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Journal of Medicinal Chemistry Nov 2022A new series of seven gold(I) complexes (-) containing 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene (IPr) and phosphane ligands (L1-L7) were synthesized and...
A new series of seven gold(I) complexes (-) containing 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene (IPr) and phosphane ligands (L1-L7) were synthesized and evaluated for antitumor activity in ovarian cancer (OvCa) models. The synthesized complexes were characterized by IR, mass spectrometry and NMR spectroscopy, and complex was characterized by XRD crystallography. The antiproliferative effect of the new complexes (-) was found to be higher than cisplatin and auranofin in OvCa cells sensitive and resistant to cisplatin. The anticancer activity of the most active complex was investigated using OvCa models, including three-dimensional (3D) multicellular tumor spheroids and tumor xenografts. Both cisplatin and auranofin were used for comparative purposes. Complex induced apoptosis, mitochondrial reactive oxygen species, and DNA damage; caused a G1 phase cell cycle arrest, inhibited proteasome activity, and cell migration; modified actin polymerization; and significantly inhibited OvCa murine xenografts. These promising results suggest further preclinical testing of these complexes for future applications.
Topics: Humans; Female; Mice; Animals; Cisplatin; Auranofin; Antineoplastic Agents; Ovarian Neoplasms; Cell Line, Tumor; Coordination Complexes
PubMed: 36278959
DOI: 10.1021/acs.jmedchem.2c00737 -
Journal of Applied Microbiology Sep 2022This study was performed to identify the potential for repurposing auranofin as an antibiotic adjuvant against carbapenemase-producing Acinetobacter baumannii.
AIMS
This study was performed to identify the potential for repurposing auranofin as an antibiotic adjuvant against carbapenemase-producing Acinetobacter baumannii.
METHODS AND RESULTS
The clinically isolated A. baumannii strains used in this study were all resistant to carbapenems and harboured the bla gene. The synergistic effect of auranofin and doripenem against carbapenemase-producing A. baumannii was confirmed through checkerboard and growth kinetic analyses. This study also demonstrated the inhibitory effects of auranofin against A. baumannii biofilms. The anti-biofilm effects of auranofin were visualized by confocal laser scanning microscopy (CLSM). Furthermore, auranofin inhibited motility, one of the virulence factors. Additionally, the changes in the expression of carbapenemase-, biofilm- and efflux pump-related genes induced by auranofin were confirmed via quantitative polymerase chain reaction (qPCR).
CONCLUSIONS
Our results demonstrated that auranofin has an antibacterial effect with doripenem and an inhibitory effect on several factors related to carbapenem resistance.
SIGNIFICANCE AND IMPACT OF THE STUDY
This study suggests that auranofin is a promising antibiotic adjuvant that can be used to prevent antibiotic resistance in carbapenem-resistant A. baumannii.
Topics: Acinetobacter Infections; Acinetobacter baumannii; Anti-Bacterial Agents; Auranofin; Bacterial Proteins; Carbapenems; Doripenem; Drug Resistance, Multiple, Bacterial; Humans; Microbial Sensitivity Tests; beta-Lactamases
PubMed: 35633297
DOI: 10.1111/jam.15644 -
International Journal of Molecular... Jun 2022The biological properties of sixteen structurally related monoanionic gold (III) bis(dithiolene/ diselenolene) complexes were evaluated. The complexes differ in the...
The biological properties of sixteen structurally related monoanionic gold (III) bis(dithiolene/ diselenolene) complexes were evaluated. The complexes differ in the nature of the heteroatom connected to the gold atom (AuS for dithiolene, AuSe for diselenolene), the substituent on the nitrogen atom of the thiazoline ring (Me, Et, Pr, iPr and Bu), the nature of the exocyclic atom or group of atoms (O, S, Se, C(CN)) and the counter-ion (PhP or EtN). The anticancer and antimicrobial activities of all the complexes were investigated, while the anti-HIV activity was evaluated only for selected complexes. Most complexes showed relevant anticancer activities against Cisplatin-sensitive and Cisplatin-resistant ovarian cancer cells A2780 and OVCAR8, respectively. After 48 h of incubation, the IC values ranged from 0.1-8 μM (A2780) and 0.8-29 μM (OVCAR8). The complexes with the PhP ([]) counter-ion are in general more active than their EtN ([]) analogues, presenting IC values in the same order of magnitude or even lower than Auranofin. Studies in the zebrafish embryo model further showed that, despite their marked anticancer effect, the complexes with [] counter-ion exhibited low in vivo toxicity. In general, the exocyclic exchange of sulfur by oxygen or ylidenemalononitrile (C(CN)) enhanced the compounds toxicity. Most complexes containing the [] counter ion exhibited exceptional antiplasmodial activity against the parasite liver stages, with submicromolar IC values ranging from 400-700 nM. In contrast, antibacterial/fungi activities were highest for most complexes with the [] counter-ion. Auranofin and two selected complexes [][AuSBu(=S)] and [][AuSEt(=S)] did not present anti-HIV activity in TZM-bl cells. Mechanistic studies for selected complexes support the idea that thioredoxin reductase, but not DNA, is a possible target for some of these complexes. The complexes [] [AuSBu(=S)], [] [AuSEt(=S)], [] [AuSEt(=Se)] and [] [AuSeiPr(=S)] displayed a strong quenching of the fluorescence intensity of human serum albumin (HSA), which indicates a strong interaction with this protein. Overall, the results highlight the promising biological activities of these complexes, warranting their further evaluation as future drug candidates with clinical applicability.
Topics: Animals; Antineoplastic Agents; Auranofin; Cell Line, Tumor; Cisplatin; Female; Gold; Humans; Ovarian Neoplasms; Zebrafish
PubMed: 35806151
DOI: 10.3390/ijms23137146 -
Cellular Physiology and Biochemistry :... 2015The antiinflammatory, antimicrobial and anticancer drug auranofin has previously been shown to trigger apoptosis, the suicidal death of nucleated cells. Side effects of...
BACKGROUND/AIMS
The antiinflammatory, antimicrobial and anticancer drug auranofin has previously been shown to trigger apoptosis, the suicidal death of nucleated cells. Side effects of the drug include anaemia. At least in theory the anaemia could result from stimulation of suicidal death of erythrocytes or eryptosis, which involves cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface.
METHODS
Stimulators of eryptosis include oxidative stress and increase of cytosolic Ca2+-activity ([Ca2+]i). In the present study, phosphatidylserine exposure at the cell surface was estimated from annexin V binding, cell volume from forward scatter, hemolysis from hemoglobin release, reactive oxygen species (ROS) from 2',7'-dichlorodihydrofluorescein diacetate (DCFDA) fluorescence, and [Ca2+]i from Fluo3-fluorescence.
RESULTS
A 24 hours exposure of human erythrocytes to auranofin (≥5 µg/ml) significantly increased the percentage of annexin-V-binding cells (from 2.2 ± 0.5 to 17.4 ± 1.5%), significantly decreased forward scatter and significantly enhanced ROS. At higher concentrations (10 µg/ml) auranofin triggered slight hemolysis (from 2.1 ± 0.2 to 3.2 ± 0.3%).
CONCLUSIONS
Auranofin stimulates cell shrinkage and phospholipid scrambling of the erythrocyte cell membrane, an effect at least partially due to induction of oxidative stress.
Topics: Annexin A5; Apoptosis; Auranofin; Calcium; Cell Membrane; Cell Size; Dose-Response Relationship, Drug; Erythrocytes; Hemolysis; Humans; Oxidative Stress; Phosphatidylserines
PubMed: 26397807
DOI: 10.1159/000430228 -
Microbiology Spectrum Dec 2022Alternative antimicrobial therapies are urgently required for the multidrug-resistant bacterial pathogen Neisseria gonorrhoeae, for which currently ceftriaxone is the...
Alternative antimicrobial therapies are urgently required for the multidrug-resistant bacterial pathogen Neisseria gonorrhoeae, for which currently ceftriaxone is the only remaining recommended first-line therapy. Repurposing of drugs that are approved for other clinical applications offers an efficient approach for development of alternative antimicrobial therapies. Auranofin, cannabidivarin, and tolfenamic acid were recently identified to display antimicrobial activity against N. gonorrhoeae. Here, we investigated their activity against a collection of 575 multidrug-resistant clinical isolates. All three compounds displayed consistent antimicrobial activity against all isolates, including against strains associated with the high-level ceftriaxone-resistant FC428 clone, with both the mode and MIC for auranofin of 0.5 mg/L, while both the mode and MIC for cannabidivarin and tolfenamic acid were 8 mg/L. Correlations between MICs of ceftriaxone and auranofin, cannabidivarin or tolfenamic acid were low, indicating that development of cross-resistance is unlikely. Furthermore, antimicrobial synergy analysis between ceftriaxone and auranofin, cannabidivarin, or tolfenamic acid by determination of the fractional inhibitory concentration index (FICI) resulted in an interpretation of indifference. Finally, time-kill analyses showed that all three compounds are bactericidal against both the N. gonorrhoeae ATCC 49226 reference strain and an FC428-associated clinical isolate, with particularly cannabidivarin displaying rapid bactericidal activity. Overall, auranofin, cannabidivarin, and tolfenamic acid displayed consistent antimicrobial activity against multidrug-resistant N. gonorrhoeae, warranting further exploration of their suitability as alternative antimicrobials for treatment of gonococcal infections. Neisseria gonorrhoeae is a major public health concern because of the high incidence of gonorrhea and the increasingly limited options for antimicrobial therapy. Strains associated with the FC428 clone are a particular concern because they have shown global dissemination and they display high-level resistance against the currently recommended ceftriaxone therapy. Therefore, development of alternative antimicrobial therapies is urgently required to ensure treatment of gonorrhea remains available in the future. Repurposing of clinically approved drugs could be a rapid approach for the development of such alternative antimicrobials. In this study, we showed that repurposing of auranofin, cannabidivarin, and tolfenamic acid for antimicrobial therapy of gonorrhea deserves further clinical explorations because these compounds displayed consistent antimicrobial activity against a large collection of contemporary multidrug-resistant gonococcal isolates that included strains associated with the FC428 clone.
Topics: Humans; Neisseria gonorrhoeae; Gonorrhea; Ceftriaxone; Auranofin; Anti-Bacterial Agents; Anti-Infective Agents; Microbial Sensitivity Tests; Drug Resistance, Bacterial
PubMed: 36350125
DOI: 10.1128/spectrum.03952-22 -
Dalton Transactions (Cambridge, England... Sep 2022A novel gold(I) complex inspired by the known medicinal inorganic compounds auranofin and thimerosal, namely ethylthiosalicylate(triethylphosphine)gold(I) (AFETT...
A novel gold(I) complex inspired by the known medicinal inorganic compounds auranofin and thimerosal, namely ethylthiosalicylate(triethylphosphine)gold(I) (AFETT hereafter), was synthesized and characterised and its structure was resolved through X-ray diffraction. The solution behavior of AFETT and its interactions with two biologically relevant proteins ( human serum albumin and haemoglobin) and with a synthetic dodecapeptide reproducing the C-terminal portion of thioredoxin reductase were comparatively analyzed through P NMR and ESI-MS. Remarkable binding properties toward these biomolecules were disclosed. Moreover, the cytotoxic effects produced by AFETT on two ovarian cancer cell lines (A2780 and A2780 R) and one colorectal cancer cell line (HCT116) were analyzed and found to be strong and nearly superimposable to those of auranofin. Interestingly, for both compounds, the ability to induce downregulation of vimentin expression in A2780 R cells was evidenced. Despite its close similarity to auranofin, AFETT is reported to exhibit some peculiar and distinctive features such as a lower lipophilicity, an increased water solubility and a faster reactivity towards the selected target biomolecules. These differences might confer to AFETT significant pharmaceutical and therapeutic advantages over auranofin itself.
Topics: Antineoplastic Agents; Auranofin; Cell Line, Tumor; Female; Gold; Humans; Ovarian Neoplasms
PubMed: 36000524
DOI: 10.1039/d2dt00836j -
Scientific Reports Jul 2022Anticancer drugs and molecular targeted therapies are used for refractory desmoid-type fibromatosis (DF), but occasionally cause severe side effects. The purpose of this...
Anticancer drugs and molecular targeted therapies are used for refractory desmoid-type fibromatosis (DF), but occasionally cause severe side effects. The purpose of this study was to identify an effective drug with fewer side effects against DF by drug repositioning, and evaluate its efficacy. FDA-approved drugs that inhibit the proliferation of DF cells harboring S45F mutations of CTNNB1 were screened. An identified drug was subjected to the investigation of apoptotic effects on DF cells with analysis of Caspase 3/7 activity. Expression of β-catenin was evaluated with western blot analysis, and immunofluorescence staining. Effects of the identified drug on in vivo DF were analyzed using Apc1638N mice. Auranofin was identified as a drug that effectively inhibits the proliferation of DF cells. Auranofin did not affect Caspase 3/7 activity compared to control. The expression level of β-catenin protein was not changed regardless of auranofin concentration. Auranofin effectively inhibited the development of tumorous tissues by both oral and intraperitoneal administration, particularly in male mice. Auranofin, an anti-rheumatic drug, was identified to have repositioning effects on DF. Since auranofin has been used for many years as an FDA-approved drug, it could be a promising drug with fewer side effects for DF.
Topics: Animals; Auranofin; Caspase 3; Fibromatosis, Aggressive; Male; Mice; Mutation; beta Catenin
PubMed: 35831372
DOI: 10.1038/s41598-022-15756-9 -
Clinical and Molecular Hepatology Oct 2022
Topics: Humans; Non-alcoholic Fatty Liver Disease; Auranofin; NF-E2-Related Factor 2; Gold; Multifactorial Inheritance; Drug Repositioning; Liver; Fibrosis; Liver Cirrhosis; Signal Transduction
PubMed: 35989091
DOI: 10.3350/cmh.2022.0208 -
Redox Biology Jul 2020The failure of insulin-producing β-cells is the underlying cause of hyperglycemia in diabetes mellitus. β-cell decay has been linked to hypoxia, chronic inflammation,...
The failure of insulin-producing β-cells is the underlying cause of hyperglycemia in diabetes mellitus. β-cell decay has been linked to hypoxia, chronic inflammation, and oxidative stress. Thioredoxin (Trx) proteins are major actors in redox signaling and essential for signal transduction and the cellular stress response. We have analyzed the cytosolic, mitochondrial, and extracellular Trx system proteins in hypoxic and cytokine-induced stress using β-cell culture, isolated pancreatic islets, and pancreatic islet transplantation modelling low oxygen supply. Protein levels of cytosolic Trx1 and Trx reductase (TrxR) 1 significantly decreased, while mitochondrial Trx2 and TrxR2 increased upon hypoxia and reoxygenation. Interestingly, Trx1 was secreted by β-cells during hypoxia. Moreover, murine and human pancreatic islet grafts released Trx1 upon glucose stimulation. Survival of transplanted islets was substantially impaired by the TrxR inhibitor auranofin. Since a release was prominent upon hypoxia, putative paracrine effects of Trx1 on β-cells were examined. In fact, exogenously added recombinant hTrx1 mitigated apoptosis and preserved glucose sensitivity in pancreatic islets subjected to hypoxia and inflammatory stimuli, dependent on its redox activity. Human subjects were studied, demonstrating a transient increase in extracellular Trx1 in serum after glucose challenge. This increase correlated with better pancreatic islet function. Moreover, hTrx1 inhibited the migration of primary murine macrophages. In conclusion, our study offers evidence for paracrine functions of extracellular Trx1 that improve the survival and function of pancreatic β-cells.
Topics: Animals; Auranofin; Humans; Mice; Oxidation-Reduction; Oxidative Stress; Thioredoxin-Disulfide Reductase; Thioredoxins
PubMed: 32473461
DOI: 10.1016/j.redox.2020.101570 -
Nan Fang Yi Ke Da Xue Xue Bao = Journal... Apr 2022To construct a HEK293 cell line stably overexpressing TrxR1 as a cell model for functional study of TrxR1 and screening of TrxR1-targeting drugs.
OBJECTIVE
To construct a HEK293 cell line stably overexpressing TrxR1 as a cell model for functional study of TrxR1 and screening of TrxR1-targeting drugs.
METHODS
gene was amplified by PCR and ligated with the lentivirus expression vector pLVX-Puro, which was transformed into and identified by Sanger dideoxy sequencing. HEK293 cells were infected with the recombinant lentivirus vector (pLVX-Puro-TXNRD1) and screened with Puromycin for cell clones with stable TrxR1 overexpression (HEK293-TrxR1-OE cells). HEK293-TrxR1-OE cells, along with HEK293 cells infected with pLVX-Puro vector (HEK293-NC) and normal HEK293 cells, were tested for mRNA and protein expression levels of TrxR1 using RT-qPCR and Western blotting. TrxR1 enzyme activity in the cells was evaluated with insulin endpoint assay and TRFS-green probe imaging. The sensitivity of the cells to auranofin, a specific TrxR1 inhibitor, was determined with CCK8 assay.
RESULTS
gene was successfully inserted into the lentiviral vector pLVX-Puro as confirmed by DNA sequencing. The enzyme activity and mRNA and protein expression levels of TrxR1 were significantly higher in HEK293-TrxR1-OE cells than in HEK293 and HEK293-NC cells ( < 0.005). The inhibitory effects of auranofin on proliferation and cellular TrxR1 enzyme activity were significantly attenuated in HEK293-TrxR1-OE cells as compared with HEK293 and HEK293-NC cells ( < 0.005).
CONCLUSION
We successfully obtained a HEK293 cell line with stable TrxR1 overexpression, which shows resistance to auranofin and can be used for screening TrxR1 targeting drugs.
Topics: Auranofin; Cell Line, Tumor; Genetic Vectors; HEK293 Cells; Humans; Lentivirus; RNA, Messenger; Transfection
PubMed: 35527491
DOI: 10.12122/j.issn.1673-4254.2022.04.11