) is an anti-arthritic drug considered for combined chemotherapy due to its ability to impair the redox homeostasis in tumor cells. In this study, we asked whether AF may in addition radiosensitize tumor cells by targeting thioredoxin reductase (TrxR), a critical enzyme in the antioxidant defense system operating through the reductive protein thioredoxin. Our principal findings in murine 4T1 and EMT6 tumor cells are that AF at 3-10 μM is a potent radiosensitizer in vitro, and that at least two mechanisms are involved in TrxR-mediated radiosensitization...
March 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/28402987/new-insights-into-redox-homeostasis-as-a-therapeutic-target-in-b-cell-malignancies
#2
Agnieszka Graczyk-Jarzynka, Radoslaw Zagozdzon, Angelika Muchowicz, Marta Siernicka, Malgorzata Firczuk, Przemyslaw Juszczynski
PURPOSE OF REVIEW: The goal of this review is to summarize recent advances in our understanding of the regulation of redox homeostasis and the subtype-specific role of antioxidant enzymes in B-cell-derived malignancies. Furthermore, it presents selected prooxidative therapeutic strategies against B-cell neoplasms. RECENT FINDINGS: Recent reports have shown that the disturbed redox homeostasis in B-cell malignancies is regulated by cancer-specific signaling pathways and therefore varies between the individual subtypes...
April 13, 2017: Current Opinion in Hematology
https://www.readbyqxmd.com/read/28389407/d-penicillamine-combined-with-inhibitors-of-hydroperoxide-metabolism-enhances-lung-and-breast-cancer-cell-responses-to-radiation-and-carboplatin-via-h2o2-mediated-oxidative-stress
#3
Sebastian J Sciegienka, Shane R Solst, Kelly C Falls, Joshua D Schoenfeld, Adrienne R Klinger, Natalie L Ross, Samuel N Rodman, Douglas R Spitz, Melissa A Fath
D-penicillamine (DPEN), a copper chelator, has been used in the treatment of Wilson's disease, cystinuria, and rheumatoid arthritis. Recent evidence suggests that DPEN in combination with biologically relevant copper (Cu) concentrations generates H2O2 in cancer cell cultures, but the effects of this on cancer cell responses to ionizing radiation and chemotherapy are unknown. Increased steady-state levels of H2O2 were detected in MB231 breast and H1299 lung cancer cells following treatment with DPEN (100µM) and copper sulfate (15µM)...
April 5, 2017: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/28358030/allosteric-cross-talk-in-chromatin-can-mediate-drug-drug-synergy
#4
Zenita Adhireksan, Giulia Palermo, Tina Riedel, Zhujun Ma, Reyhan Muhammad, Ursula Rothlisberger, Paul J Dyson, Curt A Davey
Exploitation of drug-drug synergism and allostery could yield superior therapies by capitalizing on the immensely diverse, but highly specific, potential associated with the biological macromolecular landscape. Here we describe a drug-drug synergy mediated by allosteric cross-talk in chromatin, whereby the binding of one drug alters the activity of the second. We found two unrelated drugs, RAPTA-T and auranofin, that yield a synergistic activity in killing cancer cells, which coincides with a substantially greater number of chromatin adducts formed by one of the compounds when adducts from the other agent are also present...
March 30, 2017: Nature Communications
https://www.readbyqxmd.com/read/28319891/time-and-cell-resolved-dynamics-of-redox-sensitive-nrf2-hif-and-nf-%C3%AE%C2%BAb-activities-in-3d-spheroids-enriched-for-cancer-stem-cells
#5
Anna P Kipp, Stefanie Deubel, Elias S J Arnér, Katarina Johansson
Cancer cells have an altered redox status, with changes in intracellular signaling pathways. The knowledge of how such processes are regulated in 3D spheroids, being well-established tumor models, is limited. To approach this question we stably transfected HCT116 cells with a pTRAF reporter that enabled time- and cell-resolved activity monitoring of three redox-regulated transcription factors Nrf2, HIF and NF-κB in spheroids enriched for cancer stem cells. At the first day of spheroid formation, these transcription factors were activated and thereafter became repressed...
March 10, 2017: Redox Biology
https://www.readbyqxmd.com/read/28300829/cystatin-sn-inhibits-auranofin-induced-cell-death-by-autophagic-induction-and-ros-regulation-via-glutathione-reductase-activity-in-colorectal-cancer
#6
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
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...
March 16, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28222166/correction-auranofin-inhibits-retinal-pigment-epithelium-cell-survival-through-reactive-oxygen-species-dependent-epidermal-growth-factor-receptor-mitogen-activated-protein-kinase-signaling-pathway
#7
Xiaodong Chen, Radouil Tzekov, Mingyang Su, Haiyan Hong, Wang Min, Aidong Han, Wensheng Li
[This corrects the article DOI: 10.1371/journal.pone.0166386.].
2017: PloS One
https://www.readbyqxmd.com/read/28218611/auranofin-an-inhibitor-of-thioredoxin-reductase-induces-apoptosis-in-hepatocellular-carcinoma-hep3b-cells-by-generation-of-reactive-oxygen-species
#8
Hyun Hwang-Bo, Jin-Woo Jeong, Min Ho Han, Cheol Park, Su-Hyun Hong, Gi-Young Kim, Sung-Kwon Moon, Jaehun Cheong, Wun-Jae Kim, Young Hyun Yoo, Yung Hyun Choi
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...
February 20, 2017: General Physiology and Biophysics
https://www.readbyqxmd.com/read/28155927/mononuclear-gold-iii-complexes-with-l-histidine-containing-dipeptides-tuning-the-structural-and-biological-properties-by-variation-of-the-n-terminal-amino-acid-and-counter-anion
#9
Beata Warżajtis, Biljana Đ Glišić, Nada D Savić, Aleksandar Pavic, Sandra Vojnovic, Aleksandar Veselinović, Jasmina Nikodinovic-Runic, Urszula Rychlewska, Miloš I Djuran
Gold(iii) complexes with different l-histidine-containing dipeptides, [Au(Gly-l-His-NA,NP,N3)Cl]Cl·3H2O (1a), [Au(Gly-l-His-NA,NP,N3)Cl]NO3·1.25H2O (1b), [Au(l-Ala-l-His-NA,NP,N3)Cl][AuCl4]·H2O (2a), [Au(l-Ala-l-His-NA,NP,N3)Cl]NO3·2.5H2O (2b), [Au(l-Val-l-His-NA,NP,N3)Cl]Cl·2H2O (3), [Au(l-Leu-l-His-NA,NP,N3)Cl]Cl (4a) and [Au(l-Leu-l-His-NA,NP,N3)Cl][AuCl4]·H2O (4b), have been synthesized and structurally characterized by spectroscopic ((1)H NMR, IR and UV-vis) and single-crystal X-ray diffraction techniques...
February 3, 2017: Dalton Transactions: An International Journal of Inorganic Chemistry
https://www.readbyqxmd.com/read/28149831/repurposing-approach-identifies-auranofin-with-broad-spectrum-antifungal-activity-that-targets-mia40-erv1-pathway
#10
Shankar Thangamani, Matthew Maland, Haroon Mohammad, Pete E Pascuzzi, Larisa Avramova, Carla M Koehler, Tony R Hazbun, Mohamed N Seleem
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 Candida cells encased in a biofilm...
2017: Frontiers in Cellular and Infection Microbiology
https://www.readbyqxmd.com/read/28129719/differences-in-reperfusion-induced-mitochondrial-oxidative-stress-and-cell-death-between-hippocampal-ca1-and-ca3-subfields-are-due-to-the-mitochondrial-thioredoxin-system
#11
Bocheng Yin, Germán Barrionuevo, Ines Batinic-Haberle, Mats Sandberg, Stephen G Weber
AIMS: The susceptibility of CA1 over CA3 to damage from cerebral ischemia may be related to the differences in reactive oxygen species (ROS) production/removal between the two hippocampal subfields. We aimed to measure CA1/CA3 differences in net ROS production in real time in the first 30 min of reperfusion in pyramidal cells. We aimed to determine the underlying cause of the differential vulnerability of CA1 and CA3. RESULTS: Real-time determinations of mitochondrial H2O2 and, independently, glutathione (GSH) redox status from roGFP-based probes in individual pyramidal cells in organotypic hippocampal cultures during oxygen-glucose deprivation (OGD)-reperfusion (RP) demonstrate a significantly more oxidizing environment during RP in CA1 than CA3 mitochondria...
March 7, 2017: Antioxidants & Redox Signaling
https://www.readbyqxmd.com/read/28098782/auranofin-inhibits-the-enzyme-activity-of-pasteurella-multocida-toxin-pmt-in-human-cells-and-protects-cells-from-intoxication
#12
Stefan Carle, Thorsten Brink, Joachim H C Orth, Klaus Aktories, Holger Barth
The AB-type protein toxin from Pasteurella multocida (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...
January 13, 2017: Toxins
https://www.readbyqxmd.com/read/28045936/detoxification-of-mitochondrial-oxidants-and-apoptotic-signaling-are-facilitated-by-thioredoxin-2-and-peroxiredoxin-3-during-hyperoxic-injury
#13
Benjamin J Forred, Darwin R Daugaard, Brianna K Titus, Ryan R Wood, Miranda J Floen, Michelle L Booze, Peter F Vitiello
Mitochondria play a fundamental role in the regulation of cell death during accumulation of oxidants. High concentrations of atmospheric oxygen (hyperoxia), used clinically to treat tissue hypoxia in premature newborns, is known to elicit oxidative stress and mitochondrial injury to pulmonary epithelial cells. A consequence of oxidative stress in mitochondria is the accumulation of peroxides which are detoxified by the dedicated mitochondrial thioredoxin system. This system is comprised of the oxidoreductase activities of peroxiredoxin-3 (Prx3), thioredoxin-2 (Trx2), and thioredoxin reductase-2 (TrxR2)...
2017: PloS One
https://www.readbyqxmd.com/read/27956714/auranofin-suppresses-plasminogen-activator-inhibitor-2-expression-through-annexin-a5-induction-in-human-prostate-cancer-cells
#14
Dong-Won Shin, Yeo-Jung Kwon, Dong-Jin Ye, Hyoung-Seok Baek, Joo-Eun Lee, Young-Jin Chun
Auranofin has been developed as antirheumatic drugs, which is currently under clinical development for the treatment of chronic lymphocytic leukemia. Previous report showed that auranofin induced apoptosis by enhancement of annexin A5 expression in PC-3 cells. To understand the role of annexin A5 in auranofin-mediated apoptosis, we performed microarray data analysis to study annexin A5-controlled gene expression in annexin A5 knockdown PC-3 cells. Of differentially expressed genes, plasminogen activator inhibitor (PAI)-2 was increased by annexin A5 siRNA confirmed by qRT-PCR and western blot...
March 1, 2017: Biomolecules & Therapeutics
https://www.readbyqxmd.com/read/27924803/gsk-3beta-inhibitor-induces-expression-of-nrf2-trxr2-signaling-pathway-to-protect-against-renal-ischemia-reperfusion-injury-in-diabetic-rats
#15
Bo Hu, Yuhong Wu, Jie Liu, Xiaohua Shen, Fei Tong, Guangtao Xu, Ruilin Shen
BACKGROUND/AIMS: Diabetes mellitus (DM) can lead to renal damage and dysfunction, and exacerbate renal ischemia/reperfusion injury (RI/RI). The aim of this study was to investigate the protective effect of GSK-3β inhibitor TDZD-8 against RI/RI through Nrf2/TrxR2 signaling pathway in a rat DM model. METHODS: A DM rat model was established by a single injection of streptozocin. Diabetic rats were pretreated with TDZD-8 (1 mg/kg bw) or TDZD-8+auranofin (10 nmol/L, 5ml/kg bw), and then subjected to 45-min ischemia and 24-h reperfusion...
2016: Kidney & Blood Pressure Research
https://www.readbyqxmd.com/read/27863422/in-silico-and-in-vitro-drug-screening-identifies-new-therapeutic-approaches-for-ewing-sarcoma
#16
Ziyan Y Pessetto, Bin Chen, Hani Alturkmani, Stephen Hyter, Colleen A Flynn, Michael Baltezor, Yan Ma, Howard G Rosenthal, Kathleen A Neville, Scott J Weir, Atul J Butte, Andrew K Godwin
The long-term overall survival of Ewing sarcoma (EWS) patients remains poor; less than 30% of patients with metastatic or recurrent disease survive despite aggressive combinations of chemotherapy, radiation and surgery. To identify new therapeutic options, we employed a multi-pronged approach using in silico predictions of drug activity via an integrated bioinformatics approach in parallel with an in vitro screen of FDA-approved drugs. Twenty-seven drugs and forty-six drugs were identified, respectively, to have anti-proliferative effects for EWS, including several classes of drugs in both screening approaches...
January 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/27863404/kallikrein-related-peptidase-6-induces-chemotherapeutic-resistance-by-attenuating-auranofin-induced-cell-death-through-activation-of-autophagy-in-gastric-cancer
#17
Tae Woo Kim, Seon-Jin Lee, Jong-Tae Kim, Sun Jung Kim, Jeong-Ki Min, Kwang-Hee Bae, Haiyoung Jung, Bo-Yeon Kim, Jong-Seok Lim, Young Yang, Do-Young Yoon, Yong-Kyung Choe, Hee Gu Lee
Kallikrein-related peptidase 6 (KLK6) is a biomarker of gastric cancer associated with poor prognosis. Mechanisms by which KLK6 could be exploited for chemotherapeutic use are unclear. We evaluated auranofin (AF), a compound with cytotoxic effects, in KLK6-deficient cells, and we investigated whether KLK6 expression induces autophagy and acquisition of drug resistance in gastric cancer. Using cultured human cells and a mouse xenograft model, we investigated how KLK6 affects antitumor-reagent-induced cell death and autophagy...
November 15, 2016: Oncotarget
https://www.readbyqxmd.com/read/27846303/auranofin-inhibits-retinal-pigment-epithelium-cell-survival-through-reactive-oxygen-species-dependent-epidermal-growth-factor-receptor-mitogen-activated-protein-kinase-signaling-pathway
#18
Xiaodong Chen, Radouil Tzekov, Mingyang Su, Haiyan Hong, Wang Min, Aidong Han, Wensheng Li
Abnormal survival of retinal pigment epithelium (RPE) cells contributes to the pathogenesis of proliferative vitreoretinopathy (PVR), a sight-threatening disease. In this study, we explored the effect of the anti-rheumatic agent auranofin (AF) on RPE cell survival and studied the underlying signaling mechanisms in vitro. Our results showed that AF inhibited ARPE-19 cell survival in a dose and time-dependent manner. Application of AF induced several effects: a significant decrease in total epidermal growth factor receptor (EGFR) and an increase in phosphorylated EGFR and mitogen-activated protein kinase (MAPK), including extracellular signal-regulated kinase (ERK), P38 mitogen-activated protein kinase (P38MAPK), c-Jun N-terminal kinase (JNK), c-Jun, mitogen activated protein kinase activated protein kinase 2(MAPKAPK2), and heat shock protein 27 (HSP27)...
2016: PloS One
https://www.readbyqxmd.com/read/27845352/tusc2-fus1-erlotinib-induced-vulnerabilities-in-epidermal-growth-factor-receptor-egfr-wildtype-non-small-cell-lung-cancer-nsclc-targeted-by-the-repurposed-drug-auranofin
#19
Cao Xiaobo, Mourad Majidi, Meng Feng, Ruping Shao, Jing Wang, Yang Zhao, Veerabhadran Baladandayuthapani, Juhee Song, Bingliang Fang, Lin Ji, Reza Mehran, Jack A Roth
Expression of the TUSC2/FUS1 tumor suppressor gene in TUSC2 deficient EGFR wildtype lung cancer cells increased sensitivity to erlotinib. Microarray mRNA expression analysis of TUSC2 inducible lung cancer cells treated with erlotinib uncovered defects in the response to oxidative stress suggesting that increasing reactive oxygen species (ROS) would enhance therapeutic efficacy. Addition of the thioredoxin reductase 1 inhibitor (TXNRD1) auranofin (AF) to NSCLC cells treated with combination of TUSC2 forced expression with erlotinib increased tumor cell apoptosis and inhibited colony formation...
November 15, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27826141/rapid-antimicrobial-susceptibility-test-for-identification-of-new-therapeutics-and-drug-combinations-against-multidrug-resistant-bacteria
#20
Wei Sun, Rebecca A Weingarten, Miao Xu, Noel Southall, Sheng Dai, Paul Shinn, Philip E Sanderson, Peter R Williamson, Karen M Frank, Wei Zheng
Current antimicrobial susceptibility testing has limited screening capability for identifying empirical antibiotic combinations to treat severe bacterial infections with multidrug-resistant (MDR) organisms. We developed a new antimicrobial susceptibility assay using automated ultra-high-throughput screen technology in combination with a simple bacterial growth assay. A rapid screening of 5170 approved drugs and other compounds identified 25 compounds with activities against MDR Klebsiella pneumoniae. To further improve the efficacy and reduce the effective drug concentrations, we applied a targeted drug combination approach that integrates drugs' clinical antimicrobial susceptibility breakpoints, achievable plasma concentrations, clinical toxicities and mechanisms of action to identify optimal drug combinations...
November 9, 2016: Emerging Microbes & Infections
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