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Auranofin

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https://www.readbyqxmd.com/read/28098782/auranofin-inhibits-the-enzyme-activity-of-pasteurella-multocida-toxin-pmt-in-human-cells-and-protects-cells-from-intoxication
#1
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
#2
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
#3
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...
December 13, 2016: 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
#4
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
#5
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...
November 16, 2016: 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
#6
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
#7
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
#8
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
#9
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
https://www.readbyqxmd.com/read/27821451/phase-i-clinical-trial-results-of-auranofin-a-novel-antiparasitic-agent
#10
Edmund V Capparelli, Robin Bricker-Ford, M John Rogers, James H McKerrow, Sharon L Reed
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...
January 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/27813112/developmental-toxicity-of-auranofin-in-zebrafish-embryos
#11
Xiao-Yan Gao, Kang Li, Ling-Ling Jiang, Ming-Fang He, Cun-Hai Pu, Dongzhou Kang, Jingjing Xie
Auranofin (AF) is used in clinic for the treatment of rheumatoid arthritis, repurposing of AF as an anticancer drug has just finished a phase I/II clinical trial, but the developmental toxicity of AF remains obscure. This study focused on its developmental toxicity by using zebrafish embryos. Zebrafish embryos were exposed to different concentrations (1, 2.5, 5, 10 μm) of AF from 2 h post-fertilization (hpf) to 72 hpf. At 72 hpf, two major developmental defects caused by AF were found, namely severe pericardial edema and hypopigmentation, when embryos were exposed to concentrations higher than 2...
November 4, 2016: Journal of Applied Toxicology: JAT
https://www.readbyqxmd.com/read/27756752/tsc2-deficiency-unmasks-a-novel-necrosis-pathway-that-is-suppressed-by-the-rip1-rip3-mlkl-signaling-cascade
#12
Piotr T Filipczak, Cindy Thomas, Wenshu Chen, Andrew Salzman, Jacob D McDonald, Yong Lin, Steven A Belinsky
Tuberous sclerosis complex (TSC) is a genetic multiorgan disorder characterized by the development of neoplastic lesions in kidney, lung, brain, heart, and skin. It is caused by an inactivating mutation in tumor suppressor genes coding the TSC1/TSC2 complex, resulting in the hyperactivation of mTOR- and Raf/MEK/MAPK-dependent signaling that stimulates tumor cell proliferation and metastasis. Despite its oncogenic effect, cells with TSC deficiency were more sensitive to oxidative stress and dependent on mitochondrial metabolism, providing a rationale for a new therapeutic approach...
December 15, 2016: Cancer Research
https://www.readbyqxmd.com/read/27733046/targeting-of-the-glutathione-thioredoxin-and-nrf2-antioxidant-systems-in-head-and-neck-cancer
#13
Jong-Lyel Roh, Hye Jin Jang, Eun Hye Kim, Daiha Shin
AIMS: The glutathione (GSH), thioredoxin (Trx), and Nrf2 systems represent a major defense against reactive oxygen species (ROS), the cellular imbalance of which in cancer promotes growth and therapeutic resistance. This study investigated whether targeting the GSH, Trx, and Nrf2 antioxidant systems effectively eliminated head and neck cancer (HNC). RESULTS: At high concentrations, auranofin, but not buthionine sulfoximine (BSO) alone, decreased the viability of HNC, whereas even at low concentrations, auranofin plus BSO synergized to kill HNC cells...
October 12, 2016: Antioxidants & Redox Signaling
https://www.readbyqxmd.com/read/27698473/apocynin-and-nox2-regulate-nf-%C3%AE%C2%BAb-by-modifying-thioredoxin-1-redox-state
#14
Silvia Cellone Trevelin, Célio Xavier Dos Santos, Raphael Gomes Ferreira, Larissa de Sá Lima, Rangel Leal Silva, Cristoforo Scavone, Rui Curi, José Carlos Alves-Filho, Thiago Mattar Cunha, Pérsio Roxo-Júnior, Maria-Célia Cervi, Francisco Rafael Martins Laurindo, John Stephen Hothersall, Andrew M Cobb, Min Zhang, Aleksandar Ivetic, Ajay M Shah, Lucia Rossetti Lopes, Fernando Queiroz Cunha
The reactive-oxygen-species-(ROS)-generating-enzyme Nox2 is essential for leukocyte anti-microbial activity. However its role in cellular redox homeostasis and, consequently, in modulating intracellular signaling pathways remains unclear. Herein, we show Nox2 activation favors thioredoxin-1 (TRX-1)/p40phox interaction, which leads to exclusion of TRX-1 from the nucleus. In contrast, the genetic deficiency of Nox2 or its pharmacological inhibition with apocynin (APO) results in reductive stress after lipopolysaccharide-(LPS)-cell stimulation, which causes nuclear accumulation of TRX-1 and enhanced transcription of inflammatory mediators through nuclear-factor-(NF)-κB...
October 4, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27692298/linking-genotoxicity-and-cytotoxicity-with-membrane-fluidity-a-comparative-study-in-ovarian-cancer-cell-lines-following-exposure-to-auranofin
#15
Deepu Oommen, Nicholas J F Dodd, Dennis Yiannakis, Rana Moyeed, Awadhesh N Jha
Auranofin, an organogold compound classified as an anti-rheumatic agent is under phase 2 clinical trials for re-purposing to treat recurrent epithelial ovarian cancer. We have reported earlier that Breast cancer 1, early onset (BRCA1) mutant ovarian cancer cells exhibit increased sensitivity to auranofin. BRCA1 is a DNA repair protein whose functional status is critical in the prognosis of ovarian cancer. Apart from DNA repair capability of cancer cells, membrane fluidity is also implicated in modulating resistance to chemotherapeutics...
October 2016: Mutation Research
https://www.readbyqxmd.com/read/27643875/enhancement-of-radiation-response-in-breast-cancer-stem-cells-by-inhibition-of-thioredoxin-and-glutathione-dependent-metabolism
#16
Samuel N Rodman, Jacquelyn M Spence, Tyler J Ronnfeldt, Yueming Zhu, Shane R Solst, Rebecca A O'Neill, Bryan G Allen, Xiangming Guan, Douglas R Spitz, Melissa A Fath
The goal of this study was to determine if depletion of glutathione (GSH) and inhibition of thioredoxin (Trx) reductase (TrxR) activity could enhance radiation responses in human breast cancer stem cells by a mechanism involving thiol-dependent oxidative stress. The following were used to inhibit GSH and Trx metabolism: buthionine sulfoximine (BSO), a GSH synthesis inhibitor; sulfasalazine (SSZ), an inhibitor of xc(-) cysteine/glutamate antiporter; auranofin (Au), a thioredoxin reductase inhibitor; or 2-AAPA, a GSH-reductase inhibitor...
October 2016: Radiation Research
https://www.readbyqxmd.com/read/27581528/serum-thioredoxin-reductase-is-highly-increased-in-mice-with-hepatocellular-carcinoma-and-its-activity-is-restrained-by-several-mechanisms
#17
Le Zhang, Qing Cheng, Longjie Zhang, Yijun Wang, Gary F Merrill, Tal Ilani, Deborah Fass, Elias S J Arnér, Jinsong Zhang
Increased thioredoxin reductase (TrxR) levels in serum were recently identified as possible prognostic markers for human prostate cancer or hepatocellular carcinoma. We had earlier shown that serum levels of TrxR protein are very low in healthy mice, but can in close correlation to alanine aminotransferase (ALT) increase more than 200-fold upon chemically induced liver damage. We also found that enzymatic TrxR activity in serum is counteracted by a yet unidentified oxidase activity in serum. In the present study we found that mice carrying H22 hepatocellular carcinoma tumors present highly increased levels of TrxR in serum, similarly to that reported in human patients...
August 28, 2016: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/27567536/expression-of-the-thioredoxin-system-in-an-in-vivo-like-cancer-cell-environment-upon-auranofin-treatment
#18
Maneet Bhatia, Carrie J Lovitt, Prahlad V Raninga, Vicky M Avery, Giovanna Di Trapani, Kathryn F Tonissen
As essential elements of the tumor microenvironment, the variable oxygenation state of the tumor tissue, the extracellular matrix (ECM) and different cell types are important determinants of carcinogenesis. These elements may also influence how tumor cells respond to therapeutic treatments. In the present study, we assessed the anti-cancer activity of auranofin and its effect on the thioredoxin (Trx) system under conditions that closely resemble the in vivo tumor microenvironment with respect to the oxygen levels and tissue architecture...
October 2016: European Journal of Cell Biology
https://www.readbyqxmd.com/read/27485632/dual-pharmacological-inhibition-of-glutathione-and-thioredoxin-systems-synergizes-to-kill-colorectal-carcinoma-stem-cells
#19
Genki Tanaka, Ken-Ichi Inoue, Takayuki Shimizu, Kazumi Akimoto, Keiichi Kubota
NRF2 stabilizes redox potential through genes for glutathione and thioredoxin antioxidant systems. Whether blockade of glutathione and thioredoxin is useful in eliminating cancer stem cells remain unknown. We used xenografts derived from colorectal carcinoma patients to investigate the pharmacological inhibition of glutathione and thioredoxin systems. Higher expression of five glutathione S-transferase isoforms (GSTA1, A2, M4, O2, and P1) was observed in xenograft-derived spheroids than in fibroblasts. Piperlongumine (2...
September 2016: Cancer Medicine
https://www.readbyqxmd.com/read/27485086/evaluation-of-giardia-lamblia-thioredoxin-reductase-as-drug-activating-enzyme-and-as-drug-target
#20
David Leitsch, Joachim Müller, Norbert Müller
The antioxidative enzyme thioredoxin reductase (TrxR) has been suggested to be a drug target in several pathogens, including the protist parasite Giardia lamblia. TrxR is also believed to catalyse the reduction of nitro drugs, e.g. metronidazole and furazolidone, a reaction required to render these compounds toxic to G. lamblia and other microaerophiles/anaerobes. It was the objective of this study to assess the potential of TrxR as a drug target in G. lamblia and to find direct evidence for the role of this enzyme in the activation of metronidazole and other nitro drugs...
December 2016: International Journal for Parasitology, Drugs and Drug Resistance
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