Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.338
Filtrar
1.
Pharm Res ; 37(3): 44, 2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-31993760

RESUMO

PURPOSE: This prospective study aimed to evaluate the effects of genetic polymorphisms in sulindac-related metabolizing enzyme genes including FMO3 and AOX1 on the population pharmacokinetics of sulindac in 58 pregnant women with preterm labor. METHODS: Plasma samples were collected at 1.5, 4, and 10 h after first oral administration of sulindac. Plasma concentrations of sulindac and its active metabolite (sulindac sulfide) were determined, and pharmacokinetic analysis was performed with NONMEM 7.3. RESULTS: The mean maternal and gestational ages at the time of dosing were 32.5 ± 4.4 (range, 20-41) years and 27.4 ± 4.4 (range, 16.4-33.4) weeks, respectively. In the population pharmacokinetic analysis, one depot compartment model of sulindac with absorption lag time best described the data. The metabolism of sulindac and sulindac sulfide was described using Michaelis-Menten kinetics. In stepwise modeling, gestational age impacted volume of distribution (Vc), and FMO3 rs2266782 was shown by the Michaelis constant to affect conversion of sulindac sulfide to sulindac (KM32); these were retained in the final model. CONCLUSIONS: Genetic polymorphisms of FMO3 and AOX1 could affect the pharmacokinetics of sulindac in women who undergo preterm labor. The results of this study could help clinicians develop individualized treatment plans for administering sulindac.


Assuntos
Aldeído Oxidase/genética , Anti-Inflamatórios/farmacocinética , Trabalho de Parto Prematuro/metabolismo , Oxigenases/genética , Polimorfismo Genético/fisiologia , Sulindaco/farmacocinética , Adulto , Aldeído Oxidase/metabolismo , Feminino , Genótipo , Idade Gestacional , Humanos , Modelos Biológicos , Oxigenases/metabolismo , Gravidez , Estudos Prospectivos , Transdução de Sinais , Sulindaco/análogos & derivados , Sulindaco/metabolismo
2.
Int J Pharm ; 567: 118476, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31255778

RESUMO

The polymorphism of sulindac was investigated by Raman investigations, mainly in the low-wavenumber region in order to analyze the influence of the amorphization method on recrystallization and crystalline form stability. By devitrification of the quenched liquid, it was found that the undercooled liquid crystallizes into Form I, and a polymorphic transformation by cooling Form I toward Form IV, was clearly revealed. The low-wavenumber spectra of polymorphic forms are direct fingerprints of crystals, indicating a degree of disorder of Form IV intermediate between those of the ordered Form II (commercial form) and the relatively disordered Form I. This study has shown the enantiotropic relationship between Forms I and IV and that both the temperature of crystallization and the physical stability of Form I prepared is dependent on the technique used for preparing amorphous sulindac.


Assuntos
Anti-Inflamatórios não Esteroides/química , Sulindaco/química , Cristalização , Análise Espectral Raman , Vitrificação
3.
Artif Cells Nanomed Biotechnol ; 47(1): 1746-1757, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31062618

RESUMO

To evaluate the safety and efficacy of novel cobalt complex with sulindac (Co-SLD), the zebrafish and oral squamous cell carcinoma CAL27 were investigated in the present study. The developmental toxicity of Co-SLD ranging from 5 to 20 µM was determined by exposure to 3-144-h post-fertilization (hpf) zebrafish. Our data showed that Co-SLD did not cause to the appreciable toxicity at low concentration (5 and 10 µM). A remarkable toxicity was observed at high concentration (20 µM), including increased mortality and malformation, delayed hatchability, reduced heart rate as well as suppressed behaviour. With regard to the antitumor activity of Co-SLD, inhibited cell growth and migration capability were outstandingly observed in oral squamous cell carcinoma treated with 10 and 20 µM Co-SLD, which could be mainly attributed to the Co-SLD-elicited mitochondrial damage as marked by the depression of mitochondrial membrane potential, ROS accumulation and ATP depletion. Furthermore, administration of 10 µM Co-SLD was an optimal concentration not only to avoid the normal tissue toxicity, but also to enhance the killing of cancer cells via disrupting mitochondrial dysfunction. Taken together the above results demonstrated the desirable response of oral squamous cell carcinoma to Co-SLD.


Assuntos
Carcinoma de Células Escamosas/patologia , Cobalto/química , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Mitocôndrias/efeitos dos fármacos , Neoplasias Bucais/patologia , Sulindaco/química , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/toxicidade , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Complexos de Coordenação/toxicidade , Relação Dose-Resposta a Droga , Humanos , Locomoção/efeitos dos fármacos , Mitocôndrias/patologia , Peixe-Zebra
4.
Nat Commun ; 10(1): 1463, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30931933

RESUMO

Retinoid X receptor-alpha (RXRα) is a potent regulator of inflammatory responses; however, its therapeutic potential for inflammatory cancer remains to be explored. We previously discovered that RXRα is abnormally cleaved in tumor cells and tissues, producing a truncated RXRα (tRXRα). Here, we show that transgenic expression of tRXRα in mice accelerates the development of colitis-associated colon cancer (CAC). The tumorigenic effect of tRXRα is primarily dependent on its expression in myeloid cells, which results in interleukin-6 (IL-6) induction and STAT3 activation. Mechanistic studies reveal an extensive interaction between tRXRα and TRAF6 in the cytoplasm of macrophages, leading to TRAF6 ubiquitination and subsequent activation of the NF-κB inflammatory pathway. K-80003, a tRXRα modulator derived from nonsteroidal anti-inflammatory drug (NSAID) sulindac, suppresses the growth of tRXRα-mediated colorectal tumor by inhibiting the NF-κB-IL-6-STAT3 signaling cascade. These results provide new insight into tRXRα action and identify a promising tRXRα ligand for treating CAC.


Assuntos
Carcinogênese/genética , Colite/genética , Neoplasias Colorretais/genética , Interleucina-6/imunologia , Receptor X Retinoide alfa/genética , Fator de Transcrição STAT3/imunologia , Animais , Carcinogênese/imunologia , Colite/imunologia , Colite Ulcerativa/imunologia , Colo/efeitos dos fármacos , Colo/imunologia , Colo/metabolismo , Neoplasias Colorretais/imunologia , Meios de Cultivo Condicionados , Modelos Animais de Doenças , Células HCT116 , Humanos , Inflamação , Macrófagos/imunologia , Camundongos , NF-kappa B/imunologia , Receptor X Retinoide alfa/imunologia , Transdução de Sinais , Sulindaco/análogos & derivados , Sulindaco/farmacologia , Fator 6 Associado a Receptor de TNF/imunologia
5.
Cell Tissue Res ; 376(3): 377-388, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30758710

RESUMO

In the current experiment, the combined regime of resveratrol and a Wnt-3a inhibitor, sulindac, were examined on the angiogenic potential of cancer stem cells from human colon adenocarcinoma cell line HT-29 during 7 days. Cancer stem cells were enriched via a magnetic-activated cell sorter technique and cultured in endothelial induction medium containing sulindac and resveratrol. Expression of endothelial markers such as the von Willebrand factor (vWF) and vascular endothelial cadherin (VE-cadherin) and genes participating in mesenchymal-to-epithelial transition was studied by real-time PCR assay. Protein levels of Wnt-3a and angiogenic factor YKL-40 were examined by western blotting. ELISA was used to determine the level of N-acetylgalactosaminyltransferase 11 (GALNT11) during mesenchymal-endothelial transition. Autophagy status was monitored by PCR array under treatment with the resveratrol plus sulindac. Results showed that resveratrol and sulindac had the potential to decrease the cell survival of HT-29 cancer cells and the clonogenic capacity of cancer stem cells compared with the control (p < 0.05). The expression of VE-cadherin and vWF was induced in cancer stem cells incubated with endothelial differentiation medium enriched with resveratrol (p < 0.05). Interestingly, the Wnt-3a level was increased in the presence of resveratrol and sulindac (p < 0.05). YKL-40 was reduced after cell exposure to sulindac and resveratrol. The intracellular content of resistance factor GALNT11 was diminished after treatment with resveratrol (p < 0.05). Resveratrol had the potential to induce the transcription of autophagy signaling genes in cancer stem cells during endothelial differentiation (p < 0.05). These data show that resveratrol could increase cancer stem cell trans-differentiation toward endothelial lineage while decrease cell resistance by modulation of autophagy signaling and GALNT11 synthesis.


Assuntos
Antineoplásicos/farmacologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Células-Tronco Neoplásicas/efeitos dos fármacos , Resveratrol/farmacologia , Sulindaco/farmacologia , Proteína Wnt3A/antagonistas & inibidores , Antígenos CD/metabolismo , Autofagia/efeitos dos fármacos , Caderinas/metabolismo , Diferenciação Celular/efeitos dos fármacos , Proteína 1 Semelhante à Quitinase-3/metabolismo , Células HT29 , Humanos , N-Acetilgalactosaminiltransferases/metabolismo , Células-Tronco Neoplásicas/patologia , Transdução de Sinais/efeitos dos fármacos , Fator de von Willebrand/metabolismo
6.
J Endod ; 45(4): 364-371, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30737050

RESUMO

INTRODUCTION: This review aimed to find the most effective oral premedication in reducing pain in adults after nonsurgical root canal therapy (NSRCT) using network meta-analysis. METHODS: The review protocol was registered in the PROSPERO database (CRD42017071899). A literature search was performed in the MEDLINE and EBSCOhost databases until June 2017 with no language restriction. Randomized controlled trials evaluating the efficacy of oral premedications, whether given alone or in combination, compared with other agents, placebo, or no treatment in adult patients before NSRCT for postoperative pain were included. Nonintervention studies, nonendodontic studies, animal studies, and reviews were excluded. The quality of the studies was assessed using the revised Cochrane risk of bias tool. Pair-wise meta-analysis, network meta-analysis, and quality of evidence assessment using the Grading of Recommendations Assessment, Development and Evaluation criteria was performed. RESULTS: Eleven studies comparing pharmacologic groups of medications were included in the primary analysis. Compared with placebo, corticosteroids (prednisolone 30-40 mg) was ranked best for reducing postoperative pain (median difference [MD] = -18.14 [95% confidence interval (CI), -32.90 to -3.37] for the pain score at 6 hours; MD = -22.17 [95% CI, -36.03 to -8.32] for the pain score at 12 hours; and MD = -21.50 [95% CI, -37.95 to -5.06] for the pain score at 24 hours). However, the evidence was very low (6 and 24 hours) to moderate quality (12 hours). Nonsteroidal anti-inflammatory drugs were ranked least among the medications, and the quality of this evidence was very low. Additional analysis based on the chemical name showed that sulindac, ketorolac, and ibuprofen significantly reduced pain at 6 hours, whereas piroxicam and prednisolone significantly reduced the pain at 12 and 24 hours. Etodolac was found to be least effective in reducing pain. Overall, the evidence was of moderate to very low quality. CONCLUSIONS: Based on the limited and low-quality evidence, oral premedication with piroxicam or prednisolone could be recommended for controlling postoperative pain after NSRCT. However, more trials are warranted to confirm the results with a higher quality of evidence.


Assuntos
Dor Pós-Operatória/etiologia , Dor Pós-Operatória/prevenção & controle , Piroxicam/administração & dosagem , Prednisolona/administração & dosagem , Pré-Medicação , Ensaios Clínicos Controlados Aleatórios como Assunto , Tratamento do Canal Radicular/efeitos adversos , Administração Oral , Adolescente , Adulto , Idoso , Anti-Inflamatórios não Esteroides/administração & dosagem , Bases de Dados Bibliográficas , Feminino , Humanos , Ibuprofeno/administração & dosagem , Cetorolaco/administração & dosagem , Masculino , Pessoa de Meia-Idade , Tratamento do Canal Radicular/métodos , Sulindaco/administração & dosagem , Resultado do Tratamento , Adulto Jovem
7.
Br J Cancer ; 120(5): 537-546, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30739913

RESUMO

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) have been proposed as chemopreventive agents for many tumours; however, the mechanism responsible for their anti-neoplastic activity remains elusive and the side effects due to cyclooxygenase (COX) inhibition prevent this clinical application. METHODS: Molecular biology, in silico, cellular and in vivo tools, including innovative in vivo imaging and classical biochemical assays, were applied to identify and characterise the COX-independent anti-cancer mechanism of NSAIDs. RESULTS: Here, we show that tumour-protective functions of NSAIDs and exisulind (a sulindac metabolite lacking anti-inflammatory activity) occur through a COX-independent mechanism. We demonstrate these NSAIDs counteract carcinogen-induced proliferation by inhibiting the sirtuin 1 (SIRT1) deacetylase activity, augmenting acetylation and activity of the tumour suppressor p53 and increasing the expression of the antiproliferative gene p21. These properties are shared by all NSAIDs except for ketoprofen lacking anti-cancer properties. The clinical interest of the mechanism identified is underlined by our finding that p53 is activated in mastectomy patients undergoing intraoperative ketorolac, a treatment associated with decreased relapse risk and increased survival. CONCLUSION: Our study, for the first-time, links NSAID chemopreventive activity with direct SIRT1 inhibition and activation of the p53/p21 anti-oncogenic pathway, suggesting a novel strategy for the design of tumour-protective drugs.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Anticarcinógenos/farmacologia , Inibidor de Quinase Dependente de Ciclina p21/efeitos dos fármacos , Inibidores de Ciclo-Oxigenase/farmacologia , Sirtuína 1/efeitos dos fármacos , Sulindaco/análogos & derivados , Proteína Supressora de Tumor p53/efeitos dos fármacos , Animais , Anti-Inflamatórios não Esteroides/efeitos adversos , Anticarcinógenos/efeitos adversos , Linhagem Celular Tumoral , Simulação por Computador , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Inibidores de Ciclo-Oxigenase/efeitos adversos , Humanos , Cetorolaco/efeitos adversos , Cetorolaco/uso terapêutico , Camundongos , Modelos Moleculares , Sirtuína 1/metabolismo , Sulindaco/farmacologia , Proteína Supressora de Tumor p53/metabolismo
8.
Int J Pharm ; 557: 273-279, 2019 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-30597269

RESUMO

We studied the pharmacokinetics, biodistribution and metabolism of phospho-sulindac (PS), a novel agent efficacious in the treatment of dry eye, formulated in nanoparticles (PS-NPs) following its topical administration to the eye of New Zealand White rabbits. The nanoparticles were spherical with effective diameter = 108.9 ±â€¯41.7 nm, zeta potential = -21.70 ±â€¯3.78 mV, drug loading = 7%, and entrapment efficiency = 46.4%. Of the total PS delivered topically to the eye, >95% was retained in the anterior segment, predominantly in the cornea (Cmax = 101.3 µM; Tmax = 1 h; T1/2 = 2.6 h; area AUC0-16h = 164.4 µM·h) and conjunctiva (Cmax = 89.4 µM; Tmax = 0.25 h; T1/2 = 3.1 h; AUC0-16h = 63.5 µM·h), the tissues most affected by dry eye disease. No PS or its metabolites were detected in the systemic circulation. PS was metabolized to PS sulfide and PS sulfone; all three molecules were hydrolyzed to sulindac, which was converted to sulindac sulfide and sulindac sulfone. A solution formulation of PS provided lower PS levels in ocular tissues but higher levels of PS metabolites, compared to PS-NPs. Therefore, NPs represent an effective formulation for the topical ocular administration of PS for anterior segment diseases, such as dry eye disease.


Assuntos
Sistemas de Liberação de Medicamentos , Olho/metabolismo , Nanopartículas/administração & dosagem , Compostos Organofosforados/administração & dosagem , Sulindaco/análogos & derivados , Administração Intravenosa , Administração Tópica , Animais , Masculino , Nanopartículas/química , Compostos Organofosforados/sangue , Compostos Organofosforados/química , Compostos Organofosforados/farmacocinética , Coelhos , Sulindaco/administração & dosagem , Sulindaco/sangue , Sulindaco/química , Sulindaco/farmacocinética , Distribuição Tecidual
9.
Bioorg Chem ; 85: 413-419, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30665035

RESUMO

Retinoid X receptor alpha (RXRα), a central member of the nuclear receptor superfamily and a key regulator of many signal transduction pathways, has been an attractive drug target. We previously discovered that an N-terminally truncated form of RXRα can be induced by specific ligands to form homotetramers, which, as a result of conformational selection, forms the basis for inhibiting the nongenomic activation of RXRα. Here, we report the identification and characterization of atorvastatin as a new RXRα tetramer stabilizer by using structure-based virtual screening and demonstrate that virtual library screening can be used to aid in identifying RXRα ligands that can induce its tetramerization. In this study, docking was applied to screen the FDA-approved small molecule drugs in the DrugBank 4.0 collection. Two compounds were selected and purchased for testing. We showed that the selected atorvastatin could bind to RXRα to promote RXRα-LBD tetramerization. We also showed that atorvastatin possessed RXRα-dependent apoptotic effects. In addition, we used a chemical approach to aid in the studies of the binding mode of atorvastatin.


Assuntos
Atorvastatina/farmacologia , Multimerização Proteica/efeitos dos fármacos , Receptor X Retinoide alfa/metabolismo , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Atorvastatina/química , Atorvastatina/metabolismo , Sítios de Ligação , Avaliação Pré-Clínica de Medicamentos , Humanos , Ligantes , Células MCF-7 , Ligação Proteica/efeitos dos fármacos , Domínios Proteicos , Estabilidade Proteica/efeitos dos fármacos , Sulindaco/análogos & derivados , Sulindaco/metabolismo
10.
Int J Med Sci ; 16(1): 180-188, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30662341

RESUMO

Aim: Autosomal dominant polycystic kidney disease is one of the most common genetic renal diseases. Cyclooxygenase plays an important role in epithelial cell proliferation and may contribute to the mechanisms underlying cyst formation. The aim of the present study was to evaluate the role of cyclooxygenase inhibition in the cyst progression in polycystic kidney disease. Method: Pkd2WS25/- mice, a murine model which harbors a compound cis-heterozygous mutation of the Pkd2 gene were used. Cyclooxygenase expression was assessed in both human and murine kidney specimens. Pkd2WS25/- mice were treated with Sulindac (a nonselective cyclooxygenase inhibitor) or vehicle for 8 months starting at three weeks age, and then renal cyst burden was assessed by kidney weight and volume. Results: Cyclooxygenase-2 expression was up-regulated compared to control kidneys as shown by RNase protection in human polycystic kidneys and immunoblot in mouse Pkd2WS25/- kidneys. Cyclooxygenase-2 expression was up-regulated in the renal interstitium as well as focal areas of the cystic epithelium (p<0.05). Basal Cyclooxygenase-1 levels were unchanged in both immunohistochemistry and real-time PCR. Administration of Sulindac to Pkd2WS25/- mice and to control mice for 8 months resulted in reduced kidney weights and volume in cystic mice. Renal function and electrolytes were not significantly different between groups. Conclusion: Thus treatment of a murine model of polycystic kidney disease with Sulindac results in decreased kidney cyst burden. These findings provide additional implications for the use of Cyclooxygenase inhibition as treatment to slow the progression of cyst burden in patients with polycystic kidney disease.


Assuntos
Inibidores de Ciclo-Oxigenase/uso terapêutico , Rim Policístico Autossômico Dominante/tratamento farmacológico , Sulindaco/uso terapêutico , Animais , Proliferação de Células/efeitos dos fármacos , Cistos/metabolismo , Cistos/fisiopatologia , Dinoprostona/biossíntese , Modelos Animais de Doenças , Progressão da Doença , Taxa de Filtração Glomerular/efeitos dos fármacos , Humanos , Camundongos , Terapia de Alvo Molecular , Mutação , Prostaglandina-E Sintases/biossíntese , Prostaglandina-Endoperóxido Sintases/biossíntese , Prostaglandinas/biossíntese , Canais de Cátion TRPP/genética , Canais de Cátion TRPP/metabolismo
11.
Carbohydr Polym ; 208: 261-268, 2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30658799

RESUMO

In this work, biodegradable biomaterial films for sulindac (SLD) recognition are synthesized from mungbean starch (MBS), PVA, and plasticizers by using UV irradiation process and casting methods. The optimal UV irradiation time for the preparation of SLD imprinted biomaterials films was about 30 min. Mechanical properties, recognition ability, and SLD release property for prepared films were investigated. From the results of recognition ability, we verified that these SLD imprinted biomaterial films have the binding site for SLD. The release properties of SLD was examined with the change of pH and temperature. The results indicate that the SLD release in pH 10.0 was higher than in pH 4.0. SLD release was also evaluated using an artificial skin. Results of the artificial skin test verified that SLD was released constantly for 20 days.


Assuntos
Materiais Biocompatíveis/química , Amido/química , Sulindaco/química , Vigna/química , Sistemas de Liberação de Medicamentos/métodos , Membranas Artificiais , Solubilidade
12.
Neuropharmacology ; 147: 74-86, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-29792283

RESUMO

Many available drugs have been repurposed as treatments for neurodevelopmental disorders. In the specific case of fragile X syndrome, many clinical trials of available drugs have been conducted with the goal of disease modification. In some cases, detailed understanding of basic disease mechanisms has guided the choice of drugs for clinical trials, and several notable successes in fragile X clinical trials have led to common use of drugs such as minocycline in routine medical practice. Newer technologies like Disease-Gene Expression Matching (DGEM) may allow for more rapid identification of promising repurposing candidates. A DGEM study predicted that sulindac could be therapeutic for fragile X, and subsequent preclinical validation studies have shown promising results. The use of combinations of available drugs and nutraceuticals has the potential to greatly expand the options for repurposing, and may even be a viable business strategy. This article is part of the Special Issue entitled 'Drug Repurposing: old molecules, new ways to fast track drug discovery and development for CNS disorders'.


Assuntos
Reposicionamento de Medicamentos , Síndrome do Cromossomo X Frágil/tratamento farmacológico , Animais , Dissulfiram/farmacologia , Humanos , Metoprolol/farmacologia , Minociclina/farmacologia , Atividade Motora/efeitos dos fármacos , Ensaios Clínicos Controlados Aleatórios como Assunto , Sulindaco/farmacologia
13.
Biochem Biophys Res Commun ; 505(4): 1203-1210, 2018 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-30327144

RESUMO

Sulindac sulfone is a metabolite of sulindac, a non-steroidal anti-inflammatory drug (NSAID), without anti-inflammatory ability. However, sulindac sulfone has been reported to significantly reduce polyps in patients with colorectal adenomatous polyposis in clinical trials. Thus, sulindac sulfone is expected to be useful for the chemoprevention of neoplasia with few side effects related to anti-inflammatory ability. To date, the molecular targets of sulindac sulfone have not yet fully investigated. Therefore, in order to newly identify sulindac sulfone-binding proteins, we generated sulindac sulfone-fixed FG beads and purified sulindac sulfone-binding proteins from human colon cancer HT-29 cells. we identified mitochondrial outer membrane proteins voltage-dependent anion channel (VDAC) 1 and VDAC2 as novel molecular targets of sulindac sulfone, and sulindac sulfone directly bound to both VDAC1 and VDAC2. Double knockdown of VDAC1 and VDAC2 by siRNA inhibited growth and arrested the cell cycle at G1 phase in HT-29 cells. Depletion of VDAC1 and VDAC2 also inhibited the mTORC1 pathway with a reduction in cyclin D1. Interestingly, these effects were consistent with those of sulindac sulfone against human colon cancer cells, suggesting that sulindac sulfone negatively regulates the function of VDAC1 and VDAC2. In the present study, our data suggested that VDAC1 and VDAC2 are direct targets of sulindac sulfone which suppresses the mTORC1 pathway and induces G1 arrest.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Antineoplásicos/farmacologia , Neoplasias do Colo/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/antagonistas & inibidores , Sulindaco/análogos & derivados , Canal de Ânion 1 Dependente de Voltagem/antagonistas & inibidores , Canal de Ânion 2 Dependente de Voltagem/antagonistas & inibidores , Trifosfato de Adenosina/biossíntese , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/metabolismo , Antineoplásicos/química , Antineoplásicos/metabolismo , Pontos de Checagem do Ciclo Celular , Neoplasias do Colo/patologia , Células HT29 , Humanos , Sulindaco/química , Sulindaco/metabolismo , Sulindaco/farmacologia , Canal de Ânion 1 Dependente de Voltagem/metabolismo , Canal de Ânion 2 Dependente de Voltagem/metabolismo
14.
Int J Pharm ; 549(1-2): 161-168, 2018 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-30056217

RESUMO

Sulindac loaded poly(HEMA) cross-linked microparticles were synthesized via one-pot free-radical dispersion polymerisation in supercritical carbon dioxide (scCO2) in presence of photocleavable diblock stabilisers based on polyethylene oxide (PEO) and poly(heptadecafluorodecyl acrylate) (PFDA) bearing a o-nitrobenzyl photosensitive junction (hv) (PEO-hv-PFDA), and ethylene glycol dimethacrylate (EGDMA) as cross-linker. Poly(HEMA) cross-linked microparticles either empty or sulindac loaded were obtained with well-defined spherical morphology with the sizes between 250 and 350 nm. Additionally, upon UV-photolysis the stabiliser on the surface was cleaved which permits to microparticles to be redispersed in water leading to water swollen microgels about 2.1-3.6 µm. Moreover, the release behaviour from obtained microgels indicated the sustained release of sulindac over 10 days. Besides, the surface modification after UV-photolysis was studied and proved that the particles can be functionalised with further chemistries.


Assuntos
Dióxido de Carbono/química , Química Farmacêutica/métodos , Poliaminas/química , Poli-Hidroxietil Metacrilato/análogos & derivados , Sulindaco/administração & dosagem , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/química , Reagentes para Ligações Cruzadas/química , Preparações de Ação Retardada , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Metacrilatos/química , Microesferas , Tamanho da Partícula , Polietilenoglicóis/química , Poli-Hidroxietil Metacrilato/química , Sulindaco/química
15.
J Biochem Mol Toxicol ; 32(10): e22198, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29999212

RESUMO

A systematic investigation of the chemopreventive effect of sulindac (SL) in combination with either epigallocatechin gallate (EGCG) or kaempferol similar (KMP) has been carried out 1,2-dimethyl hydrazine-treated rats (DMH). Those SL combinations with KMP and EGCG have enhanced the SL activity producing greater antioxidant, anti-inflammatory, antiproliferating, and apoptotic activities in both combinations than SL alone. The chemopreventive effects of SL with both EGCG and KMP were demonstrated by a decrease in thiobaribituric acid reactive substances level, tissue nitric oxide (NO), serum, and tissue ß-catenin as well as a reduction in the multiplicity of aberrant crypt foci (ACF) with alleviation in the dysplastic changes that resulted from DMH administration. Down-regulation of proliferating cell nuclear antigen (PCNA) and cyclooxygenase-2 (COX-2) were also confirmed by immunohistochemical staining. The current study paves the way for the use of sulindac combination with kaempferol or EGCG as potential chemopreventive agents against colon cancer with more effect in combination with EGCG.


Assuntos
1,2-Dimetilidrazina/toxicidade , Anticarcinógenos/farmacologia , Carcinógenos/toxicidade , Catequina/análogos & derivados , Neoplasias do Colo/prevenção & controle , Quempferóis/farmacologia , Lesões Pré-Cancerosas/prevenção & controle , Sulindaco/farmacologia , Animais , Anticarcinógenos/administração & dosagem , Catequina/administração & dosagem , Catequina/farmacologia , Neoplasias do Colo/induzido quimicamente , Neoplasias do Colo/metabolismo , Ciclo-Oxigenase 2/metabolismo , Regulação para Baixo/efeitos dos fármacos , Quimioterapia Combinada , Quempferóis/administração & dosagem , Masculino , Óxido Nítrico/metabolismo , Lesões Pré-Cancerosas/induzido quimicamente , Lesões Pré-Cancerosas/metabolismo , Antígeno Nuclear de Célula em Proliferação/metabolismo , Ratos Sprague-Dawley , Sulindaco/administração & dosagem , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo , beta Catenina/sangue , beta Catenina/metabolismo
16.
Neoplasma ; 65(3): 376-388, 2018 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-29788733

RESUMO

Glioblastoma tumors (GBM) are very heterogeneous, being comprised of several cell subtypes, including glioblastoma stem cells (GSC). These tumors have a high rate of recurrence after initial treatment and one of the most prevalent theories to explain this is the cancer stem cell theory, which proposes that glioblastomas arise from mutations that transform normal neural stem cells (NSC) into GSC, which are highly resistant to oxidative stress and anti-cancer therapies. Sulindac is a non-steroidal anti-inflammatory drug (NSAID) that has been shown to protect the normal cells against oxidative damage by initiating a preconditioning response, but selectively sensitizes several cancer cell lines to agents that affect mitochondrial respiration, resulting in enhanced killing of the cancer cells. These effects of sulindac are independent of its NSAID activity. There is little information on the effect of sulindac on normal and cancer stem cells. To study the effect of sulindac on both normal and cancer stem cells, we have isolated normal neural stem cells (NSC), from mice hippocampi and glioblastoma stem cells (GSC) from a glioma cell line, U87. As expected from previous studies sulindac can protect normal astrocytes against oxidative stress. Sulindac induces differentiation of both NSC and GSC cells and sulindac upregulates neurogenesis in NSC. The differentiated NSC are also protected from oxidative stress damage, whereas the differentiation of GSC by sulindac increases the sensitivity of these cells to agents that cause oxidative stress. The S epimer of sulindac is more effective than the R epimer in inducing neuronal differentiation in both NSC and GSC. These results indicate that the ability of sulindac to induce GSC differentiation may have therapeutic value in preventing tumour recurrence.


Assuntos
Diferenciação Celular , Glioblastoma/patologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Estresse Oxidativo , Sulindaco/farmacologia , Animais , Linhagem Celular Tumoral , Glioblastoma/tratamento farmacológico , Humanos , Camundongos , Recidiva Local de Neoplasia
17.
Bioorg Med Chem Lett ; 28(12): 2136-2142, 2018 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-29776741

RESUMO

Non-steroidal anti-inflammatory drugs (NSAIDs) have a variety of potential indications that include management of pain and inflammation as well as chemoprevention and/or treatment of cancer. Furthermore, a specific form of ibuprofen, dexibuprofen or the S-(+) form, shows interesting neurological activities and has been proposed for the treatment of Alzheimer's disease. In a continuation of our work probing the anticancer activity of small sulindac libraries, we have prepared and screened a small diversity library of α-methyl substituted sulindac amides in the profen class. Several compounds of this series displayed promising activity compared with a lead sulindac analog.


Assuntos
Amidas/farmacologia , Antineoplásicos/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Sulindaco/farmacologia , Amidas/síntese química , Amidas/química , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-Atividade , Sulindaco/síntese química , Sulindaco/química
18.
Can J Gastroenterol Hepatol ; 2018: 6152928, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29686976

RESUMO

Microsatellite instability (MSI) is caused by DNA mismatch repair deficiency and is an important prognostic and predictive biomarker in colorectal cancer but relatively few studies have exploited mouse models in the study of its clinical utility. Furthermore, most previous studies have looked at MSI in the small intestine rather than the colon of mismatch repair deficient Msh2-knockout (KO) mice. Here we compared Msh2-KO, p53-KO, and wild type (WT) mice that were treated with the carcinogen azoxymethane (AOM) and the nonsteroidal anti-inflammatory drug sulindac or received no treatment. The induced tumors and normal tissue specimens from the colon were analysed with a panel of five mononucleotide repeat markers. MSI was detected throughout the normal colon in untreated Msh2-KO mice and this involved contraction of the repeat sequences compared to WT. The markers with longer mononucleotide repeats (37-59) were the most sensitive for MSI while the markers with shorter repeats (24) showed only minor change. AOM exposure caused further contraction of the Bat37 and Bat59 repeats in the distal colon of Msh2-KO mice which was reversed by sulindac. Thus AOM-induced carcinogenesis is associated with increased instability of mononucleotide repeats in the colon of Msh2-KO mice but not in WT or p53-KO mice. Chemoprevention of these tumors by sulindac treatment reversed or prevented the increased MSI.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Neoplasias do Colo/genética , Instabilidade de Microssatélites , Proteína 2 Homóloga a MutS/genética , Sulindaco/farmacologia , Proteína Supressora de Tumor p53/genética , Animais , Azoximetano , Colo , Neoplasias do Colo/induzido quimicamente , Modelos Animais de Doenças , Camundongos , Camundongos Knockout , Instabilidade de Microssatélites/efeitos dos fármacos , Repetições de Microssatélites/efeitos dos fármacos
19.
Future Med Chem ; 10(7): 743-753, 2018 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-29671617

RESUMO

AIM: Experimental and epidemiological studies and clinical trials suggest that nonsteroidal anti-inflammatory drugs possess antitumor potential. Sulindac, a widely used nonsteroidal anti-inflammatory drug, can prevent adenomatous colorectal polyps and colon cancer, especially in patients with familial adenomatous polyposis. Sulindac sulfide amide (SSA) is an amide-linked sulindac sulfide analog that showed in vivo antitumor activity in a human colon tumor xenograft model. Results/methodology: A new analog series with heterocyclic rings such as oxazole or thiazole at the C-2 position of sulindac was prepared and screened against prostate, colon and breast cancer cell lines to probe the effect of these novel substitutions on the activity of sulindac analogs. CONCLUSION: In general, replacement of the amide function of SSA analogs had a negative impact on the cell lines tested. A small number of hits incorporating rigid oxazole or thiazole groups in the sulindac scaffold in place of the amide linkage show comparable activity to our lead agent SSA.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias/prevenção & controle , Oxazóis/química , Sulindaco/análogos & derivados , Sulindaco/uso terapêutico , Tiazóis/química , Anti-Inflamatórios não Esteroides/química , Antineoplásicos/química , Linhagem Celular Tumoral , Cromatografia Líquida de Alta Pressão , Cromatografia em Camada Delgada , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Xenoenxertos , Humanos , Masculino , Espectroscopia de Prótons por Ressonância Magnética , Espectrometria de Massas por Ionização por Electrospray , Sulindaco/química
20.
Transl Res ; 198: 58-72, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29702077

RESUMO

Dry eye disease (DED) currently has no satisfactory treatment partly because of the lack of informative animal models. We evaluated the anti-inflammatory phosphosulindac (PS) for the treatment of DED using a new rabbit model of DED based on the concanavalin A (Con A) acute DED model: we injected all lacrimal glands with Con A weekly under ultrasound guidance, which prolonged DED to >3 weeks, and thoroughly assessed efficacy with tear break-up time (TBUT), tear osmolarity, Schirmer test, and tear lactoferrin levels. Rabbits with DED (n = 8-10 eyes per group) were treated topically with PS or vehicle 3×/day for 21days. PS restored TBUT, tear osmolarity, and lactoferrin levels (P < 0.0001-0.04) to normal but did not significantly improve the results of the Schirmer test. PS showed no side effects and was much more efficacious than cyclosporine or lifitegrast. In the cornea, PS suppressed the activation of nuclear factor kappa-B, the levels of transforming growth factor beta, interleukin-1 beta, interleukin-6, and interleukin-8, and the levels of matrix metalloproteinase (MMP)-1 and MMP-9, and MMP activity. Levels of prostaglandin E2 (PGE2) in tears and cornea were preserved in PS-treated rabbits. Ketorolac and diclofenac, two ophthalmic NSAIDs causing corneal melt, nearly completely suppressed PGE2 levels but had no effect on MMPs. The effects of PS on PGE2 and MMPs likely account for its apparent ocular safety. Our results establish an animal model for acute and chronic DED suitable for drug efficacy studies and indicate that PS merits evaluation for DED.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Concanavalina A/toxicidade , Modelos Animais de Doenças , Síndromes do Olho Seco/tratamento farmacológico , Compostos Organofosforados/uso terapêutico , Coelhos , Sulindaco/análogos & derivados , Administração Oftálmica , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Células Cultivadas , Doença Crônica , Citocinas/metabolismo , Dinoprostona/metabolismo , Humanos , Lactoferrina/metabolismo , Metaloproteinase 1 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Compostos Organofosforados/administração & dosagem , Concentração Osmolar , Sulindaco/administração & dosagem , Sulindaco/uso terapêutico , Lágrimas/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA