Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 583
Filtrar
1.
Life Sci ; 270: 119141, 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33529672

RESUMO

Although the proteins in bromodomain and extra-terminal domain (BET) family are promising therapy drug targets for numerous human diseases, the binding effectiveness is interfered by the competition from non-BET protein BRD9. In this study, molecular docking, molecular dynamics simulations, binding free energy calculations and per-residue energy decomposition methods were employed to clarify the selective inhibition mechanism of nitroxoline. The results showed that the different cavity volume of effective embedding inhibitor and the changes in conserved residues were associated with the significant higher selectivity of inhibitor nitroxoline for BET family than non-BET protein (BRD9). In addition, the non-polar interactions occurred in Phe83, Val87 at ZA loop, and the polar interaction appeared in Met132, Asn135 at BC loop. Therefore, when designing a new inhibitor, it could better improve the inhibitor activity by introducing the heteroatom conjugated pyridine-like moiety and the strong electron-withdrawing nitro-like moiety. Overall, this study not only clarified the molecular mechanism of the selective inhibition of nitroxoline, but also provided insight into designing more effective BET inhibitors in next step.


Assuntos
Nitroquinolinas/metabolismo , Nitroquinolinas/farmacologia , Proteínas/metabolismo , Sítios de Ligação , Desenho de Fármacos , Descoberta de Drogas , Humanos , Simulação de Acoplamento Molecular/métodos , Simulação de Dinâmica Molecular , Nitroquinolinas/química , Proteínas Nucleares/metabolismo , Ligação Proteica , Domínios Proteicos , Proteínas/antagonistas & inibidores , Relação Estrutura-Atividade , Fatores de Transcrição/metabolismo
2.
Proc Natl Acad Sci U S A ; 117(46): 28918-28921, 2020 11 17.
Artigo em Inglês | MEDLINE | ID: mdl-33168727

RESUMO

REV1/POLζ-dependent mutagenic translesion synthesis (TLS) promotes cell survival after DNA damage but is responsible for most of the resulting mutations. A novel inhibitor of this pathway, JH-RE-06, promotes cisplatin efficacy in cancer cells and mouse xenograft models, but the mechanism underlying this combinatorial effect is not known. We report that, unexpectedly, in two different mouse xenograft models and four human and mouse cell lines we examined in vitro cisplatin/JH-RE-06 treatment does not increase apoptosis. Rather, it increases hallmarks of senescence such as senescence-associated ß-galactosidase, increased p21 expression, micronuclei formation, reduced Lamin B1, and increased expression of the immune regulators IL6 and IL8 followed by cell death. Moreover, although p-γ-H2AX foci formation was elevated and ATR expression was low in single agent cisplatin-treated cells, the opposite was true in cells treated with cisplatin/JH-RE-06. These observations suggest that targeting REV1 with JH-RE-06 profoundly affects the nature of the persistent genomic damage after cisplatin treatment and also the resulting physiological responses. These data highlight the potential of REV1/POLζ inhibitors to alter the biological response to DNA-damaging chemotherapy and enhance the efficacy of chemotherapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Inibidores Enzimáticos/farmacologia , Neoplasias/tratamento farmacológico , Nitroquinolinas/farmacologia , Nucleotidiltransferases/antagonistas & inibidores , Envelhecimento/efeitos dos fármacos , Envelhecimento/patologia , Envelhecimento/fisiologia , Animais , Linhagem Celular Tumoral , Cisplatino/administração & dosagem , Cisplatino/farmacologia , DNA/biossíntese , Dano ao DNA/fisiologia , Reparo do DNA , Replicação do DNA , DNA Polimerase Dirigida por DNA/metabolismo , Resistencia a Medicamentos Antineoplásicos , Sinergismo Farmacológico , Inibidores Enzimáticos/administração & dosagem , Humanos , Proteínas Mad2/metabolismo , Camundongos , Mutagênese , Neoplasias/enzimologia , Neoplasias/patologia , Proteínas Nucleares/metabolismo , Nucleotidiltransferases/metabolismo , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
3.
ChemMedChem ; 15(24): 2477-2490, 2020 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-32744405

RESUMO

Nitroxoline, a well-known antimicrobial agent, has been identified in several independent studies, and on different molecular targets, as a promising candidate to be repurposed for cancer treatment. One specific target of interest concerns cathepsin B, a lysosomal peptidase involved in the degradation of the extracellular matrix (ECM), leading to tumor invasion, metastasis and angiogenesis. However, dedicated optimization of the nitroxoline core is needed to actually deliver a nitroxoline-based antitumor drug candidate. Within that context, 34 novel nitroxoline analogs were synthesized and evaluated for their relative cathepsin B inhibitory activity, their antiproliferative properties and their antimicrobial activity. More than twenty analogs were shown to exert a similar or even slightly higher cathepsin B inhibitory activity compared to nitroxoline. The implemented modifications of the nitroxoline scaffold and the resulting SAR information can form an eligible basis for further optimization toward more potent cathepsin B inhibitors in the quest for a clinical nitroxoline-based antitumor agent.


Assuntos
Antibacterianos/farmacologia , Antineoplásicos/farmacologia , Catepsina B/antagonistas & inibidores , Nitroquinolinas/farmacologia , Inibidores de Proteases/farmacologia , Antibacterianos/síntese química , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Escherichia coli/efeitos dos fármacos , Humanos , Testes de Sensibilidade Microbiana , Nitroquinolinas/síntese química , Inibidores de Proteases/síntese química , Pseudomonas aeruginosa/efeitos dos fármacos
4.
J Enzyme Inhib Med Chem ; 35(1): 1331-1344, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32588672

RESUMO

Pancreatic cancer (PC) is one of the deadliest carcinomas and in most cases, which are diagnosed with locally advanced or metastatic disease, current therapeutic options are highly unsatisfactory. Based on the anti-proliferative effects shown by nitroxoline, an old urinary antibacterial agent, we explored a large library of newly synthesised derivatives to unravel the importance of the OH moiety and pyridine ring of the parent compound. The new derivatives showed a valuable anti-proliferative effect and some displayed a greater effect as compared to nitroxoline against three pancreatic cancer cell lines with different genetic profiles. In particular, in silico pharmacokinetic data, clonogenicity assays and selectivity indexes of the most promising compounds showed several advantages for such derivatives, as compared to nitroxoline. Moreover, some of these novel compounds had stronger effects on cell viability and/or clonogenic capacity in PC cells as compared to erlotinib, a targeted agent approved for PC treatment.


Assuntos
Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Nitroquinolinas/síntese química , Nitroquinolinas/farmacologia , Neoplasias Pancreáticas/patologia , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Linhagem Celular Tumoral , Humanos , Nitroquinolinas/química , Espectroscopia de Prótons por Ressonância Magnética , Relação Estrutura-Atividade
5.
Int J Mol Sci ; 21(9)2020 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-32380772

RESUMO

Various factors leads to cancer; among them oxidative damage is believed to play an important role. Moreover, it is important to identify a method to detect the oxidative damage. Recently, electrochemical sensors have been considered as the one of the most important techniques to detect DNA damage, owing to its rapid detection. However, electrode materials play an important role in the properties of electrochemical sensor. Currently, researchers have aimed to develop novel electrode materials for low-level detection of biomarkers. Herein, we report the facile hydrothermal synthesis of NiCo2O4 micro flowers (MFs) and NiCo2S4 micro spheres (Ms) and evaluate their electrochemical properties for the detection of carcinogen-causing biomarker 4-nitroquinoline n-oxide (4-NQO) in human blood serum and saliva samples. Moreover, as-prepared composites were fabricated on a glass carbon electrode (GCE), and its electrochemical activities for the determination of 4-NQO were investigated by using various electrochemical techniques. Fascinatingly, the NiCo2S4-Ms showed a very low detection limit of 2.29 nM and a wider range of 0.005 to 596.64 µM for detecting 4-NQO. Finally, the practical applicability of NiCo2S4-Ms in the 4-NQO spiked human blood serum and saliva samples were also investigated.


Assuntos
Técnicas Biossensoriais , Carcinógenos/análise , Técnicas Eletroquímicas , Nitroquinolinas/análise , Estresse Oxidativo , Técnicas de Química Sintética , Eletrodos , Nanoestruturas/química , Nanoestruturas/ultraestrutura , Níquel/química , Sensibilidade e Especificidade , Análise Espectral
6.
Sci Rep ; 10(1): 2574, 2020 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-32054977

RESUMO

We recently identified nitroxoline as a repurposed drug candidate in pancreatic cancer (PC) showing a dose-dependent antiproliferative activity in different PC cell lines. This antibiotic is effective in several in vitro and animal cancer models. To date, the mechanisms of nitroxoline anticancer action are largely unknown. Using shotgun proteomics we identified 363 proteins affected by nitroxoline treatment in AsPC-1 pancreatic cancer cells, including 81 consistently deregulated at both 24- and 48-hour treatment. These proteins previously unknown to be affected by nitroxoline were mostly downregulated and interconnected in a single highly-enriched network of protein-protein interactions. Integrative proteomic and functional analyses revealed nitroxoline-induced downregulation of Na/K-ATPase pump and ß-catenin, which associated with drastic impairment in cell growth, migration, invasion, increased ROS production and induction of DNA damage response. Remarkably, nitroxoline induced a previously unknown deregulation of molecules with a critical role in cell bioenergetics, which resulted in mitochondrial depolarization. Our study also suggests that deregulation of cytosolic iron homeostasis and of co-translational targeting to membrane contribute to nitroxoline anticancer action. This study broadens our understanding of the mechanisms of nitroxoline action, showing that the drug modulates multiple proteins crucial in cancer biology and previously unknown to be affected by nitroxoline.


Assuntos
Proteínas de Neoplasias/genética , Nitroquinolinas/farmacologia , Neoplasias Pancreáticas/tratamento farmacológico , Proteômica , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia
7.
Anticancer Agents Med Chem ; 20(3): 346-358, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31566137

RESUMO

BACKGROUND: The first choice of treatment in Hepatocellular Carcinoma (HCC) is 5-fluorouracil (5-FU). Nitroxoline (NIT), a potent inhibitor of Cathepsin B, impairs tumor progression by decreased extracellular matrix degradation. The objective of the current project was designed to target nanoparticles for co-delivery of 5-FU and NIT in order to enhance the 5-FU cytotoxic effects and reduce the metastatic properties of HepG2 cells. METHODS: 5-FU and NIT were loaded in chitosan-chondroitin nanoparticles. To target the CD44 receptors of HepG2 cells, Hyaluronic Acid (HA) was conjugated to the chondroitin by adipic acid dihydrazide and the conjugation was confirmed by FTIR and 1HNMR. After physicochemical characterization and optimization of the processing variables, MTT assay was done on HepG2 and NIH3T3 cell lines to determine the cytotoxic properties of HA targeted nanoparticles. Migration of the cells was studied to compare the co-delivery of the drugs with each drug alone. RESULTS: The optimized nanoparticles showed the particle size of 244.7±16.3nm, PDI of 0.30±0.03, drug entrapment efficiency of 46.3±5.0% for 5-FU and 75.1±0.9% for NIT. The drug release efficiency up to 8 hours was about 37.6±0.9% for 5-FU and 62.9±0.7% for NIT. The co-delivery of 5-FU and NIT in targeted nanoparticles showed significantly more cytotoxicity than the mixture of the two free drugs, non-targeted nanoparticles or each drug alone and reduced the IC50 value of 5-FU from 3.31±0.65µg/ml to 0.17±0.03µg/ml and the migration of HepG2 cells was also reduced to five-fold. CONCLUSION: Co-delivery of 5-FU and NIT by HA targeted chitosan-chondroitin nanoparticles may be promising in HCC.


Assuntos
Antineoplásicos/química , Carcinoma Hepatocelular/tratamento farmacológico , Fluoruracila/química , Neoplasias Hepáticas/tratamento farmacológico , Nanocápsulas/química , Nitroquinolinas/química , Inibidores de Proteases/química , Animais , Antineoplásicos/farmacologia , Catepsina B/antagonistas & inibidores , Quitosana/química , Condroitina/química , Liberação Controlada de Fármacos , Quimioterapia Combinada , Fluoruracila/farmacologia , Células Hep G2 , Humanos , Ácido Hialurônico/metabolismo , Camundongos , Terapia de Alvo Molecular , Células NIH 3T3 , Nitroquinolinas/farmacologia , Inibidores de Proteases/farmacologia
8.
J Antimicrob Chemother ; 75(2): 300-308, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31633764

RESUMO

OBJECTIVES: To determine the mechanism of resistance to the antibiotic nitroxoline in Escherichia coli. METHODS: Spontaneous nitroxoline-resistant mutants were selected at different concentrations of nitroxoline. WGS and strain reconstruction were used to define the genetic basis for the resistance. The mechanistic basis of resistance was determined by quantitative PCR (qPCR) and by overexpression of target genes. Fitness costs of the resistance mutations and cross-resistance to other antibiotics were also determined. RESULTS: Mutations in the transcriptional repressor emrR conferred low-level resistance to nitroxoline [nitroxoline MIC (MICNOX)=16 mg/L] by increasing the expression of the emrA and emrB genes of the EmrAB-TolC efflux pump. These resistant mutants showed no fitness reduction and displayed cross-resistance to nalidixic acid. Second-step mutants with higher-level resistance (MICNOX=32-64 mg/L) had mutations in the emrR gene, together with either a 50 kb amplification, a mutation in the gene marA, or an IS upstream of the lon gene. The latter mutations resulted in higher-level nitroxoline resistance due to increased expression of the tolC gene, which was confirmed by overexpressing tolC from an inducible plasmid in a low-level resistance mutant. Furthermore, the emrR mutations conferred a small increase in resistance to nitrofurantoin only when combined with an nfsAB double-knockout mutation. However, nitrofurantoin-resistant nfsAB mutants showed no cross-resistance to nitroxoline. CONCLUSIONS: Mutations in different genes causing increased expression of the EmrAB-TolC pump lead to an increased resistance to nitroxoline. The structurally similar antibiotics nitroxoline and nitrofurantoin appear to have different modes of action and resistance mechanisms.


Assuntos
Farmacorresistência Bacteriana/genética , Proteínas de Escherichia coli , Escherichia coli/genética , Nitroquinolinas , Antibacterianos/farmacologia , Escherichia coli/efeitos dos fármacos , Proteínas de Escherichia coli/genética , Testes de Sensibilidade Microbiana , Mutação , Nitroquinolinas/farmacologia
9.
Acta Biochim Pol ; 66(4): 521-531, 2019 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-31834689

RESUMO

Cancer is a disease receiving an outstanding input of funds for basic and clinical research but is, nevertheless, still the second leading cause of death in the developed world and a great burden for health systems. New drugs are therefore needed to improve therapy, prolong survival of cancer patients and improve their quality of life. The high cost of development and clinical evaluation of new drugs limits the number that actually enter clinical use. To overcome this problem, repurposing of established drugs for new indications has gained a lot of interest, especially in the field of oncology. The well-established antimicrobial agent nitroxoline has been identified as a promising candidate to be repurposed for cancer treatment in several independent studies. Here we have reviewed a wide range of molecular mechanisms and tumor models involving nitroxoline in impairment of tumor progression. Furthermore, nitroxoline was used as a lead compound for structure-based chemical synthesis of new derivatives in order to improve its potency as well as selectivity for various targets. The potent antitumor activity of nitroxoline points strongly in the direction of its repurposing for cancer treatment and to the benefits of this strategy for patients and healthcare system.


Assuntos
Carcinogênese/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Nitroquinolinas/uso terapêutico , Anti-Infecciosos/uso terapêutico , Proliferação de Células/efeitos dos fármacos , Reposicionamento de Medicamentos , Humanos
10.
Sci Rep ; 9(1): 16613, 2019 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-31719653

RESUMO

Glioblastoma multiforme (GBM) is one of the most aggressive human tumors with poor survival rates. The current standard treatment includes chemotherapy with temozolomide (TMZ), but acquisition of resistance is a persistent clinical problem limiting the successful treatment of GBM. The purpose of our study was to investigate therapeutic effects of nitroxoline (NTX) against TMZ-resistant GBM in vitro and in vivo in TMZ-resistant GBM-bearing mouse model, which was correlated with diffusion-weighted imaging (DWI). For in vitro study, we used TMZ-resistant GBM cell lines and evaluated therapeutic effects of NTX by clonogenic and migration assays. Quantitative RT-PCR was used to investigate the expression level of TMZ-resistant genes after NTX treatment. For in vivo study, we performed 9.4 T MR imaging to obtain T2WI for tumor volume measurement and DWI for assessment of apparent diffusion coefficient (ADC) changes by NTX in TMZ-resistant GBM mice (n = 8). Moreover, we performed regression analysis for the relationship between ADC and histological findings, which reflects the changes in cellularity and apurinic/apyrimidinic endonuclease-1 (APE-1) expression. We observed the recovery of TMZ-induced morphological changes, a reduced number of colonies and a decreased rate of migration capacity in TMZ-resistant cells after NTX treatment. The expression of APE-1 was significantly decreased in TMZ-resistant cells after NTX treatment compared with those without treatment. In an in vivo study, NTX reduced tumor growth in TMZ-resistant GBM mice (P = 0.0122). Moreover, ADC was increased in the NTX-treated TMZ-resistant GBM mice compared to the control group (P = 0.0079), which was prior to a tumor volume decrease. The cellularity and APE-1 expression by histology were negatively correlated with the ADC value, which in turn resulted in longer survival in NTX group. The decreased expression of APE-1 by NTX leads to therapeutic effects and is inversely correlated with ADC in TMZ-resistant GBM. Therefore, NTX is suggested as potential therapeutic candidate against TMZ-resistant GBM.


Assuntos
Antineoplásicos Alquilantes/uso terapêutico , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/metabolismo , Glioblastoma/tratamento farmacológico , Nitroquinolinas/uso terapêutico , Temozolomida/uso terapêutico , Animais , Linhagem Celular Tumoral , Imagem de Difusão por Ressonância Magnética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Sinergismo Farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioblastoma/diagnóstico por imagem , Glioblastoma/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Transplante de Neoplasias
11.
Chem Res Toxicol ; 32(11): 2182-2191, 2019 11 18.
Artigo em Inglês | MEDLINE | ID: mdl-31638783

RESUMO

Oxidative stress has been documented as one of the significant causes of neurodegenerative diseases. Therefore, antioxidant therapy for the prevention of neurodegenerative diseases seems to be an interesting strategy in drug discovery. The quinoline-based compound, namely 5-nitro-8-quinolinol (NQ), has shown excellent antimicrobial, anticancer, and anti-inflammatory activities. However, its neuroprotective effects and precise molecular mechanisms in human neuronal cells have not been elucidated. In this work, the effects of NQ on cell viability and morphology were evaluated by the MTT assay and microscopic observation. Moreover, the underlying mechanisms of this compound, inducing the survival rate of neuronal cells under oxidative stress, were investigated by reactive oxygen species (ROS) assay, flow cytometry, Western blotting, and immunofluorescence techniques. In addition, the molecular interaction of sirtuin1 (SIRT1) with NQ was constructed using the AutoDock 4.2 program. Interestingly, NQ protected SH-SY5Y cells against H2O2-induced neurotoxicity through scavenging ROS, upregulating the levels of SIRT1 and FOXO3a, increasing the levels of antioxidant enzymes (catalase and superoxide dismutase), promoting antiapoptotic BCL-2 protein expression, and reducing apoptosis. Besides, molecular docking also revealed that NQ interacted satisfactorily with the active site of SIRT1 similar to the resveratrol, which is the SIRT1 activator and strong antioxidant. These findings suggest that NQ prevents oxidative-stress-induced neurodegeneration because of its antioxidant capacity as well as antiapoptotic property through SIRT1-FOXO3a signaling pathway. Thus, NQ might be a drug that could be repurposed for prevention of neurodegeneration.


Assuntos
Reposicionamento de Medicamentos , Doenças Neurodegenerativas/prevenção & controle , Neurônios/efeitos dos fármacos , Nitroquinolinas/farmacologia , Substâncias Protetoras/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Proteína Forkhead Box O3/metabolismo , Humanos , Peróxido de Hidrogênio/toxicidade , Simulação de Acoplamento Molecular , Neurônios/metabolismo , Neurônios/patologia , Espécies Reativas de Oxigênio/metabolismo , Sirtuína 1/metabolismo
12.
Inorg Chem ; 58(18): 12334-12347, 2019 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-31464130

RESUMO

Lysosomal cysteine peptidase cathepsin B (catB) is an important tumor-promoting factor involved in tumor progression and metastasis representing a relevant target for the development of new antitumor agents. In the present study, we synthesized 11 ruthenium compounds bearing either the clinical agent nitroxoline that was previously identified as potent selective reversible inhibitor of catB activity or its derivatives. We demonstrated that organoruthenation is a viable strategy for obtaining highly effective and specific inhibitors of catB endo- and exopeptidase activity, as shown using enzyme kinetics and microscale thermophoresis. Furthermore, we showed that the novel metallodrugs by catB inhibition significantly impair processes of tumor progression in in vitro cell based functional assays at low noncytotoxic concentrations. Generally, by using metallodrugs we observed an improvement in catB inhibition, a reduction of extracellular matrix degradation and tumor cell invasion in comparison to free ligands, and a correlation with the reactivity of the monodentate halide leaving ligand.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Catepsina B/antagonistas & inibidores , Invasividade Neoplásica/prevenção & controle , Nitroquinolinas/farmacologia , Rutênio/farmacologia , Antineoplásicos/química , Neoplasias da Mama/patologia , Catepsina B/metabolismo , Linhagem Celular Tumoral , Feminino , Humanos , Modelos Moleculares , Invasividade Neoplásica/patologia , Nitroquinolinas/química , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Rutênio/química
13.
J Antimicrob Chemother ; 74(10): 2934-2937, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31292653

RESUMO

BACKGROUND: Infections caused by carbapenemase-producing Enterobacterales (CPE) constitute a major global health concern and are associated with increased morbidity and mortality. Nitroxoline is an old antibiotic, which has recently been re-launched for the treatment of uncomplicated urinary tract infection. Because of low resistance rates it could be an interesting option for treatment of MDR isolates, yet data on CPE susceptibility are scarce. OBJECTIVES: To analyse the in vitro activity of nitroxoline against CPE. METHODS: MICs of nitroxoline were determined by agar dilution for a collection of well-characterized carbapenemase producers (n = 105), producing OXA-48-like (n = 36), VIM (n = 21), IMI (n = 9), IMP (n = 6), NDM (n = 22), KPC (n = 11), OXA-58 (n = 2) and GES (n = 2). For comparison, MICs of ertapenem, imipenem and meropenem were determined by agar gradient diffusion. RESULTS: For all 105 isolates, the MIC50/90 of nitroxoline was 8/16 mg/L. All Escherichia coli isolates (30/30, 100%) showed low MICs of 2-8 mg/L and were susceptible to nitroxoline. MICs of 32 mg/L were recorded for five isolates of VIM- and IMI-producing Enterobacter cloacae (n = 3) and OXA- and VIM-producing Klebsiella pneumoniae (n = 2). CONCLUSIONS: Nitroxoline exhibited excellent in vitro activity against most isolates producing common and rare carbapenemases. If the current EUCAST susceptibility breakpoint of ≤16 mg/L for E. coli in uncomplicated urinary tract infections was applied, 95.2% (100/105) of isolates would be classified as susceptible. Nitroxoline could therefore be an alternative oral option for treatment of uncomplicated urinary tract infections caused by CPE.


Assuntos
Anti-Infecciosos Urinários/farmacologia , Enterobacteriáceas Resistentes a Carbapenêmicos/efeitos dos fármacos , Enterobacter cloacae/efeitos dos fármacos , Escherichia coli/efeitos dos fármacos , Klebsiella pneumoniae/efeitos dos fármacos , Nitroquinolinas/farmacologia , Humanos , Imipenem/farmacologia , Meropeném/farmacologia , Testes de Sensibilidade Microbiana
14.
Int J Biol Sci ; 15(5): 919-928, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31182913

RESUMO

Programmed cell death protein 1 (PD-1) blockade is a promising therapeutic strategy against prostate cancer. Nitroxoline has been found to have effective anticancer properties in several cancer types. We investigated the efficacy of a combination therapy involving nitroxoline and PD-1 blockade in a prostate cancer mouse model. In our in vitro analysis, we found that nitroxoline inhibited the viability and proliferation of the mouse prostate cancer cell line RM9-Luc-PSA. Additionally, nitroxoline downregulated the expressions of phospho-PI3 kinase, phospho-Akt (Thr308), phospho-Akt (Ser473), phospho-GSK-3ß, Bcl-2, and Bcl-xL. Nitroxoline also downregulated programmed death-ligand 1 (PD-L1) expression levels in prostate cancer cell line and tumor tissue. In our murine prostate cancer orthotopic model, nitroxoline plus PD-1 blockade synergistically suppressed tumor growth when compared with nitroxoline or PD-1 blockade alone, leading to reductions in tumor weight, bioluminescence tumor signals, and serum prostate-specific antigen levels. Furthermore, fluorescence-activated cell sorting analysis showed that the combination strategy significantly enhanced antitumor immunity by increasing CD44+CD62L+CD8+ memory T cell numbers and reducing myeloid-derived suppressor cell numbers in peripheral blood. In conclusion, our findings suggest that nitroxoline plus PD-1 blockade may be a promising treatment strategy in patients with prostate cancer.


Assuntos
Nitroquinolinas/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Animais , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Sinergismo Farmacológico , Citometria de Fluxo , Humanos , Imuno-Histoquímica , Imunoterapia , Masculino , Camundongos , Camundongos Endogâmicos C57BL
15.
J Med Microbiol ; 68(7): 991-995, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31162022

RESUMO

In 2018, the European Centre for Disease Prevention and Control reported the first cases of extensively drug-resistant Neisseria gonorrhoeae infections in Europe. Seeking new options for antimicrobial therapy we investigated the susceptibility of N. gonorrhoeae to nitroxoline (NIT) and mecillinam (MCM), both of which are currently only indicated to treat uncomplicated urinary tract infections. Clinical N. gonorrhoeae isolates with non-susceptibility to penicillin from two German medical centres were included (n =27). Most isolates were also non-susceptible to a range of other anti-gonococcal antimicrobials (cefotaxime, ciprofloxacin, azithromycin, tetracycline). All isolates were further characterized by multi-locus sequence typing. MICs of penicillin and cefotaxime were determined by agar gradient diffusion. Production of penicillinase was tested by cefinase disk test. Susceptibility of MCM was investigated by agar dilution, NIT by agar dilution and disk diffusion. Penicillin MICs ranged from 0.125 to 64 mg l-1 and MICs of cefotaxime ranged from < 0.016 to 1 mg l-1 . Five isolates were penicillinase-producers. MICs of MCM ranged from 16 to > 128 mg l-1 whereas MICs of NIT ranged from 0.125 to 2 mg l-1 . NIT disk diffusion (median zone diameter 32 mm) correlated well with results from agar dilution. We demonstrated excellent in vitro activity of NIT against clinical N. gonorrhoeae isolates with non-susceptibility to standard anti-gonococcal antibiotics. MCM activity was unsatisfactory. Correlation of agar dilution and disk diffusion in NIT susceptibility testing is an important aspect with potential clinical implications.


Assuntos
Andinocilina/farmacologia , Anti-Infecciosos Urinários/farmacologia , Neisseria gonorrhoeae/efeitos dos fármacos , Nitroquinolinas/farmacologia , Farmacorresistência Bacteriana Múltipla , Humanos , Tipagem de Sequências Multilocus , Neisseria gonorrhoeae/genética
16.
Sci Rep ; 9(1): 5585, 2019 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-30944404

RESUMO

Amide proton transfer (APT) imaging is a novel molecular MRI technique to detect endogenous mobile proteins and peptides through chemical exchange saturation transfer. In this preliminary study, the purpose was to evaluate the feasibility of APT imaging in monitoring the early therapeutic response to nitroxoline (NTX) in a temozolomide (TMZ)-resistant glioblastoma multiforme (GBM) mouse model, which was compared with diffusion-weighted imaging (DWI). Here, we prepared TMZ-resistant GBM mouse model (n = 12), which were treated with 100 mg/kg/day of NTX (n = 4) or TMZ (n = 4), or saline (n = 4) for 7 days for the evaluation of short-term treatment by using APT imaging and DWI sequentially. The APT signal intensities and apparent diffusion coefficient (ADC) values were calculated and compared before and after treatment. Moreover, immunohistological analysis was also employed for the correlation between APT imaging and histopathology. The association between the APT value and Ki-67 labeling index was evaluated by using simple linear regression analysis. The short-term NTX treatment resulted in significant decrease in APT value as compared to untreated and TMZ group, in which APT signals were increased. However, we did not observe significantly increased mean ADC value following short-term NTX treatment. The Ki-67 labeling index shows a correlation with APT value. APT imaging could show the earlier response to NTX treatment as compared to ADC values in a TMZ-resistant mouse model. We believe that APT imaging can be a useful imaging biomarker for the early therapeutic evaluation in GBM patients.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Glioma/tratamento farmacológico , Nitroquinolinas/farmacologia , Temozolomida/farmacologia , Algoritmos , Amidas/administração & dosagem , Animais , Imagem de Difusão por Ressonância Magnética/métodos , Imageamento por Ressonância Magnética/métodos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Prótons
17.
Kaohsiung J Med Sci ; 35(4): 202-208, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30896891

RESUMO

The proto-oncogene MDM2 is a nuclear-localized E3 ubiquitin ligase, which promotes tumor formation by targeting tumor suppressor proteins, such as p53, for proteasomal degradation. In this study, the anti-infective drug nitroxoline (NXQ) was screened out to effectively inhibit cell survival of small-cell lung cancer (SCLC) cells, and induce SCLC cell apoptosis by suppressing antiapoptotic proteins (such as Bcl-2 and MCL1) and upregulating proapoptotic protein Bim. In the mechanistic study, NXQ was found to downregulate MDM2 expression by inducing its proteasomal degradation, and thus upregulated p53 expression, which was a substrate protein of MDM2. Moreover, overexpression of MDM2 decreased the cytotoxicity of NXQ on SCLC cells. These results demonstrated that NXQ displayed anti-SCLC activity by suppressing MDM2 expression, which suggested that anti-infective NXQ had potential for SCLC treatment by targeting the MDM2/p53 axis.


Assuntos
Apoptose/efeitos dos fármacos , Carcinoma de Células Pequenas/metabolismo , Carcinoma de Células Pequenas/patologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Nitroquinolinas/farmacologia , Proteólise/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Humanos , Nitroquinolinas/química , Complexo de Endopeptidases do Proteassoma/metabolismo
18.
Drug Metab Dispos ; 47(5): 473-483, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30787100

RESUMO

Many promising drug candidates metabolized by aldehyde oxidase (AOX) fail during clinical trial owing to underestimation of their clearance. AOX is species-specific, which makes traditional allometric studies a poor choice for estimating human clearance. Other studies have suggested using half-life calculated by measuring substrate depletion to measure clearance. In this study, we proposed using numerical fitting to enzymatic pathways other than Michaelis-Menten (MM) to avoid missing the initial high turnover rate of product formation. Here, product formation over a 240-minute time course of six AOX substrates-O6-benzylguanine, N-(2-dimethylamino)ethyl)acridine-4-carboxamide, zaleplon, phthalazine, BIBX1382 [N8-(3-Chloro-4-fluorophenyl)-N2-(1-methyl-4-piperidinyl)-pyrimido[5,4-d]pyrimidine-2,8-diamine dihydrochloride], and zoniporide-have been provided to illustrate enzyme deactivation over time to help better understand why MM kinetics sometimes leads to underestimation of rate constants. Based on the data provided in this article, the total velocity for substrates becomes slower than the initial velocity by 3.1-, 6.5-, 2.9-, 32.2-, 2.7-, and 0.2-fold, respectively, in human expressed purified enzyme, whereas the K m remains constant. Also, our studies on the role of reactive oxygen species (ROS), such as superoxide and hydrogen peroxide, show that ROS did not significantly alter the change in enzyme activity over time. Providing a new electron acceptor, 5-nitroquinoline, did, however, alter the change in rate over time for mumerous compounds. The data also illustrate the difficulties in using substrate disappearance to estimate intrinsic clearance.


Assuntos
Aldeído Oxidase/metabolismo , Acetamidas/metabolismo , Acridinas/metabolismo , Guanidinas/metabolismo , Humanos , Hidralazina/metabolismo , Cinética , Fígado/metabolismo , Nitroquinolinas/metabolismo , Ftalazinas/metabolismo , Pirazóis/metabolismo , Pirimidinas/metabolismo , Espécies Reativas de Oxigênio/metabolismo
19.
J Med Chem ; 62(3): 1677-1683, 2019 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-30562026

RESUMO

We identify three submicromolar inhibitors with new chemical scaffolds for cystathionine γ-lyase (CSE) by a tandem-well-based high-throughput assay. NSC4056, the most potent inhibitor with an IC50 of 0.6 µM, which is also known as aurintricarboxylic acid, selectively binds to Arg and Tyr residues of CSE active site and preferably inhibits the CSE activity in cells rather than cystathionine ß-synthase (CBS), the other H2S-generating enzyme. Moreover, NSC4056 effectively rescues hypotension in hemorrhagic shock rats.


Assuntos
Ácido Aurintricarboxílico/farmacologia , Cistationina gama-Liase/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Animais , Ácido Aurintricarboxílico/química , Ácido Aurintricarboxílico/metabolismo , Domínio Catalítico/efeitos dos fármacos , Cistationina gama-Liase/química , Cistationina gama-Liase/metabolismo , Descoberta de Drogas , Inibidores Enzimáticos/metabolismo , Células HEK293 , Humanos , Masculino , Camundongos , Simulação de Acoplamento Molecular , Estrutura Molecular , Nitroquinolinas/farmacologia , Ligação Proteica , Células RAW 264.7 , Ratos Sprague-Dawley , Relação Estrutura-Atividade
20.
Eur J Med Chem ; 163: 281-294, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30529546

RESUMO

Bromodomain-containing protein 4 (BRD4), an epigenetic reader of acetyl lysine, has emerged as a promising therapeutic target for many diseases including cancer, inflammation and heart failure. Our previous study reported that nitroxoline, an FDA approved antibiotic, showed potential BRD4 inhibitory activity and antiproliferation activity against leukemia cell lines. In this study, we further explored the structure-activity relationship (SAR) around nitroxoline and employed our previously developed machine learning based activity scoring function BRD4LGR for further analysis. To improve the cellular level activity, physico-chemical properties were optimized using computational approaches. Then the candidates were tested for their ADME/T profiles. Finally, based on this rational hit-to-lead optimization strategy, 3 drug-like BRD4 inhibitors were obtained, with different profiles on cell line selectivity for multiple myeloma, leukemia and triple negative breast cancer. Further mechanism study showed these compounds could down-regulate c-Myc to inhibit cancer cell growth. This work illustrates the application of multiple computer-aided drug design techniques in a hit-to-lead optimization scenario, and provides novel potent BRD4 inhibitors with different phenotype propensities for future cancer treatment.


Assuntos
Desenho Assistido por Computador , Imidazóis/química , Nitroquinolinas/química , Proteínas Nucleares/antagonistas & inibidores , Quinolinas/química , Fatores de Transcrição/antagonistas & inibidores , Proteínas de Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Desenho de Fármacos , Humanos , Leucemia/tratamento farmacológico , Mieloma Múltiplo/tratamento farmacológico , Proteínas Proto-Oncogênicas c-myc/efeitos dos fármacos , Relação Estrutura-Atividade , Neoplasias de Mama Triplo Negativas/tratamento farmacológico
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...