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1.
Life Sci ; 252: 117610, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32259601

RESUMO

Hyperammonemia is a serious metabolic disorder associating with hepatic encephalopathy (HE) which occurs secondary to several forms of liver injury ranging from simple acute liver failure (ALF) to its most serious form; cirrhosis. The resent study highlights the possible ameliorative effect of oral nifuroxazide (25 mg/kg) against experimentally induced ALF and the subsequent HE in a well-standardized rat model. ALF and HE were induced in a rat model by I.P. injection of thioacetamide (TAA) (200 mg/kg) for 1 week at alternative days. Nifuroxazide administration for 14 days prior to and for further 7 days alongside TAA injection successfully attenuated TAA-induced ALF and HE; as demonstrated by the significant retraction in both brain and serum hyperammonemia with significant improvement in liver function biomarkers; ALT, AST, ALP, GGT, albumin, and serum total protein. This was associated with a significant restoration of both hepatic and brain oxidative stress incidences; MDA, SOD and catalase activities and GSH concentration. The observed improvement was associated with a significant reduction in liver and brain contents of c-Jun N-terminal kinase (cJNK); as an anti-inflammatory biomarker and a modulator of various pro- and anti-apoptotic proteins, caspase-8, and tumor necrosis factor-related apoptosis ligand (TRAIL); as biomarkers of apoptosis. In conclusion; the modulatory effect of nifuroxazide on cJNK/caspase-8/TRAIL signaling appears to underly its hepatoprotective effect and its ameliorative effect on HE progression.


Assuntos
Encefalopatia Hepática/tratamento farmacológico , Hidroxibenzoatos/farmacologia , Hiperamonemia/prevenção & controle , Falência Hepática Aguda/tratamento farmacológico , Nitrofuranos/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Animais , Caspase 8/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Encefalopatia Hepática/complicações , Encefalopatia Hepática/fisiopatologia , Hidroxibenzoatos/administração & dosagem , Hiperamonemia/etiologia , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Falência Hepática Aguda/complicações , Falência Hepática Aguda/fisiopatologia , Masculino , Nitrofuranos/administração & dosagem , Ratos , Ratos Sprague-Dawley , Ligante Indutor de Apoptose Relacionado a TNF/metabolismo
2.
Eur J Pharm Sci ; 140: 105092, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31634556

RESUMO

5-nitrofurans (NFs) have been in clinical use for over 60 years. These affordable drugs are used for the treatment of a broad spectrum of diseases ranging from urinary tract infections to cancer. The anti-pathogenic effect of clinical NFs occurs following a step-wise process involving activation by azoreduction, followed by nitroreduction catalysed by azoreductases and nitroreductases (NTRs), respectively. Azoreduction yields stable metabolites that have the ability to covalently bind to cellular proteins. Nitroreduction, on the other hand, occurs by type I or II reduction of the nitro group in the presence of parasitic NADPH-cytochrome P450 reductases. Type I NTRs catalyse, under anaerobic conditions, the reduction of NFs to produce anti-pathogenic hydroxylamine. Under aerobic conditions, nitroreduction catalysed by type II NTRs produces reactive oxygen and nitrogen species (ROS/RNS), causing oxidative stress to pathogens and ultimate death. This multi-activity nature of NFs thus allows the repurposing of these drugs from agricultural chemicals and basic antibiotics to efficient therapies against human life-threatening diseases. Cases of NF resistance in pathogens are also limited likely due to this multi-activity, as well as effectivity under both aerobic and anaerobic conditions. However, multi-activity of these drugs can also infer toxicity. Molecular derivatisation is an effective strategy to improve efficacy, lower toxicity, diversify activity and address pathogen resistance associated with the use of these drugs.


Assuntos
Antibacterianos/farmacologia , Reposicionamento de Medicamentos/métodos , Nitrofuranos/farmacologia , Antibacterianos/toxicidade , Catálise , Avaliação Pré-Clínica de Medicamentos/métodos , Resistência Microbiana a Medicamentos/efeitos dos fármacos , Humanos , Estrutura Molecular , NADH NADPH Oxirredutases/metabolismo , NADPH-Ferri-Hemoproteína Redutase/metabolismo , Nitrofuranos/toxicidade , Nitrogênio/química , Nitrorredutases/metabolismo , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-Atividade
3.
J Immunol ; 203(3): 736-748, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31209100

RESUMO

The pyroptotic cell death effector gasdermin D (GSDMD) is required for murine models of hereditary inflammasome-driven, IL-1ß-dependent, autoinflammatory disease, making it an attractive therapeutic target. However, the importance of GSDMD for more common conditions mediated by pathological IL-1ß activation, such as gout, remain unclear. In this study, we address whether GSDMD and the recently described GSDMD inhibitor necrosulfonamide (NSA) contribute to monosodium urate (MSU) crystal-induced cell death, IL-1ß release, and autoinflammation. We demonstrate that MSU crystals, the etiological agent of gout, rapidly activate GSDMD in murine macrophages. Despite this, the genetic deletion of GSDMD or the other lytic effector implicated in MSU crystal killing, mixed lineage kinase domain-like (MLKL), did not prevent MSU crystal-induced cell death. Consequently, GSDMD or MLKL loss did not hinder MSU crystal-mediated release of bioactive IL-1ß. Consistent with in vitro findings, IL-1ß induction and autoinflammation in MSU crystal-induced peritonitis was not reduced in GSDMD-deficient mice. Moreover, we show that the reported GSDMD inhibitor, NSA, blocks inflammasome priming and caspase-1 activation, thereby preventing pyroptosis independent of GSDMD targeting. The inhibition of cathepsins, widely implicated in particle-induced macrophage killing, also failed to prevent MSU crystal-mediated cell death. These findings 1) demonstrate that not all IL-1ß-driven autoinflammatory conditions will benefit from the therapeutic targeting of GSDMD, 2) document a unique mechanism of MSU crystal-induced macrophage cell death not rescued by pan-cathepsin inhibition, and 3) show that NSA inhibits inflammasomes upstream of GSDMD to prevent pyroptotic cell death and IL-1ß release.


Assuntos
Gota/patologia , Interleucina-1beta/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas de Ligação a Fosfato/metabolismo , Piroptose/fisiologia , Ácido Úrico/metabolismo , Acrilamidas/farmacologia , Animais , Caspase 1/metabolismo , Catepsinas/antagonistas & inibidores , Feminino , Peptídeos e Proteínas de Sinalização Intracelular/genética , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Nitrofuranos/farmacologia , Peritonite/induzido quimicamente , Peritonite/imunologia , Peritonite/patologia , Proteínas de Ligação a Fosfato/genética , Proteínas Quinases/genética , Estirenos/farmacologia , Sulfonamidas/farmacologia
4.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 50(1): 48-54, 2019 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-31037904

RESUMO

OBJECTIVE: To explore the effect of nifuroxazide on proliferation, migration, and invasion of thyroid papillary carcinoma cells. METHODS: BCPAP and TPC-1 cell lines treated with different concentration (0, 1.25, 2.5, 5, 10, 20 µmol/L) of nifuroxazide, respectively. Cell viability and proliferation of BCPAP and TPC-1 was evaluated by MTT and colony formation assay. Apoptosis analysis and cell nuclear changes were determined by staining with Hoechst 33258 and visualized by a fluorescence microscope after treatment with nifuroxazide. Western blot analysis was used to evaluate protein expressions of apoptosis and invasion of BCPAP cells treated (48 h) with nifuroxazide. Transwell assay was conducted to evaluate ability of cell migration and invasion. RESULTS: After being treated with nifuroxazide (0, 1.25, 2.5 µmol/L and 0, 1.25 µmol/L) for 24, 48, 72 h respectively, decreased proliferations of BCPAP and TPC-1 cell lines were not obvious ( P>0.05). However, treated BCPAP and TPC-1 cells with higher concentration respectively (5, 10, 20 µmol/L and 5, 10 µmol/L) of nifuroxazide for 24, 48, 72 h, the inhibitory effects were significantly obvious ( P<0.05), and the inhibitory effects were increased in a CM(155mm]concentration- and time-dependent manner. The inhibition in proliferation of TPC-1 cell with nifuroxazide (2.5, CM)]5 µmol/L) took effect from 72 h and 48 h ( P<0.05), respectively. Clone formations of BCPAP and TPC-1 cells were significantly inhibited after being exposed to nifuroxazide (2.5, 5 µmol/L) for 10 d ( P<0.05). Hoechst 33258 staining assay showed that nifuroxazide (10 µmol/L) treatment resulted in cell shrinking, nuclear fragmentation and formation of condensed nuclei with bright-blue fluorescence. After 48 h, the percentage of apoptotic cells of BCPAP and TPC-1 significantly increased respectively as the concentration of nifuroxazide with 10 µmol/L ( P<0.005). Pro-apoptotic protein CC-3 and Bax expression levels increased significantly ( P<0.05), and the expression of anti-apoptotic protein Bcl-2 decreased significantly ( P<0.05) in BCPAP cells after nifuroxazide-treatment (10 µmol/L) for 48 h. The percentage of migrations and invasions of BCPAP and TPC-1 significantly decreased ( P<0.05) in the presence of nifuroxazide (10 µmol/L, 48 h). Nifuroxazide (10 µmol/L) treatment significantly decreased the expressions of matrix metalloproteinase (MMP)-2 and MMP-9 in BCPAP cells ( P<0.05) . Expression of MMPs family inhibitor-tissue inhibitors of metalloproteinase (TIMP)-2 increased ( P<0.05). CONCLUSION: Nifuroxazide inhibits the proliferation of thyroid cancer cells BCPAP and TPC-1, induceds the cell apoptosis by up-regulating the expressions of CC-3 and Bax proteins in vitro, and blocks migration and invasion of cells in vitro by reducing protein expressions of MMP-2 and MMP-9.


Assuntos
Carcinoma Papilar , Neoplasias da Glândula Tireoide , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Humanos , Hidroxibenzoatos , Invasividade Neoplásica , Nitrofuranos
5.
ACS Appl Mater Interfaces ; 11(20): 18074-18089, 2019 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-31013055

RESUMO

Transcription factor STAT3 has been shown to regulate genes that are involved in stem cell self-renewal and thus represents a novel therapeutic target of great biological significance. However, many small-molecule agents with potential effects through STAT3 modulation in cancer therapy lack aqueous solubility and high off-target toxicity, hence impeding efficient bioavailability and activity. This work, for the first time, reports a prodrug-based strategy for selective and safer delivery of STAT3 inhibitors designed toward metastatic and drug-resistant breast cancer. We have synthesized a novel lipase-labile SN-2 phospholipid prodrug from a clinically investigated STAT3 inhibitor, nifuroxazide (Pro-nifuroxazide), which can be regioselectively cleaved by the membrane-abundant enzymes in cancer cells. Pro-nifuroxazide self-assembled to sub 20 nm nanoparticles (NPs), and the cytotoxic ability was screened in ER(+)-MCF-7 and ER(-)-MD-MB231 cells at 48-72 h using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetra-zolium bromide proliferation assay. Results indicated that Pro-nifuroxazide NPs are multifold more effective toward inhibiting cancer cells in a time-dependent manner compared to parent nifuroxazide. A remarkable improvement in the local concentration of drugs to as high as ∼240 fold when assembled into NPs is presumably the reason for this functional improvement. We also introduced molecular dynamics simulations to generate Pro-nifuroxazide nano-assembly, as a model assembly from triggerable anti-cancer drugs, to provide molecular insights correlating physicochemical and anti-cancer properties. In silico properties of Pro-nifuroxazide including size, chemistry of NPs and membrane interactions with individual molecules could be validated by in vitro functional activities in cells of breast cancer origin. The in vivo anti-cancer efficiencies of Pro-nifuroxazide NPs in nude mice xenografts with MCF-7 revealed remarkable growth inhibition of as high as 400%. Histopathological analysis corroborated these findings to show significantly high nuclear fragmentation and retracted cytoplasm. Immunostaining on tumor section demonstrated a significantly lower level of pSTAT-3 by Pro-nifuroxazide NP treatment, establishing the inhibition of STAT-3 phosphorylation. Our strategy for the first time proposes a translatable prodrug agent self-assembled into NPs and demonstrates remarkable enhancement in IC50, induced apoptosis, and reduced cancer cell population through STAT-3 inhibition via reduced phosphorylation.


Assuntos
Antineoplásicos , Hidroxibenzoatos , Nanomedicina , Neoplasias , Nitrofuranos , Pró-Fármacos , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Humanos , Hidroxibenzoatos/química , Hidroxibenzoatos/farmacocinética , Hidroxibenzoatos/farmacologia , Células MCF-7 , Camundongos , Camundongos Nus , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Nitrofuranos/química , Nitrofuranos/farmacocinética , Nitrofuranos/farmacologia , Pró-Fármacos/química , Pró-Fármacos/farmacocinética , Pró-Fármacos/farmacologia , Fator de Transcrição STAT3/antagonistas & inibidores , Fator de Transcrição STAT3/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Bioorg Med Chem Lett ; 29(10): 1232-1235, 2019 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-30879839

RESUMO

A series of eleven double prodrug derivatives of a fosmidomycin surrogate were synthesized and investigated for their ability to inhibit in vitro growth of P. falciparum and M. tuberculosis. A pivaloyloxymethyl (POM) phosphonate prodrug modification was combined with various prodrug derivatisations of the hydroxamate moiety. The majority of compounds showed activity comparable with or inferior to fosmidomycin against P. falciparum. N-benzyl substituted carbamate prodrug 6f was the most active antimalarial analog with an IC50 value of 0.64 µM. Contrary to fosmidomycin and parent POM-prodrug 5, 2-nitrofuran and 2-nitrothiophene prodrugs 6i and 6j displayed promising antitubercular activities.


Assuntos
Antimaláricos/química , Antituberculosos/química , Mycobacterium tuberculosis/efeitos dos fármacos , Plasmodium falciparum/efeitos dos fármacos , Pró-Fármacos/química , Antimaláricos/farmacologia , Antituberculosos/farmacologia , Carbamatos/química , Avaliação Pré-Clínica de Medicamentos/métodos , Fosfomicina/análogos & derivados , Fosfomicina/farmacologia , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Nitrofuranos/química , Pró-Fármacos/farmacologia , Transdução de Sinais , Relação Estrutura-Atividade
7.
Chemosphere ; 222: 381-390, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30711727

RESUMO

This paper discusses the impact of two nitrofuran-derived drugs, namely furazolidone and nitrofurantoin on growth of oat and common radish as well as their impact on bacteria Allivibrio fischeri and crustaceans Heterocypris incongruens. Results indicated that both compounds were highly phytotoxic for radish (R. sativus) being simultaneously nearly not harmful for oat (A. sativa). Growing inhibition of shoots, roots, fresh matter and photosynthetic pigments is correlated with growing concentration of drugs in soil. Ecotoxicological impact of both compounds on model luminescence bacteria Aliivibrio fischeri and freshwater crustaceans Heterocypris incongruens as a representative organisms of two different level of food chain, is also reported herein, and the obtained data show significant toxicity against these two organisms. Basing on obtained results, it was concluded that both nitrofuran drugs in case of distribution through environment, by improper utilisation after use or unplanned environmental intoxication with unused drugs may cause serious environmental problems and therefore both should be handled with a reasonable care at any step of their production or utilisation.


Assuntos
Ecotoxicologia , Furazolidona/toxicidade , Nitrofuranos/toxicidade , Nitrofurantoína/toxicidade , Aliivibrio fischeri/efeitos dos fármacos , Animais , Antibacterianos/toxicidade , Avena/efeitos dos fármacos , Avena/crescimento & desenvolvimento , Crustáceos/efeitos dos fármacos , Nitrofuranos/química , Raphanus/efeitos dos fármacos , Raphanus/crescimento & desenvolvimento , Poluentes do Solo/toxicidade
8.
Dalton Trans ; 48(8): 2683-2691, 2019 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-30706938

RESUMO

Organic pollutants, such as antibiotics, pesticides, and nitroaromatic compounds (NACs), have posed a great threat to human health and sustainable development. Therefore, the detection of these organic pollutants is of great importance but challenging. In this work, we synthesized a rigid conjugated tricarboxylic acid ligand 4,4'-(9-(4'-carboxy-[1,1'-biphenyl]-4-yl)-9H-carbazole-3,6-diyl)dibenzoic acid (H3CBCD), and employed this ligand to react with Cd(ii) ions to construct a Cd-LMOF, namely [Cd3(CBCD)2(DMA)4(H2O)2]·10DMA (Cd-CBCD). Cd-CBCD features a three-dimensional (3D) supramolecular framework based on two-dimensional (2D) layer structures through ππ stacking interactions. The fluorescence sensing measurements demonstrate that Cd-CBCD can detect nitrofurans (NFs), 4-nitroaniline (4-NA) and 2,6-dichloro-4-nitroaniline (DCN) with high selectivity and sensitivity. This work represents the first carbazole-functionalized metal-organic framework as a fluorescent sensor for the highly efficient detection of antibiotics, pesticides and nitroaromatic compounds.


Assuntos
Antibacterianos/análise , Carbazóis/química , Estruturas Metalorgânicas/química , Nitrofuranos/análise , Praguicidas/análise , Poluentes Químicos da Água/análise , Cádmio/química , Cristalografia por Raios X , Conformação Molecular , Espectrometria de Fluorescência
9.
Eur J Med Chem ; 166: 125-135, 2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30703656

RESUMO

A selectively antimycobacterial compound belonging to the nitrofuran class of antimicrobials has been developed via conjugation of the nitrofuran moiety to a series of spirocyclic piperidines through an amide linkage. It proved to have comparable activity against drug-sensitive (H37Rv) strain as well as multidrug-resistant, patient-derived strains of Mycobacterium tuberculosis. The compound is druglike, showed no appreciable cytotoxicity toward human retinal pigment epithelial cell line ARPE-19 in concentrations up to 100 µM and displayed low toxicity when evaluated in mice.


Assuntos
Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Mycobacterium tuberculosis/efeitos dos fármacos , Nitrofuranos/química , Nitrofuranos/farmacologia , Piperidinas/química , Compostos de Espiro/química , Antituberculosos/química , Antituberculosos/farmacologia , Antituberculosos/toxicidade , Linhagem Celular , Humanos , Nitrofuranos/toxicidade , Relação Estrutura-Atividade
10.
Bioorg Med Chem Lett ; 29(4): 601-606, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30600207

RESUMO

The optimization campaign for a nitrofuran antitubercular hit (N-benzyl-5-nitrofuran-2-carboxamide; JSF-3449) led to the design, synthesis, and biological profiling of a family of analogs. These compounds exhibited potent in vitro antitubercular activity (MIC = 0.019-0.20 µM) against the Mycobacterium tuberculosis H37Rv strain and low in vitro cytotoxicity (CC50 = 40->120 µM) towards Vero cells. Significant improvements in mouse liver microsomal stability and mouse pharmacokinetic profile were realized by introduction of an α, α-dimethylbenzyl moiety. Among these compounds, JSF-4088 is highlighted due to its in vitro antitubercular potency (MIC = 0.019 µM) and Vero cell cytotoxicity (CC50 > 120 µM). The findings suggest a rationale for the continued evolution of this promising series of antitubercular small molecules.


Assuntos
Antituberculosos/farmacologia , Nitrofuranos/química , Nitrofuranos/farmacologia , Animais , Antituberculosos/química , Antituberculosos/farmacocinética , Chlorocebus aethiops , Feminino , Camundongos , Testes de Sensibilidade Microbiana , Microssomos Hepáticos/efeitos dos fármacos , Mycobacterium tuberculosis/efeitos dos fármacos , Nitrofuranos/farmacocinética , Células Vero
11.
Anticancer Agents Med Chem ; 19(8): 1037-1047, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30657046

RESUMO

BACKGROUND: Drug repositioning is becoming an ideal strategy to select new anticancer drugs. In particular, drugs treating the side effects of chemotherapy are the best candidates. OBJECTIVE: In this present work, we undertook the evaluation of anti-tumour activity of two anti-diarrheal drugs (nifuroxazide and rifaximin). METHODS: Anti-proliferative effect against breast cancer cells (MDA-MB-231, MCF-7 and T47D) was assessed by MTT analysis, the Brdu incorporation, mitochondrial permeability and caspase-3 activity. RESULTS: Both the drugs displayed cytotoxic effects on MCF-7, T47D and MDA-MB-231 cells. The lowest IC50 values were obtained on MCF-7 cells after 24, 48 and 72 hours of treatment while T47D and MDA-MB-231 were more resistant. The IC50 values on T47D and MDA-MB-231 cells became significantly low after 72 hours of treatment showing a late cytotoxicity effect especially of nifuroxazide but still less important than that of MCF-7 cells. According to the IC50 values, the non-tumour cell line HEK293 seems to be less sensitive to cytotoxicity especially against rifaximin. Both the drugs have shown an accumulation of rhodamine 123 as a function of the rise of their concentrations while the Brdu incorporation decreased. Despite the absence of a significant difference in the cell cycle between the treated and non-treated MCF-7 cells, the caspase-3 activity increased with the drug concentrations rise suggesting an apoptotic effect. CONCLUSION: Nifuroxazide and rifaximin are used to overcome the diarrheal side effect of anticancer drugs. However, they have shown to be anti-tumour drugs which make them potential dual effective drugs against cancer and the side effects of chemotherapy.


Assuntos
Antineoplásicos/farmacologia , Diarreia , Reposicionamento de Medicamentos , Hidroxibenzoatos/farmacologia , Nitrofuranos/farmacologia , Rifaximina/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Diarreia/tratamento farmacológico , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HEK293 , Humanos , Hidroxibenzoatos/síntese química , Hidroxibenzoatos/química , Estrutura Molecular , Nitrofuranos/síntese química , Nitrofuranos/química , Rifaximina/síntese química , Rifaximina/química , Relação Estrutura-Atividade , Cicatrização/efeitos dos fármacos
12.
J Orthop Res ; 37(3): 789-798, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30667081

RESUMO

Mutant TP53 is a promising therapeutic target in cancers. Considering the current challenges facing the clinical treatment of cancer, as well as the urgent need to identify novel therapeutic targets in osteosarcomas, we aimed to evaluate the clinical significance of mutant TP53 in osteosarcoma patients and to explore the therapeutic effect of targeting mutant TP53 in osteosarcomas. We performed a meta-analysis to investigate the relationship between mutant TP53 and the overall survival of patients with osteosarcoma. A CRISPR-Cas9 system and a TP53 inhibitor, NSC59984, were also used to specifically knock-out and inhibit mutant TP53 in the human osteosarcoma cell lines, KHOS, and KHOSR2. The meta-analysis demonstrated that mutations in the TP53 gene could be used to predict a poor 2-year survival in osteosarcoma patients. We also demonstrated that the expression of mutant TP53 in human osteosarcoma cell lines can be efficiently knocked-out using CRISPR-Cas9, and this decreased the proliferation, migration, and tumor formation activity of these osteosarcoma cells. Moreover, drug sensitivity to doxorubicin was increased in these TP53 knock-out osteosarcoma cells. NSC59984 also showed similar anti-tumor effects as CRISPR-Cas9 targeted TP53 in the osteosarcoma cells in vitro. We have also demonstrated that the knock-out or inhibition of mutant TP53 decreased the expression of the oncogene IGF-1R, anti-apoptotic proteins Bcl-2, and Survivin in osteosarcoma cells. Collectively, these results suggest that mutant TP53 is a promising therapeutic target in osteosarcomas. Therefore, further studies exploring novel strategies to target mutant TP53 may help improve the treatment outcomes of osteosarcoma patients in the clinic. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res.


Assuntos
Neoplasias Ósseas/genética , Genes p53 , Terapia Genética , Nitrofuranos/uso terapêutico , Osteossarcoma/genética , Piperazinas/uso terapêutico , Antibióticos Antineoplásicos/uso terapêutico , Neoplasias Ósseas/terapia , Sistemas CRISPR-Cas , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Doxorrubicina/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Sinergismo Farmacológico , Humanos , Mutação , Nitrofuranos/farmacologia , Osteossarcoma/terapia , Piperazinas/farmacologia , Proteína Supressora de Tumor p53/antagonistas & inibidores , Proteína Supressora de Tumor p53/genética
13.
Invest New Drugs ; 37(5): 1006-1013, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-30680584

RESUMO

Osteosarcoma is the most common primary malignancy of bone and characterized by an appendicular primary tumor with a high rate of metastasis to the lungs. Unfortunately, there is no effective strategy to treat osteosarcoma in current clinical practice. In this study, the anticancer effects and potential mechanisms of nifuroxazide, an oral nitrofuran antibiotic, on two osteosarcoma cell lines were investigated. The results of the antiproliferative activity in vitro showed that nifuroxazide inhibited cell proliferation of UMR106 and MG63 cells in a dose- and time-dependent manner. Interestingly, nifuroxazide showed low toxicity to non-tumor cells (HEK 293 T). In addition, ROS-mitochondrial mediated apoptosis was observed after treatment of nifuroxazide. Moreover, nifuroxazide could significantly inhibit osteosarcoma cells migration and invasion via p-Stat3, MMP-2 and MMP-9 mediated signaling pathway. Taken together, our results suggested that nifuroxazide could be a promising agent for osteosarcoma treatment by inhibiting cell proliferation, inducing cell apoptosis and impairing cell migration and invasion.


Assuntos
Anti-Infecciosos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias Ósseas/patologia , Movimento Celular/efeitos dos fármacos , Hidroxibenzoatos/farmacologia , Nitrofuranos/farmacologia , Osteossarcoma/patologia , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/metabolismo , Proliferação de Células/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Osteossarcoma/tratamento farmacológico , Osteossarcoma/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Células Tumorais Cultivadas , Cicatrização/efeitos dos fármacos
14.
Dalton Trans ; 48(5): 1823-1834, 2019 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-30648712

RESUMO

The detection of nitrofuran antibiotics and toxic inorganic anions is currently necessary and challenging because their abuse and/or residuals have caused severe environmental pollution and illness. A heterometallic two-dimensional (2D) layered complex, {[Eu2Na(Hpddb)(pddb)2(CH3COO)2]·2.5(DMA)}n (1), was solvothermally synthesized and structurally and photophysically characterized. Pairs of acetate aggregated {Eu2Na(CH3COO)2} chains are periodically interconnected by V-shaped 4,4'-(pyridine-2,6-diyl)dibenzolate (pddb) linkers. More interestingly, the layered complex exhibits a bright red emission and can efficiently discriminate nitrofuran antibiotics by luminescent quenching with a strong quenching constant (Ksv) and low detection limit (LOD) of 4.93 × 104 M-1 and 0.64 µM for nitrofurazone, 4.42 × 104 M-1 and 0.68 µM for nitrofurantoin as well as 2.13 × 104 M-1 and 1.06 µM for furazolidone. Additionally, 1 can also probe trace amounts of toxic Cr2O72- and MnO4- anions with Ksv = 6.45 × 103 M-1 and LOD = 5.35 µM for Cr2O72- and Ksv = 2.84 × 103 M-1 and LOD = 5.99 µM for MnO4- anions. These interesting results indicate that heteromatallic coordination polymers can serve as favorable dual- or even multiple-responsive luminescence sensors to selectively recognize different kinds of contaminants.


Assuntos
Antibacterianos/análise , Cromo/análise , Európio/química , Substâncias Luminescentes/química , Compostos de Manganês/análise , Nitrofuranos/análise , Óxidos/análise , Sódio/química
15.
J Prosthodont ; 28(1): e222-e228, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28872730

RESUMO

PURPOSE: To evaluate microleakage in roots restored with fiber posts cemented using three different luting cements, to measure the volume of voids/gaps within the obturated/postcemented root canals, and to examine whether microleakage and the volume of voids/gaps were correlated. MATERIALS AND METHODS: Thirty-six extracted human mandibular incisors were decoronated, and the root canals were obturated using gutta-percha and sealer in the experimental groups (n = 30). Six roots were used as controls. A standard post space was prepared, and an identically sized fiber post was cemented in each experimental specimen using one of three luting cements (Panavia F2.0, Bifix SE, GC FujiCEM; n = 10 each). The specimens were scanned using micro-computed tomography, and the volume of voids/gaps was determined. The specimens were then subjected to a fluid filtration assay to evaluate microleakage. RESULTS: The volume of voids/gaps was significantly lower in the GC FujiCEM group, and significantly less microleakage occurred in the Bifix SE group compared with other groups (both p < 0.001). A significant correlation between the volume of voids/gaps and leakage was found only in the Panavia F2.0 group (p = 0.003; r = 0.830). No such correlation was found in the analysis of all groups combined. CONCLUSIONS: The group with the greatest volume of voids/gaps (Bifix SE) showed the least microleakage, and the group with the smallest volume of voids/gaps (GC FujiCEM) showed the most microleakage. Panavia F2.0 ranked between and exhibited significant correlation.


Assuntos
Cimentação/métodos , Cimentos Dentários/química , Infiltração Dentária , Técnica para Retentor Intrarradicular , Materiais Restauradores do Canal Radicular/química , Colagem Dentária , Infiltração Dentária/prevenção & controle , Materiais Dentários/química , Cavidade Pulpar/diagnóstico por imagem , Adesivos Dentinários/química , Vidro , Cimentos de Ionômeros de Vidro/química , Guta-Percha , Humanos , Hidroxibenzoatos , Incisivo , Teste de Materiais , Nitrofuranos , Cimentos de Resina , Obturação do Canal Radicular , Tratamento do Canal Radicular/métodos , Microtomografia por Raio-X
16.
Cell Chem Biol ; 25(12): 1439-1440, 2018 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-30576659

RESUMO

Aldehyde dehydrogenases (ALDHs) are known as robust markers of tumor-initiating cells and as potential therapeutic targets for cancer. In this issue of Cell Chemical Biology, Sarvi et al. (2018) demonstrate that 5-nitrofuran antibiotics can target ALDH-expressing cancer cells in two distinct ways, effectively depleting melanomas of their tumor-initiating cells.


Assuntos
Melanoma , Nitrofuranos , Aldeído Desidrogenase , Aldeído Desidrogenase 1 , Humanos , Hidroxibenzoatos , Isoenzimas , Retinal Desidrogenase
17.
ACS Chem Biol ; 13(12): 3354-3360, 2018 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-30451487

RESUMO

Hypoxia, a condition of reduced oxygen, occurs in a wide variety of biological contexts, including solid tumors and bacterial biofilms, which are relevant to human health. Consequently, the development of chemical tools to study hypoxia is vital. Here we report a hypoxia-activated, small-molecule-mediated gene expression system using a bioreductive prodrug of the inducer isopropyl 1-thio-ß-d-galactopyranoside. As a proof-of-concept we have placed the production of a green fluorescent protein under the control of hypoxia. Our system has the potential to be extended to regulate the production of any given protein of choice.


Assuntos
Expressão Gênica/efeitos dos fármacos , Proteínas de Fluorescência Verde/metabolismo , Isopropiltiogalactosídeo/análogos & derivados , Isopropiltiogalactosídeo/farmacologia , Pró-Fármacos/farmacologia , Anaerobiose/fisiologia , Linhagem Celular Tumoral , Escherichia coli/genética , Escherichia coli/metabolismo , Proteínas de Fluorescência Verde/genética , Humanos , Isopropiltiogalactosídeo/síntese química , Isopropiltiogalactosídeo/metabolismo , Nitrofuranos/síntese química , Nitrofuranos/metabolismo , Oxazinas/síntese química , Oxazinas/metabolismo , Pró-Fármacos/síntese química , Pró-Fármacos/metabolismo
18.
Cell Chem Biol ; 25(12): 1456-1469.e6, 2018 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-30293938

RESUMO

5-Nitrofurans are antibiotic pro-drugs that have potential as cancer therapeutics. Here, we show that 5-nitrofurans can be bio-activated by aldehyde dehydrogenase (ALDH) 1A1/1A3 enzymes that are highly expressed in a subpopulation of cancer-initiating (stem) cells. We discover that the 5-nitrofuran, nifuroxazide, is selective for bio-activation by ALDH1 isoforms over ALDH2, whereby it both oxidizes ALDH1 and is converted to cytotoxic metabolites in a two-hit pro-drug mechanism. We show that ALDH1High melanoma cells are sensitive to nifuroxazide, while ALDH1A3 loss-of-function mutations confer drug resistance. In tumors, nifuroxazide targets ALDH1High melanoma subpopulations with the subsequent loss of melanoma-initiating cell potential. BRAF and MEK inhibitor therapy increases ALDH1 expression in patient melanomas, and effectively combines with nifuroxazide in melanoma cell models. The selective eradication of ALDH1High cells by nifuroxazide-ALDH1 activation goes beyond current strategies based on inhibiting ALDH1 and provides a rational basis for the nifuroxazide mechanism of action in cancer.


Assuntos
Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Hidroxibenzoatos/metabolismo , Hidroxibenzoatos/farmacologia , Isoenzimas/metabolismo , Melanoma/tratamento farmacológico , Melanoma/patologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Nitrofuranos/metabolismo , Nitrofuranos/farmacologia , Retinal Desidrogenase/metabolismo , Aldeído Desidrogenase 1 , Animais , Antineoplásicos/química , Linhagem Celular Tumoral , Hidroxibenzoatos/química , Isoenzimas/antagonistas & inibidores , Melanoma/genética , Melanoma/metabolismo , Camundongos , Estrutura Molecular , Células-Tronco Neoplásicas/patologia , Nitrofuranos/química , Pró-Fármacos/química , Pró-Fármacos/metabolismo , Pró-Fármacos/farmacologia , Retinal Desidrogenase/antagonistas & inibidores
19.
Open Biol ; 8(9)2018 09 26.
Artigo em Inglês | MEDLINE | ID: mdl-30257893

RESUMO

Cytoplasmic dynein is a minus-end-directed microtubule-based motor that acts at diverse subcellular sites. During mitosis, dynein localizes simultaneously to the mitotic spindle, spindle poles, kinetochores and the cell cortex. However, it is unclear what controls the relative targeting of dynein to these locations. As dynein is heavily post-translationally modified, we sought to test a role for these modifications in regulating dynein localization. We find that dynein rapidly and strongly accumulates at mitotic spindle poles following treatment with NSC697923, a small molecule that inhibits the ubiquitin E2 enzyme, Ubc13, or treatment with PYR-41, a ubiquitin E1 inhibitor. Subsets of dynein regulators such as Lis1, ZW10 and Spindly accumulate at the spindle poles, whereas others do not, suggesting that NSC697923 differentially affects specific dynein populations. We additionally find that dynein relocalization induced by NSC697923 or PYR-41 can be suppressed by simultaneous treatment with the non-selective deubiquitinase inhibitor, PR-619. However, we did not observe altered dynein localization following treatment with the selective E1 inhibitor, TAK-243. Although it is possible that off-target effects of NSC697923 and PYR-41 are responsible for the observed changes in dynein localization, the rapid relocalization upon drug treatment highlights the highly dynamic nature of dynein regulation during mitosis.


Assuntos
Dineínas/metabolismo , Mitose , Bibliotecas de Moléculas Pequenas/farmacologia , Fuso Acromático/metabolismo , Enzimas de Conjugação de Ubiquitina/antagonistas & inibidores , Aminopiridinas/farmacologia , Benzoatos/farmacologia , Dineínas/química , Furanos/farmacologia , Células HeLa , Humanos , Cinetocoros/metabolismo , Microtúbulos/metabolismo , Nitrofuranos/farmacologia , Transporte Proteico , Pirazóis/farmacologia , Sulfonas/farmacologia , Tiocianatos/farmacologia , Ubiquitinação
20.
Eur J Med Chem ; 157: 1115-1126, 2018 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-30179748

RESUMO

Within the general nitrofuran carboxamide chemotype, chimera derivatives incorporating diversely substituted imidazoles attached via an alkylamino linker were synthesized. Antimycobacterial evaluation against drug-sensitive M. tuberculosis H37Rv strain identified five active druglike compounds which were further profiled against patient-derived M. tuberculosis strains in vitro. One of the compounds displayed promising potent activity (MIC 0.8 µg/mL) against one of such strains otherwise resistant to such first- and second-line TB therapies as streptomycin, isoniazid, rifampicin, ethambutol, kanamycin, ethionamide, capreomycin and amikacin. The compound was shown to possess low toxicity for mice (LD50 = 900.0 ±â€¯83.96 mg/kg) and to be similarly efficacious to etambutol, in the mouse model of drug-sensitive tuberculosis, and to neurotoxic cycloserine in mice infected with MDR tuberculosis.


Assuntos
Antituberculosos/farmacologia , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Imidazóis/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Nitrofuranos/farmacologia , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Antituberculosos/síntese química , Antituberculosos/química , Relação Dose-Resposta a Droga , Imidazóis/química , Estrutura Molecular , Nitrofuranos/síntese química , Nitrofuranos/química , Relação Estrutura-Atividade
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