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1.
Virology ; 547: 7-11, 2020 08.
Artigo em Inglês | MEDLINE | ID: covidwho-306356

RESUMO

SARS-COV-2 has recently emerged as a new public health threat. Herein, we report that the FDA-approved drug, auranofin, inhibits SARS-COV-2 replication in human cells at low micro molar concentration. Treatment of cells with auranofin resulted in a 95% reduction in the viral RNA at 48 h after infection. Auranofin treatment dramatically reduced the expression of SARS-COV-2-induced cytokines in human cells. These data indicate that auranofin could be a useful drug to limit SARS-CoV-2 infection and associated lung injury due to its antiviral, anti-inflammatory and anti-reactive oxygen species (ROS) properties. Further animal studies are warranted to evaluate the safety and efficacy of auranofin for the management of SARS-COV-2 associated disease.


Assuntos
Auranofina/farmacologia , Betacoronavirus/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , Antivirais/farmacologia , Betacoronavirus/fisiologia , Linhagem Celular , Infecções por Coronavirus , Citocinas , Avaliação Pré-Clínica de Medicamentos , Ouro , Humanos , Inflamação , Pandemias , Pneumonia Viral
2.
PLoS One ; 15(5): e0229630, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32401759

RESUMO

Chromoblastomycosis (CBM) is a chronic subcutaneous mycosis caused by traumatic implantation of many species of black fungi. Due to the refractoriness of some cases and common recurrence of CBM, a more effective and less time-consuming treatment is mandatory. The aim of this study was to identify compounds with in vitro antifungal activity in the Pathogen Box® compound collection against different CBM agents. Synergism of these compounds with drugs currently used to treat CBM was also assessed. An initial screening of the drugs present in this collection at 1 µM was performed with a Fonsecaea pedrosoi clinical strain according to the EUCAST protocol. The compounds with activity against this fungus were also tested against other seven etiologic agents of CBM (Cladophialophora carrionii, Phialophora verrucosa, Exophiala jeanselmei, Exophiala dermatitidis, Fonsecaea monophora, Fonsecaea nubica, and Rhinocladiella similis) at concentrations ranging from 0.039 to 10 µM. The analysis of potential synergism of these compounds with itraconazole and terbinafine was performed by the checkerboard method. Eight compounds inhibited more than 60% of the F. pedrosoi growth: difenoconazole, bitertanol, iodoquinol, azoxystrobin, MMV688179, MMV021013, trifloxystrobin, and auranofin. Iodoquinol produced the lowest MIC values (1.25-2.5 µM) and MMV688179 showed MICs that were higher than all compounds tested (5 - >10 µM). When auranofin and itraconazole were tested in combination, a synergistic interaction (FICI = 0.37) was observed against the C. carrionii isolate. Toxicity analysis revealed that MMV021013 showed high selectivity indices (SI ≥ 10) against the fungi tested. In summary, auranofin, iodoquinol, and MMV021013 were identified as promising compounds to be tested in CBM models of infection.


Assuntos
Antifúngicos/farmacologia , Cromoblastomicose/tratamento farmacológico , Sinergismo Farmacológico , Fungos/patogenicidade , Acetatos/farmacologia , Ascomicetos/efeitos dos fármacos , Ascomicetos/patogenicidade , Auranofina/farmacologia , Compostos de Bifenilo/farmacologia , Cromoblastomicose/microbiologia , Cromoblastomicose/patologia , Dioxolanos/farmacologia , Exophiala/efeitos dos fármacos , Exophiala/patogenicidade , Fungos/efeitos dos fármacos , Humanos , Iminas/farmacologia , Iodoquinol/farmacologia , Pirimidinas/farmacologia , Estrobilurinas/farmacologia , Triazóis/farmacologia
3.
Virology ; 547: 7-11, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32442105

RESUMO

SARS-COV-2 has recently emerged as a new public health threat. Herein, we report that the FDA-approved drug, auranofin, inhibits SARS-COV-2 replication in human cells at low micro molar concentration. Treatment of cells with auranofin resulted in a 95% reduction in the viral RNA at 48 h after infection. Auranofin treatment dramatically reduced the expression of SARS-COV-2-induced cytokines in human cells. These data indicate that auranofin could be a useful drug to limit SARS-CoV-2 infection and associated lung injury due to its antiviral, anti-inflammatory and anti-reactive oxygen species (ROS) properties. Further animal studies are warranted to evaluate the safety and efficacy of auranofin for the management of SARS-COV-2 associated disease.


Assuntos
Auranofina/farmacologia , Betacoronavirus/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , Antivirais/farmacologia , Betacoronavirus/fisiologia , Linhagem Celular , Infecções por Coronavirus , Citocinas , Avaliação Pré-Clínica de Medicamentos , Ouro , Humanos , Inflamação , Pandemias , Pneumonia Viral
4.
Arch Microbiol ; 202(3): 473-482, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31705142

RESUMO

The aim of this study is to evaluate the antibiofilm and antibacterial effects of auranofin against WT-ETBF, rETBF, WT-NTBF and clinically isolated Bacteroides fragilis strains. The minimum inhibitory concentration and biofilm inhibitory concentration of 0.25 µg/ml for auranofin against B. fragilis were determined, and the biofilm eradication concentration was 1 µg/ml. At an auranofin concentration of 0.5 µg/ml, little cellular metabolic activity was found. Confocal laser scanning microcopy results confirmed the inhibition of biofilm by auranofin. The effects of auranofin on the outer membrane protein (ompA) gene and the RND-type efflux pump (bmeB3) gene were investigated using quantitative real-time polymerase chain reaction (qRT-PCR). The qRT-PCR results showed that treatment with auranofin significantly reduced the gene expression compared to controls without auranofin. These data indicate the applicability of auranofin as a repurposed drug due to its inhibitory effect against biofilm formation of B. fragilis. Therefore, our study demonstrates that auranofin, already approved for human use, is a promising drug that has strong antibiofilm and antibacterial activity against B. fragilis.


Assuntos
Antibacterianos/farmacologia , Auranofina/farmacologia , Infecções por Bacteroides/microbiologia , Bacteroides fragilis/efeitos dos fármacos , Biofilmes/efeitos dos fármacos , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Infecções por Bacteroides/tratamento farmacológico , Bacteroides fragilis/genética , Bacteroides fragilis/fisiologia , Reposicionamento de Medicamentos , Regulação Bacteriana da Expressão Gênica/efeitos dos fármacos , Humanos , Testes de Sensibilidade Microbiana
5.
Int J Antimicrob Agents ; 55(3): 105828, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31669742

RESUMO

INTRODUCTION: Vancomycin-resistant enterococci (VRE) are a leading cause of nosocomial infections because of the limited number of effective therapeutic options. In an effort to repurpose FDA-approved drugs against antibiotic-resistant bacteria, auranofin has been identified as a potent drug against VRE. METHODS AND RESULTS: The present study determined that auranofin's antibacterial activity was not affected when evaluated against a higher inoculum size of VRE (~107 CFU/mL), and auranofin successfully reduced the burden of stationary phase VRE cells via a time-kill assay. In addition, auranofin reduced VRE production of key virulence factors, including proteases, lipase and haemagglutinin. The promising features of auranofin prompted evaluation of its in vivo efficacy in a lethal mouse model of VRE septicaemia. All mice receiving auranofin at 0.125 mg/kg orally, 0.125 mg/kg subcutaneously (SC) or 0.0625 mg/kg (SC) survived the lethal VRE challenge. Additionally, auranofin was superior to linezolid, the current drug of choice, in reducing VRE burden in the liver, kidneys and spleen of mice. Remarkably, auranofin successfully reduced VRE below the limit of detection in murine internal organs after 4 days of oral or subcutaneous treatment. CONCLUSION: These results indicate that auranofin warrants further investigation as a new treatment for systemic VRE infections.


Assuntos
Antibacterianos/farmacologia , Auranofina/farmacologia , Enterococos Resistentes à Vancomicina/efeitos dos fármacos , Animais , Antirreumáticos/farmacologia , Infecções por Bactérias Gram-Positivas/tratamento farmacológico , Infecções por Bactérias Gram-Positivas/microbiologia , Linezolida/farmacologia , Camundongos , Testes de Sensibilidade Microbiana , Enterococos Resistentes à Vancomicina/patogenicidade
6.
Int J Cancer ; 146(1): 123-136, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31090219

RESUMO

Triple-negative breast cancer (TNBCs) is a very aggressive and lethal form of breast cancer with no effective targeted therapy. Neoadjuvant chemotherapies and radiotherapy remains a mainstay of treatment with only 25-30% of TNBC patients responding. Thus, there is an unmet clinical need to develop novel therapeutic strategies for TNBCs. TNBC cells have increased intracellular oxidative stress and suppressed glutathione, a major antioxidant system, but still, are protected against higher oxidative stress. We screened a panel of antioxidant genes using the TCGA and METABRIC databases and found that expression of the thioredoxin pathway genes is significantly upregulated in TNBC patients compared to non-TNBC patients and is correlated with adverse survival outcomes. Treatment with auranofin (AF), an FDA-approved thioredoxin reductase inhibitor caused specific cell death and impaired the growth of TNBC cells grown as spheroids. Furthermore, AF treatment exerted a significant in vivo antitumor activity in multiple TNBC models including the syngeneic 4T1.2 model, MDA-MB-231 xenograft and patient-derived tumor xenograft by inhibiting thioredoxin redox activity. We, for the first time, showed that AF increased CD8+Ve T-cell tumor infiltration in vivo and upregulated immune checkpoint PD-L1 expression in an ERK1/2-MYC-dependent manner. Moreover, combination of AF with anti-PD-L1 antibody synergistically impaired the growth of 4T1.2 primary tumors. Our data provide a novel therapeutic strategy using AF in combination with anti-PD-L1 antibody that warrants further clinical investigation for TNBC patients.


Assuntos
Anticorpos/uso terapêutico , Auranofina/uso terapêutico , Antígeno B7-H1/imunologia , Inibidores Enzimáticos/uso terapêutico , Tiorredoxina Dissulfeto Redutase/antagonistas & inibidores , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Animais , Auranofina/farmacologia , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Espécies Reativas de Oxigênio/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
7.
J Appl Microbiol ; 128(1): 88-101, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31509623

RESUMO

AIMS: Staphylococcus aureus (a bacterial pathogen) and Candida sp. (opportunistic fungi) are two clinically relevant biofilm-forming microbes responsible for a majority of community- and nosocomial-acquired infections. Dual species biofilm formation between S. aureus and Candida sp. extremely enhances the antimicrobial resistance of the micro-organisms and is difficult to treat with antibiotic therapy. Hence, it is crucial to explore new antimicrobial agents. Auranofin (AF) is a mixed ligand gold compound and has recently been repurposed as an antibacterial and antifungal agent. However, the effects of AF against dual species biofilm have remained largely untested. METHODS AND RESULTS: In the present study, by constructing biofilms on microplates and urinary catheter surfaces, AF showed strong planktonic cells and biofilm inhibitory effects against mono- and dual culture models of S. aureus and Candida albicans but only exhibited moderate antibiofilm effects on Candida parapsilosis. Auranofin could be synergistic with subminimal inhibitory concentrations of amphotericin B against S. aureus + C. albicans/C. parapsilosis dual biofilms. Auranofin also showed effective antimicrobial effects on vancomycin-resistant strains. However, the antimicrobial effects of AF were decreased in the presence of heat-inactivated foetal bovine serum. CONCLUSIONS: In summary, AF could effectively inhibit S. aureus and C. albicans mono- and dual biofilm formation in vitro. SIGNIFICANCE AND IMPACT OF THE STUDY: Coexistence between Staphylococcus aureus and Candida sp. in dual biofilms leads to increased resistance to some conventionally used antimicrobials, indicating a need for alternative treatments. This study demonstrates the potential for the Au-containing compound AF in the treatment of dual biofilm infections and encourages further investigation of this treatment for clinical use.


Assuntos
Anti-Infecciosos/farmacologia , Auranofina/farmacologia , Biofilmes/efeitos dos fármacos , Candida/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Anfotericina B/farmacologia , Biofilmes/crescimento & desenvolvimento , Candida/crescimento & desenvolvimento , Técnicas de Cocultura , Sinergismo Farmacológico , Testes de Sensibilidade Microbiana , Especificidade da Espécie , Staphylococcus aureus/crescimento & desenvolvimento , Cateteres Urinários/microbiologia
9.
Biometals ; 32(5): 813-817, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31473877

RESUMO

The study of metal-based drugs represents an important branch of modern bioinorganic chemistry. The growing importance of this field is linked to the large success in medicine of a few metal based drugs, either in clinical use or still experimental. Moreover, these metal-based drugs are frequently used as reference compounds to assess comparatively the behavior of newly synthesized metallodrugs. For the convenience of researchers working in this area we report here a compilation of the relevant analytical and spectroscopic data of ten representative metallodrugs based on Platinum, Ruthenium, Gold and Mercury. The selected compounds, namely Cisplatin, Oxaliplatin, Carboplatin, Auranofin, Sodium Aurothiomalate, NAMI-A, KP1019, Thimerosal, Merbromin and Phenylmercury Acetate, were chosen owing to their importance in the field. We believe that this compilation may turn very helpful to researchers as these data are difficult to find and generally scattered over a large number of (old) publications.


Assuntos
Complexos de Coordenação/química , Auranofina/química , Carboplatina/química , Cisplatino/química , Ouro/química , Tiomalato Sódico de Ouro/química , Merbromina/química , Mercúrio/química , Oxaliplatina/química , Compostos de Fenilmercúrio/química , Platina/química , Rutênio/química
10.
Int J Antimicrob Agents ; 54(5): 592-600, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31394172

RESUMO

Antiretroviral therapy (ART) is typically composed of a combination of three antiretroviral drugs and is the treatment of choice for people with human immunodeficiency virus type 1/acquired immune deficiency syndrome (HIV-1/AIDS). However, it is unable to impact on viral reservoirs, which harbour latent HIV-1 genomes that are able to reignite the infection upon treatment suspension. The aim of this study was to provide an estimate of the safety of the disease-modifying antirheumatic agent auranofin and its impact on the HIV-1 reservoir in humans under intensified ART. For this purpose, an interim analysis was conducted of three of the six arms of the NCT02961829 clinical trial (five patients each) with: no intervention, i.e. continuation of first-line ART; intensified ART (ART + dolutegravir and maraviroc); and intensified ART plus auranofin. Auranofin treatment was found to be well tolerated. No major adverse events were detected apart from a transient decrease in CD4+ T-cell counts at Weeks 8 and 12. Auranofin decreased total viral DNA in peripheral blood mononuclear cells compared with ART-only regimens at Week 20 (P = 0.036) and induced a decrease in integrated viral DNA as quantified by Alu PCR. Despite the limited number of patient-derived sequences available in this study, phylogenetic analyses of nef sequences support the idea that auranofin may impact on the viral reservoir. [ClinicalTrials.gov ID: NCT02961829].


Assuntos
Antirreumáticos/uso terapêutico , Auranofina/uso terapêutico , HIV-1/genética , Provírus/efeitos dos fármacos , Provírus/genética , Latência Viral/efeitos dos fármacos , Terapia Antirretroviral de Alta Atividade , Contagem de Linfócito CD4 , DNA Viral/efeitos dos fármacos , DNA Viral/genética , Inibidores da Fusão de HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Inibidores de Integrase de HIV/uso terapêutico , HIV-1/efeitos dos fármacos , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Humanos , Maraviroc/uso terapêutico
11.
Oxid Med Cell Longev ; 2019: 3503912, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31275508

RESUMO

Osteoporosis is a degenerative metabolic disease caused by an imbalance between osteogenesis and osteoclastogenesis. Increased levels of proinflammatory cytokines combined with decreased estrogen levels, which are commonly seen in postmenopausal women, can lead to overactivation of osteoclasts. Therefore, targeting osteoclast maturation may represent a novel strategy for both treating and preventing osteoporosis. Auranofin is a gold-based compound first approved in 1985 for the treatment of rheumatic diseases. Here, we examined whether auranofin suppresses osteoclast differentiation in vitro and in vivo. Auranofin was shown to suppress receptor activator of NF-κB ligand- (RANKL-) induced osteoclastogenesis in mouse bone marrow macrophages (BMMs) and Raw264.7 macrophages. Cotreatment of macrophages with auranofin blocked the RANKL-induced inhibitors of κB kinase (IKK) phosphorylation, resulting in inhibition of nuclear translocation of p65. The pan-caspase inhibitor nivocasan potently reduced not only inflammasome-mediated interleukin-1ß (IL-1ß) secretion but also osteoclast differentiation in BMMs. Auranofin suppressed inflammasome activation, as evidenced by decreased production of cleaved IL-1ß in both bone marrow-derived macrophages (BMDMs) and J774.A1 cells. Loss of both bone mass in ovariectomized mice was significantly recovered by oral administration of auranofin. Taken together, these data strongly support the use of auranofin for the prevention of osteoclast-related osteoporosis.


Assuntos
Antirreumáticos/uso terapêutico , Auranofina/uso terapêutico , Inflamassomos/metabolismo , NF-kappa B/metabolismo , Osteoclastos/metabolismo , Osteoporose/tratamento farmacológico , Animais , Antirreumáticos/farmacologia , Auranofina/farmacologia , Feminino , Humanos , Camundongos , Osteoclastos/citologia , Osteoporose/genética , Osteoporose/patologia , Transfecção
12.
J Appl Microbiol ; 127(2): 459-471, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31087803

RESUMO

AIMS: The aim of this study was to assess anti-biofilm and antimicrobial effects of auranofin, an anti-rheumatic agent, on uropathogenic Escherichia coli (UPEC) biofilm formation. METHODS AND RESULTS: The minimum inhibitory concentration and biofilm inhibition concentration of auranofin against UPEC ranged from 24 to 32 µg ml-1 . Biofilm eradication concentration and XTT reduction concentration of auranofin were found to be at 112 µg ml-1 . Confocal laser scanning microscopy results confirmed that biofilm was inhibited by auranofin. These results indicate that auranofin possesses potent anti-biofilm and antimicrobial activities against UPEC. Effects of auranofin on type 1 fimbriae gene (fimH) and response regulator gene (rpoS) to stress were explored using quantitative real time-polymerase chain reaction. In addition, combination of auranofin and tetracycline showed synergistic effect. CONCLUSIONS: These data indicate that auranofin has inhibitory effect on biofilm formation and synergistic effect on UPEC infection when it is combined with tetracycline. SIGNIFICANCE AND IMPACT OF THE STUDY: Our study strongly suggest that auranofin is a promising alternative anti-biofilm and antimicrobial agent to prevent UPEC biofilm formation in UTIs. Auranofin already approved for human use have the advantage of being able to be put into clinical use relatively quickly.


Assuntos
Antibacterianos/farmacologia , Auranofina/farmacologia , Biofilmes/efeitos dos fármacos , Escherichia coli Uropatogênica/efeitos dos fármacos , Adesinas de Escherichia coli/genética , Adesinas de Escherichia coli/metabolismo , Reposicionamento de Medicamentos , Proteínas de Fímbrias/genética , Proteínas de Fímbrias/metabolismo , Humanos , Tetraciclina/farmacologia , Escherichia coli Uropatogênica/genética , Escherichia coli Uropatogênica/isolamento & purificação , Escherichia coli Uropatogênica/fisiologia
13.
Biochimie ; 162: 46-54, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30946948

RESUMO

Auranofin is a gold (I)-containing compound used for the treatment of rheumatic arthritis. Auranofin has anticancer activity in animal models and is approved for clinical trials for lung and ovarian carcinomas. Both the cytosolic and mitochondrial forms of the selenoprotein thioredoxin reductase (TrxR) are well documented targets of auranofin. Auranofin was recently reported to also inhibit proteasome activity at the level of the proteasome-associated deubiquitinases (DUBs) UCHL5 and USP14. We here set out to re-examine the molecular mechanism underlying auranofin cytotoxicity towards cultured cancer cells. The effects of auranofin on the proteasome were examined in cells and in vitro, effects on DUB activity were assessed using different substrates. The cellular response to auranofin was compared to that of the 20S proteasome inhibitor bortezomib and the 19S DUB inhibitor b-AP15 using proteomics. Auranofin was found to inhibit mitochondrial activity and to an induce oxidative stress response at IC50 doses. At 2-3-fold higher doses, auranofin inhibits proteasome processing in cells. At such supra-pharmacological concentrations USP14 activity was inhibited. Analysis of protein expression profiles in drug-exposed tumor cells showed that auranofin induces a response distinct from that of the 20S proteasome inhibitor bortezomib and the DUB inhibitor b-AP15, both of which induced similar responses. Our results support the notion that the primary mechanism of action of auranofin is TrxR inhibition and suggest that proteasome DUB inhibition is an off-target effect. Whether proteasome inhibition will contribute to the antineoplastic effect of auranofin in treated patients is unclear but remains a possibility.


Assuntos
Antineoplásicos/farmacologia , Auranofina/farmacologia , Reposicionamento de Medicamentos , Selenoproteínas/antagonistas & inibidores , Tiorredoxina Redutase 1/antagonistas & inibidores , Tiorredoxina Redutase 2/antagonistas & inibidores , Bortezomib/farmacologia , Células HCT116 , Células HEK293 , Células HeLa , Humanos , Mitocôndrias/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Piperidonas/farmacologia , Complexo de Endopeptidases do Proteassoma/efeitos dos fármacos , Inibidores de Proteassoma/farmacologia , Tiorredoxina Redutase 2/metabolismo , Ubiquitina Tiolesterase/antagonistas & inibidores
14.
J Cancer Res Clin Oncol ; 145(6): 1495-1507, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31028540

RESUMO

PURPOSE: Constructed from a theoretical framework, the coordinated undermining of survival paths in glioblastoma (GBM) is a combination of nine drugs approved for non-oncological indications (CUSP9; aprepitant, auranofin, captopril, celecoxib, disulfiram, itraconazole, minocycline, quetiapine, and sertraline) combined with temozolomide (TMZ). The availability of these drugs outside of specialized treatment centers has led patients to embark on combination treatments without systematic follow-up. However, no experimental data on efficacy using the CUSP9 strategy in GBM have been reported. METHODS: Using patient-derived glioblastoma stem cell (GSC) cultures from 15 GBM patients, we described stem cell properties of individual cultures, determined the dose-response relationships of the drugs in the CUSP9, and assessed the efficacy the CUSP9 combination with TMZ in concentrations clinically achievable. The efficacy was evaluated by cell viability, cytotoxicity, and sphere-forming assays in both primary and recurrent GSC cultures. RESULTS: We found that CUSP9 with TMZ induced a combination effect compared to the drugs individually (p < 0.0001). Evaluated by cell viability and cytotoxicity, 50% of the GSC cultures displayed a high sensitivity to the drug combination. In clinical plasma concentrations, the effect of the CUSP9 with TMZ was superior to TMZ monotherapy (p < 0.001). The Wnt-signaling pathway has been shown important in GSC, and CUSP9 significantly reduces Wnt-activity. CONCLUSIONS: Adding experimental data to the theoretical rationale of CUSP9, our results demonstrate that the CUSP9 treatment strategy can induce a combination effect in both treatment-naïve and pretreated GSC cultures; however, predicting response in individual cultures will require further profiling of GSCs.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Animais , Aprepitanto/administração & dosagem , Aprepitanto/farmacologia , Auranofina/administração & dosagem , Auranofina/farmacologia , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Captopril/administração & dosagem , Captopril/farmacologia , Celecoxib/administração & dosagem , Celecoxib/farmacologia , Dissulfiram/administração & dosagem , Dissulfiram/farmacologia , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , Itraconazol/administração & dosagem , Itraconazol/farmacologia , Camundongos , Camundongos SCID , Minociclina/administração & dosagem , Minociclina/farmacologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Fumarato de Quetiapina/administração & dosagem , Fumarato de Quetiapina/farmacologia , Reprodutibilidade dos Testes , Sertralina/administração & dosagem , Sertralina/farmacologia , Transdução de Sinais/efeitos dos fármacos , Temozolomida/administração & dosagem , Temozolomida/farmacologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Chem Pharm Bull (Tokyo) ; 67(3): 186-191, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30827998

RESUMO

Gold compounds have a long history of use in medicine. Auranofin was developed more than 30 years ago as an oral therapy for rheumatoid arthritis. Now, however, auranofin is rarely used in clinical practice despite its efficacy for treating rheumatoid arthritis because more novel antirheumatic medications are available. Although its use in clinical practice has decreased, studies on auranofin have continued and it shows promise for the treatment of several different diseases, including cancer and bacterial and parasitic infections. Several potential novel applications of auranofin for treating human disease have been proposed. Auranofin inhibits the activity of thioredoxin reductase (TrxR), an enzyme of the thioredoxin (Trx) system that is important for maintaining the intracellular redox state. Particularly in cancers, TrxR inhibition leads to an increase in cellular oxidative stress and induces apoptosis. TrxR overexpression is associated with aggressive tumor progression and poor survival in patients with breast, ovarian, and lung cancers. The Trx system may represent an attractive target for the development of new cancer treatments. Therefore, the TrxR inhibitor auranofin may be a potent anticancer agent. This review summarizes the current understanding of auranofin for cancer therapy.


Assuntos
Antineoplásicos/farmacologia , Auranofina/farmacologia , Animais , Apoptose/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Humanos , Neoplasias/enzimologia , Neoplasias/metabolismo , Neoplasias/patologia , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , Tiorredoxina Dissulfeto Redutase/antagonistas & inibidores , Tiorredoxina Dissulfeto Redutase/metabolismo , Tiorredoxinas/metabolismo
16.
Oxid Med Cell Longev ; 2019: 6452390, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30906503

RESUMO

Hepatitis C virus (HCV) is a blood-borne pathogen causing acute and chronic hepatitis. A significant number of people chronically infected with HCV develop cirrhosis and/or liver cancer. The pathophysiologic mechanisms of hepatocyte damage associated with chronic HCV infection are not fully understood yet, mainly due to the lack of an in vitro system able to recapitulate the stages of infection in vivo. Several studies underline that HCV virus replication depends on redox-sensitive cellular pathways; in addition, it is known that virus itself induces alterations of the cellular redox state. However, the exact interplay between HCV replication and oxidative stress has not been elucidated. In particular, the role of reduced glutathione (GSH) in HCV replication and infection is still not clear. We set up an in vitro system, based on low m.o.i. of Huh7.5 cell line with a HCV infectious clone (J6/JFH1), that reproduced the acute and persistent phases of HCV infection up to 76 days of culture. We demonstrated that the acute phase of HCV infection is characterized by the elevated levels of reactive oxygen species (ROS) associated in part with an increase of NADPH-oxidase transcripts and activity and a depletion of GSH accompanied by high rates of viral replication and apoptotic cell death. Conversely, the chronic phase is characterized by a reestablishment of reduced environment due to a decreased ROS production and increased GSH content in infected cells that might concur to the establishment of viral persistence. Treatment with the prooxidant auranofin of the persistently infected cultures induced the increase of viral RNA titer, suggesting that a prooxidant state could favor the reactivation of HCV viral replication that in turn caused cell damage and death. Our results suggest that targeting the redox-sensitive host-cells pathways essential for viral replication and/or persistence may represent a promising option for contrasting HCV infection.


Assuntos
Hepacivirus/fisiologia , Hepatite C Crônica/patologia , Hepatite C Crônica/virologia , Fígado/patologia , Fígado/virologia , Estresse Oxidativo , Auranofina/farmacologia , Células Cultivadas , Glutationa/metabolismo , Hepacivirus/efeitos dos fármacos , Humanos , Modelos Biológicos , NADPH Oxidases/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , RNA Viral/genética , Espécies Reativas de Oxigênio/metabolismo
17.
Artigo em Inglês | MEDLINE | ID: mdl-30873389

RESUMO

Intravascular catheter related bloodstream infections (CRBSIs) are a leading cause of hospital-acquired infections worldwide, resulting not only in the burden of cost and morbidity for patients but also in the over-consumption of medical resources for hospitals and health care organizations. In this study, a novel auranofin releasing antibacterial and antibiofilm polyurethane (PU) catheter coating was developed and investigated for future use in preventing CRBSIs. Auranofin is an antirheumatic drug with recently identified antimicrobial properties. The drug carrier, PU, acts as a barrier surrounding the antibacterial agent, auranofin, to extend the drug release profile and improve its long-term antibacterial and antibiofilm efficacy and potentially the length of catheter implantation within a patient. The PU+auranofin coatings developed here were found to be highly stretchable (exhibiting ~500% percent elongation), which is important for the compliance of the material on a flexible catheter. PU+auranofin coated catheters were able to inhibit the growth of methicillin-resistant Staphylococcus aureus (MRSA) for 8 to 26 days depending on the specific drug concentration utilized during the dip coating process. The PU+auranofin coated catheters were also able to completely inhibit MRSA biofilm formation in vitro, an effect that was not observed with auranofin or PU alone. Lastly, these coatings were found to be hemocompatible with human erythrocytes and maintain liver cell viability.


Assuntos
Anti-Infecciosos/farmacologia , Auranofina/farmacologia , Biofilmes/efeitos dos fármacos , Cateteres , Portadores de Fármacos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Poliuretanos , Anti-Infecciosos/farmacocinética , Auranofina/farmacocinética , Biofilmes/crescimento & desenvolvimento , Fenômenos Químicos , Materiais Revestidos Biocompatíveis , Staphylococcus aureus Resistente à Meticilina/crescimento & desenvolvimento
18.
Mol Oncol ; 13(5): 1180-1195, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30861284

RESUMO

B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is a genetically heterogeneous blood cancer characterized by abnormal expansion of immature B cells. Although intensive chemotherapy provides high cure rates in a majority of patients, subtypes harboring certain genetic lesions, such as MLL rearrangements or BCR-ABL1 fusion, remain clinically challenging, necessitating a search for other therapeutic approaches. Herein, we aimed to validate antioxidant enzymes of the thioredoxin system as potential therapeutic targets in BCP-ALL. We observed oxidative stress along with aberrant expression of the enzymes associated with the activity of thioredoxin antioxidant system in BCP-ALL cells. Moreover, we found that auranofin and adenanthin, inhibitors of the thioredoxin system antioxidant enzymes, effectively kill BCP-ALL cell lines and pediatric and adult BCP-ALL primary cells, including primary cells cocultured with bone marrow-derived stem cells. Furthermore, auranofin delayed the progression of leukemia in MLL-rearranged patient-derived xenograft model and prolonged the survival of leukemic NSG mice. Our results unveil the thioredoxin system as a novel target for BCP-ALL therapy, and indicate that further studies assessing the anticancer efficacy of combinations of thioredoxin system inhibitors with conventional anti-BCP-ALL drugs should be continued.


Assuntos
Auranofina/farmacologia , Diterpenos de Caurano/farmacologia , Sistemas de Liberação de Medicamentos , Proteínas de Neoplasias/antagonistas & inibidores , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Tiorredoxinas/antagonistas & inibidores , Animais , Linhagem Celular Tumoral , Feminino , Proteínas de Fusão bcr-abl/metabolismo , Rearranjo Gênico , Histona-Lisina N-Metiltransferase/genética , Histona-Lisina N-Metiltransferase/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos NOD , Proteína de Leucina Linfoide-Mieloide/genética , Proteína de Leucina Linfoide-Mieloide/metabolismo , Proteínas de Neoplasias/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Tiorredoxinas/genética , Tiorredoxinas/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Invest New Drugs ; 37(6): 1166-1176, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-30825105

RESUMO

Small cell lung cancer (SCLC) is a highly lethal malignancy with the 5-year survival rate of less than 7%. Chemotherapy-resistance is a major challenge for SCLC treatment in clinic. In the study, we developed a high-throughput drug screen strategy to identify new drugs that can enhance the sensitivity of chemo-drug cisplatin in SCLC. This screen identified auranofin, a US Food and Drug Administration (FDA)-approved drug used therapeutically for rheumatoid arthritis, as a sensitizer of cisplatin. Further study validated that auranofin synergistically enhanced the anti-tumor activity of cisplatin in chemo-resistant SCLC cells, which was accompanied by the enhanced induction of cell cycle arrest and apoptosis. The synergistic action of auranofin and cisplatin was through ROS overproduction, thereby leading to mitochondrial dysfunction and DNA damage. Furthermore, in vivo study demonstrated that the combination treatment of auranofin and cisplatin dramatically inhibited tumor growth in SCLC. Therefore, our study provides a rational basis for further clinical study to test whether auranofin could enhance the sensitivity of cisplatin-based therapy in SCLC patients.


Assuntos
Antineoplásicos/administração & dosagem , Auranofina/administração & dosagem , Cisplatino/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Dano ao DNA , Ensaios de Seleção de Medicamentos Antitumorais , Ensaios de Triagem em Larga Escala , Humanos , Neoplasias Pulmonares/metabolismo , Camundongos Nus , Mitocôndrias/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Carcinoma de Pequenas Células do Pulmão/metabolismo
20.
Phytother Res ; 33(5): 1384-1393, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30887612

RESUMO

Evidence suggests that auranofin (AF) exhibits anticancer activity by inhibiting thioredoxin reductase (TrxR). Here, in this study, we have investigated the synergistic effects of AF and morin and their mechanism for the anticancer effects focusing on apoptosis in Hep3B human hepatocellular carcinoma cells. We assessed the anticancer activities by annexin V/PI double staining, caspase, and TrxR activity assay. Morin enhances the inhibitory effects on TrxR activity of AF as well as reducing cell viability. Annexin V/PI double staining revealed that morin/AF cotreatment induced apoptotic cell death. Morin enhances AF-induced mitochondrial membrane potential (ΔΨm) loss and cytochrome c release. Further, morin/AF cotreatment upregulated death receptor DR4/DR5, modulated Bcl-2 family members (upregulation of Bax and downregulation of Bcl-2), and activated caspase-3, -8, and -9. Morin also enhances AF-induced reactive oxygen species (ROS) generation. The anticancer effects results from caspase-dependent apoptosis, which was triggered via extrinsic pathway by upregulating TRAIL receptors (DR4/DR5) and enhanced via intrinsic pathway by modulating Bcl-2 and inhibitor of apoptosis protein family members. These are related to ROS generation. In conclusion, this study provides evidence that morin can enhance the anticancer activity of AF in Hep3B human hepatocellular carcinoma cells, indicating that its combination could be an alternative treatment strategy for the hepatocellular carcinoma.


Assuntos
Auranofina/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Flavonoides/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/patologia , Caspases/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Citocromos c/metabolismo , Regulação para Baixo/efeitos dos fármacos , Humanos , Proteínas Inibidoras de Apoptose/metabolismo , Neoplasias Hepáticas/patologia , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos
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