Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 931
Filtrar
1.
PLoS One ; 15(7): e0235743, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32645052

RESUMO

Granulomatosis with polyangiitis (GPA) is an autoimmune disease affecting mainly small blood vessels. B-cells are important in the GPA pathogenesis as precursors of autoantibody-producing cells but likely also contribute (auto)antibody-independently. This has been underlined by the effectiveness of B-cell-depletion (with Rituximab) in inducing and maintaining disease remission. Mycophenolate-mofetil (MMF) and azathioprine (AZA) are immunosuppressive therapies frequently used in GPA-patients. Interestingly, MMF-treated GPA-patients are more prone to relapses than AZA-treated patients, while little is known about the influence of these drugs on B-cells. We investigated whether MMF or AZA treatment (or their active compounds) alters the circulating B-cell subset distribution and has differential effects on in vitro B-cell proliferation and cytokine production in GPA-patients that might underlie the different relapse rate. Circulating B-cell subset frequencies were determined in samples from AZA-treated (n = 13), MMF-treated (n = 12), untreated GPA-patients (n = 19) and matched HCs (n = 41). To determine the ex vivo effects of the active compounds of MMF and AZA, MPA and 6-MP respectively, on B-cell proliferation and cytokine production, PBMCs of untreated GPA-patients (n = 29) and matched HCs (n = 30) were cultured for 3-days in the presence of CpG-oligodeoxynucleotides (CpG) with MPA or 6-MP. After restimulation (with phorbol myristate acetate, calcium-ionophore), cytokine-positive B-cell frequencies were measured. Finally, to assess the effect of MMF or AZA treatment on in vitro B-cell proliferation and cytokine production, PBMCs of MMF-treated (n = 18), and AZA-treated patients (n = 28) and HCs (n = 41) were cultured with CpG. The memory B-cell frequency was increased in AZA- compared to MMF-treated patients, while no other subset was different. The active compounds of MMF and AZA showed in vitro that MPA decreased B-cell proliferation in GPA-patients and HCs. B-cell proliferation in MMF- and AZA-treated patients was not different. Finally, the IL-6+ B-cell frequency was decreased by MPA compared to 6-MP. No differences in IL-10+, IL-6+ or TNFα+ B-cell proportions or proliferation were found in MMF- and AZA-treated patients. Our results indicate that MMF could be superior to AZA in inhibiting B-cell cytokine production in GPA-patients. Future studies should assess the effects of these immunosuppressive drugs on other immune cells to elucidate mechanisms underlying the potential differences in relapse rates.


Assuntos
Linfócitos B/imunologia , Granulomatose com Poliangiite , Imunossupressores/farmacologia , Ácido Micofenólico/farmacologia , Adulto , Idoso , Azatioprina/farmacologia , Subpopulações de Linfócitos B/imunologia , Linfócitos B/efeitos dos fármacos , Linfócitos B/metabolismo , Proliferação de Células/efeitos dos fármacos , Citocinas/metabolismo , Feminino , Citometria de Fluxo , Granulomatose com Poliangiite/tratamento farmacológico , Granulomatose com Poliangiite/imunologia , Humanos , Interleucina-6/metabolismo , Masculino , Mercaptopurina/farmacologia , Pessoa de Meia-Idade
2.
Indian J Gastroenterol ; 39(2): 153-160, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32468382

RESUMO

BACKGROUND: The development of anti-drug antibodies (ADA) to tumor necrosis factor (TNF-α) inhibitors is a significant result contributing to the loss of clinical response in inflammatory bowel disease (IBD). AIMS: We performed a systematic review and meta-analysis to assess whether the addition of immunomodulators to TNF-α inhibitors lead to reversal of antibody formation in TNF-α inhibitor-treated IBD patients. METHODS: We conducted a comprehensive search of electronic databases from inception through October 2018 in order to identify specific studies describing clinical response in IBD patients following the addition of immunomodulators (methotrexate or thiopurines) to TNF-α inhibitors. Clinical response was expressed as an improvement of symptoms, with a noted decrease or complete elimination of ADA against TNF-α inhibitors. The meta-analysis was performed using the DerSimonian and Laird random-effect model. RESULTS: Four studies were included in our final meta-analysis, which reported outcomes in 72 patients receiving TNF-α inhibitors. Forty-nine of the seventy-two (68%) patients received either methotrexate (19) or thiopurines (30). The average follow up period was 13.5 months. The overall pooled clinical response was 73.86% (95% confidence interval [CI] = 47.36-94.38, I2 = 60.77%). CONCLUSION: In our meta-analysis, addition of immunomodulators to TNF-α inhibitors was shown to restore the clinical response in 74% of the patients by either decreasing or completely eliminating anti-drug antibody levels. Further long-term multicenter studies are needed to validate these findings.


Assuntos
Anticorpos/sangue , Formação de Anticorpos/efeitos dos fármacos , Fatores Imunológicos/administração & dosagem , Fatores Imunológicos/farmacologia , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/imunologia , Mercaptopurina/análogos & derivados , Metotrexato/administração & dosagem , Metotrexato/farmacologia , Inibidores do Fator de Necrose Tumoral/imunologia , Inibidores do Fator de Necrose Tumoral/uso terapêutico , Mercaptopurina/administração & dosagem , Mercaptopurina/farmacologia , Resultado do Tratamento , Inibidores do Fator de Necrose Tumoral/efeitos adversos , Fator de Necrose Tumoral alfa
3.
PLoS One ; 15(4): e0231651, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32294118

RESUMO

INTRODUCTION: The nudix hydrolase 15 (NUDT15) gene acts in the metabolism of thiopurine, by catabolizing its active metabolite thioguanosine triphosphate into its inactivated form, thioguanosine monophosphate. The frequency of alternative NUDT15 alleles, in particular those that cause a drastic loss of gene function, varies widely among geographically distinct populations. In the general population of northern Brazilian, high toxicity rates (65%) have been recorded in patients treated with the standard protocol for acute lymphoblastic leukemia, which involves thiopurine-based drugs. The present study characterized the molecular profile of the coding region of the NUDT15 gene in two groups, non-admixed Amerindians and admixed individuals from the Amazon region of northern Brazil. METHODS: The entire NUDT15 gene was sequenced in 64 Amerindians from 12 Amazonian groups and 82 admixed individuals from northern Brazil. The DNA was extracted using phenol-chloroform. The exome libraries were prepared using the Nextera Rapid Capture Exome (Illumina) and SureSelect Human All Exon V6 (Agilent) kits. The allelic variants were annotated in the ViVa® (Viewer of Variants) software. RESULTS: Four NUDT15 variants were identified: rs374594155, rs1272632214, rs147390019, andrs116855232. The variants rs1272632214 and rs116855232 were in complete linkage disequilibrium, and were assigned to the NUDT15*2 genotype. These variants had high frequencies in both our study populations in comparison with other populations catalogued in the 1000 Genomes database. We also identified the NUDT15*4 haplotype in our study populations, at frequencies similar to those reported in other populations from around the world. CONCLUSION: Our findings indicate that Amerindian and admixed populations from northern Brazil have high frequencies of the NUDT15 haplotypes that alter the metabolism profile of thiopurines.


Assuntos
Povos Indígenas/genética , Pirofosfatases/genética , Antimetabólitos Antineoplásicos/farmacologia , Antimetabólitos Antineoplásicos/uso terapêutico , Brasil , Humanos , Mercaptopurina/farmacologia , Mercaptopurina/uso terapêutico , Polimorfismo de Nucleotídeo Único , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Pirofosfatases/metabolismo
4.
Mater Sci Eng C Mater Biol Appl ; 108: 110461, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31924029

RESUMO

A novel bio-responsive co-delivery system based on Poly(DEA)-b-Poly(ABMA-co-OEGMA) (PDPAO, prepared by reversible addition-fragmentation chain transfer (RAFT) polymerization) copolymers was constructed for enhanced cellular internalization and effective combination therapy. Reduction-sensitive 6-mercaptopurine (6MP) based prodrug and pH-sensitive doxorubicin (DOX) based prodrug were grafted onto PDPAO by an azide-alkyne "Click Chemistry" reaction to acquire a pH/reduction-sensitive polymeric prodrug (PDPAO@imine-DOX/cis-6MP), which was able to self-aggregate to form polymeric micelles (M(DOX/6MP)) with an average particle size of 116 ± 2 nm in the water. The resultant micelles could maintain a stable sphere structure and show stability with a small particles' dispersion index in the blood. Importantly, it has been observed that the pH-sensitive surface charge-conversion accompanied pH-triggered DOX release in the biomimetic extracellular acidic environment of tumor tissue and a rapid dual-drug release triggered by pH and GSH in the intracellular environment. The in vitro evaluation of micelles on human cervical cancer (HeLa) and human promyelocytic leukemia (HL-60) cells showed an enhanced cellular uptake because of charge-conversion and exhibited a higher cell-killing performance. Moreover, the graft ratio of DOX and 6MP showed the ability to adjust the cytotoxicity; the micelles with a graft ratio of 2: 1 (M(DOX2/6MP)) displayed the higher cellular inhibition on either HeLa (combination index (CI) = 0.62) or HL-60 (CI = 0.35) cells. Overall, this novel dual-drug-conjugated delivery system might have important potential applications for combination therapy of cancer.


Assuntos
Química Click , Doxorrubicina , Portadores de Fármacos , Mercaptopurina , Neoplasias/tratamento farmacológico , Pró-Fármacos , Preparações de Ação Retardada/síntese química , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacologia , Doxorrubicina/química , Doxorrubicina/farmacologia , Portadores de Fármacos/síntese química , Portadores de Fármacos/química , Portadores de Fármacos/farmacologia , Células HL-60 , Células HeLa , Humanos , Mercaptopurina/química , Mercaptopurina/farmacologia , Neoplasias/metabolismo , Neoplasias/patologia , Pró-Fármacos/síntese química , Pró-Fármacos/química , Pró-Fármacos/farmacologia
5.
Leukemia ; 34(3): 882-894, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31645647

RESUMO

Thiopurines are widely used as antileukemia agents and immunosuppressants. Recent large-scale clinical studies revealed a strong association between the NUDT15 p.Arg139Cys (NUDT15R139C) polymorphism and severe thiopurine-induced leukocytopenia. We established knock-in mice harboring p.Arg138Cys (Nudt15R138C), which corresponds to the human polymorphism. A clinically relevant dose of mercaptopurine (MP) induced lethal cytopenia in Nudt15R138C-harboring mice. MP dose reduction attenuated the hematopoietic toxicity, phenocopying clinical observations and providing Nudt15 genotype-based tolerable doses of MP. High-dose MP induced acute damage to hematopoietic stem and progenitor cells (HSPCs) in Nudt15R138C/R138C mice. A competitive transplantation assay revealed that not only Nudt15R138C/R138C HSPCs, but also Nudt15+/R138C HSPCs suffered stronger damage than Nudt15+/+ HSPCs, even by lower-dose MP, after long-term administration. In a Nudt15 genotype-based posttransplantation leukemia recurrence model generated by bone marrow replacement with congenic wild-type cells and a small number of leukemia stem cells, MP prolonged the survival of mice with posttransplantation Nudt15R138C/R138C leukemia recurrence. In conclusion, our model will facilitate NUDT15 genotype-based precision medicine by providing safer estimates for MP dosing, and our findings highlighted the high susceptibility of hematopoietic stem cells to MP and suggested that exploiting thiopurine toxicity might be a novel treatment approach for leukemia in NUDT15R139C-harboring patients.


Assuntos
Células-Tronco Hematopoéticas/efeitos dos fármacos , Leucemia/tratamento farmacológico , Mercaptopurina/farmacologia , Pirofosfatases/genética , Animais , Reparo do DNA , Feminino , Citometria de Fluxo , Técnicas de Introdução de Genes , Genótipo , Células-Tronco Hematopoéticas/citologia , Humanos , Leucemia/genética , Leucopenia/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Polimorfismo Genético
6.
Biochem Pharmacol ; 172: 113770, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31862449

RESUMO

The antimetabolite 6-mercaptopurine (6-MP) is an important component in the treatment of specific cancer subtypes, however, the development of drug resistance and dose-limiting toxicities can limit its effectiveness. The therapeutic activity of 6-MP requires cellular uptake, enzymatic conversion to thio-GMP and incorporation of thio-GTP into RNA and DNA, as well as inhibition of de novo purine synthesis by methyl-thio-IMP. Mechanisms that prevent 6-MP entry into the cell, prevent 6-MP metabolism or deplete thiopurine intermediates, can all lead to 6-MP resistance. We previously conducted a high-throughput screen for inhibitors of the multidrug transporter MRP4 using 6-MP sensitivity as the readout. In addition to MRP4-specific inhibitors, we identified a compound, CCI52, that sensitized cell lines to 6-MP independent of this transporter. CCI52 and its more stable analogue CCI52-14 also function as effective chemosensitizers in vivo, substantially extending survival in a transgenic mouse cancer model treated with 6-MP. Chemosensitization was associated with an increase in thio-IMP, suggesting that CCI52 functions directly on 6-MP uptake or metabolism. In addition to its chemosensitizing effects, CCI52 and CCI52-14 inhibited the growth of MYCN-amplified high-risk neuroblastoma cell lines and delayed tumor progression in a MYCN-driven, transgenic mouse model of neuroblastoma. These multifunctional inhibitors may be useful for the further development of anticancer agents and as tools to better understand 6-MP metabolism.


Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Mercaptopurina/administração & dosagem , Mercaptopurina/farmacologia , Neuroblastoma/tratamento farmacológico , Tiazóis/farmacologia , Animais , Antimetabólitos Antineoplásicos/administração & dosagem , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Camundongos Transgênicos , Estrutura Molecular , Proteína Proto-Oncogênica N-Myc/genética , Proteína Proto-Oncogênica N-Myc/metabolismo , Neoplasias Experimentais/tratamento farmacológico , Neuroblastoma/patologia , Tiazóis/efeitos adversos , Tiazóis/química
7.
PLoS One ; 14(11): e0225122, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31714926

RESUMO

BACKGROUND: Several antineoplastic drugs have been proposed as new compounds for pulmonary arterial hypertension treatment but many have cardiotoxic side effects. The chemotherapeutic agent 6-mercaptopurine may have an effect in treatment of pulmonary arterial hypertension but at the same time, its effects on the afterload adaption of the right ventricle is unpredictable due to interaction with multiple downstream signalling pathways in the cardiomyocytes. We investigated the direct cardiac effects of 6-mercaptopurine in rats with isolated right heart failure caused by pulmonary trunk banding (PTB). METHODS: Male Wistar rat weanlings (112±2 g) were randomized to sham operation (sham, n = 10) or PTB. The PTB animals were randomized to placebo (PTB-control, n = 10) and 6-mercaptopurine (7.5 mg/kg/day) groups with treatment start before the PTB procedure (PTB-prevention, n = 10) or two weeks after (PTB-reversal, n = 10). Right ventricular effects were evaluated by echocardiography, cardiac MRI, invasive pressure-volume measurements, and histological and molecular analyses. RESULTS: PTB increased right ventricular afterload and caused right ventricular hypertrophy and failure. 6-mercaptopurine did not improve right ventricular function nor reduce right ventricular remodelling in both prevention and reversal studies compared with placebo-treated rats. CONCLUSION: Treatment with 6-mercaptopurine did not have any beneficial or detrimental effects on right ventricular function or remodelling. Our data suggest that treatment of pulmonary arterial hypertension with 6-mercaptopurine is not harmful to the failing right ventricle.


Assuntos
Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/fisiopatologia , Hipertensão Pulmonar/complicações , Mercaptopurina/farmacologia , Animais , Apoptose/efeitos dos fármacos , Pressão Sanguínea , Modelos Animais de Doenças , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/patologia , Ventrículos do Coração , Hemodinâmica , Masculino , Ratos Wistar , Função Ventricular Direita , Remodelação Ventricular
8.
Inorg Chem ; 58(23): 16154-16170, 2019 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-31721562

RESUMO

In this study, two new bis-cyclometalated Pt(II) complexes, [Pt(C^N)(S^N)] [S^N = deprotonated 6-mercaptopurine (6-MP) and C^N = deprotonated 2-phenylpyridine (ppy), 2a; C^N = deprotonated benzo[h]quinoline (bhq), 2b], are synthesized by the reaction of [PtR(SMe2)(C^N)] (R = Me or p-MeC6H4) with 1 equiv of 6-mercaptopurine (6-HMP) at room temperature. The complexes are fully characterized using 1H and 13C NMR spectroscopies, electrospray ionization mass spectrometry, and elemental analysis. Biomolecular interaction of complex 2a with human serum albumin (HSA) is studied by fluorescence, UV-vis, and circular dichroism (CD) spectroscopies. The binding constants (Kb) and number of binding sites (n) are evaluated using the Stern-Volmer equation. The intrinsic fluorescence of protein is quenched by a static quenching mechanism, with a binding constant of Kb ∼ 105 reflecting a high affinity of complex 2a for HSA. The thermodynamic parameters (ΔH°, ΔG°, and ΔS°) indicate that the interaction is a spontaneous process and hydrophobic forces play a main role in the reaction. The displacement experiments demonstrate that the reactive binding sites of HSA to complex 2a are mainly located within its hydrophobic cavity in subdomain IIA (site I). Synchronous fluorescence spectra reveal that complex 2a affected the microenvironment of tryptophan-214 residues in subdomain IIA of HSA. In the case of interaction of complex 2b and HSA, because of overlapping of the emission spectra of complex 2b with HSA, chemometric approaches are applied. The results indicate significant interaction between the tryptophan residue of HSA and complex 2b. Moreover, the binding of Pt(II) complexes 2a and 2b causes a reduction of the α-helix content of HSA, as obtained by far-UV CD spectroscopy. The average binding distance (r) between Pt(II) complexes and HSA is obtained by Förster's resonance energy-transfer theory. Also, a molecular docking simulation reveals that π-π-stacking and hydrophobic interactions between these complexes and HSA are significant. Furthermore, the interactions of platinum complexes, 2, with calf-thymus DNA (CT-DNA) are investigated. The UV-vis results and ethidium bromide competitive studies support an intercalative interaction of both Pt(II) complexes with DNA. The new complexes 2 are also screened for anticancer activities. The results show that complexes 2 exhibit significant anticancer activity against the K562 (chronic myelogenous leukemia) cell line.


Assuntos
Antineoplásicos/farmacologia , DNA/efeitos dos fármacos , Mercaptopurina/farmacologia , Compostos Organoplatínicos/farmacologia , Albumina Sérica Humana/efeitos dos fármacos , Antineoplásicos/síntese química , Antineoplásicos/química , Sítios de Ligação/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , DNA/química , Teoria da Densidade Funcional , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Células K562 , Mercaptopurina/química , Simulação de Acoplamento Molecular , Estrutura Molecular , Compostos Organoplatínicos/síntese química , Compostos Organoplatínicos/química , Albumina Sérica Humana/química , Relação Estrutura-Atividade , Termodinâmica
9.
Cells ; 8(10)2019 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-31658693

RESUMO

Acute myeloid leukemia (AML) is an aggressive malignancy, and many elderly/unfit patients cannot receive intensive and potentially curative therapy. These patients receive low-toxicity disease-stabilizing treatment. The combination of all-trans retinoic acid (ATRA) and the histone deacetylase inhibitor valproic acid can stabilize the disease for a subset of such patients. We performed untargeted serum metabolomic profiling for 44 AML patients receiving treatment based on ATRA and valproic acid combined with low-dose cytotoxic drugs (cytarabine, hydroxyurea, 6-mercaptopurin) which identified 886 metabolites. When comparing pretreatment samples from responders and non-responders, metabolites mainly belonging to amino acid and lipid (i.e., fatty acid) pathways were altered. Furthermore, patients with rapidly progressive disease showed an extensively altered lipid metabolism. Both ATRA and valproic acid monotherapy also altered the amino acid and lipid metabolite profiles; however, these changes were only highly significant for valproic acid treatment. Twenty-three metabolites were significantly altered by seven-day valproic acid treatment (p < 0.05, q < 0.05), where the majority of altered metabolites belonged to lipid (especially fatty acid metabolism) and amino acid pathways, including several carnitines. These metabolomic effects, and especially the effects on lipid metabolism, may be important for the antileukemic and epigenetic effects of this treatment.


Assuntos
Tratamento Farmacológico/métodos , Leucemia Mieloide Aguda/tratamento farmacológico , Metabolômica/métodos , Tretinoína/administração & dosagem , Ácido Valproico/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Aminoácidos/metabolismo , Citarabina/administração & dosagem , Citarabina/farmacologia , Feminino , Humanos , Hidroxiureia/administração & dosagem , Hidroxiureia/farmacologia , Leucemia Mieloide Aguda/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Mercaptopurina/administração & dosagem , Mercaptopurina/farmacologia , Pessoa de Meia-Idade , Resultado do Tratamento , Tretinoína/farmacologia , Ácido Valproico/farmacologia
10.
Mater Sci Eng C Mater Biol Appl ; 105: 110010, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31546426

RESUMO

The absorption and release of 6-mercaptopurine anticancer drug was investigated in biodegradable and biocompatible polymer of polylactic acid (PLA) using molecular dynamics simulation. For this purpose, the amount of mixing energy, radius of gyration, mean squared displacement and radial distribution function were computed and compared in concentrations of 5-36 wt% of 6-mercaptopurine drug. The simulation results show that increasing the concentration of the drug reduces mixing energy and PLA polymer carrier is able to carry 35.8 wt% of 6-mercaptopurine anticancer drug. Based on these results, the amount of 6-mercaptopurine release from PLA carrier 35.8 wt% of it in water environment is zero due to hydrophobic property of PLA and 6-mercaptopurine. Finally, polyethylene glycol (PEG) polymer with different percentages (10-30 wt%) was used to modify PLA carrier. The simulation results show that the rate of drug release increases by increasing the concentration of PEG polymer in the modified PLA carrier and also with increasing the percentage of drug loaded in the carrier and also the optimum weight percentage of PEG in modified PLA carrier for 35.8 wt% of drug concentration is 11 wt% and the rate of drug release is slower and equal to 4.4 molecules/ns.


Assuntos
Antineoplásicos/farmacologia , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Mercaptopurina/farmacologia , Simulação de Dinâmica Molecular , Poliésteres/química , Adsorção , Polietilenoglicóis/química , Polimerização , Solubilidade
11.
J Mol Model ; 25(10): 304, 2019 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-31493060

RESUMO

In this work, the effect of the external electric field (EF) on the drug delivery performance of peptide-based metal-organic framework (MPF) for 6-mercaptopurine (6-MP) drug is investigated by means of the molecular dynamics (MD) simulations. It is found that the strength interaction of drug molecule with MPF is decreased under the influence of the electric field. In other words, the adsorbed drug molecules have more tendencies for the interaction with the porous nanostructure in the absence of EF. According to the radial distribution function (RDF) patterns, the probability of finding drug molecules in terms of the intermolecular distance with respect to the MPF surface is lowest during the high field strength. As the EF strength increases, the spread of drug molecules around MPF results in high dynamics movement and further more diffusion coefficient of drug molecule in the simulation system. This result emphasizes the weak intermolecular interaction of drug molecules with MPF with the application of EF. Assessment of dynamical properties of 6-mercaptopurine in the presence of EF with various strengths reveals that the applied electric field can act as a trigger on liberation behavior of drug from the porous nanostructure.


Assuntos
Eletricidade , Mercaptopurina/farmacologia , Estruturas Metalorgânicas/farmacologia , Simulação de Dinâmica Molecular , Peptídeos/farmacologia , Fatores de Tempo
12.
Int J Mol Sci ; 20(17)2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31438649

RESUMO

The transforming growth factor-beta (TGF-ß) plays an important role in pathological fibrosis and cancer transformation. Therefore, the inhibition of the TGF-ß signaling pathway has therapeutic potential in the treatment of cancer. In this study, the binding modes between 47 molecules with a pyrrolotriazine-like backbone structure and transforming growth factor-beta type 1 receptor (TßR1) were simulated by molecular docking using Discovery Studio software, and their structure-activity relationships were analyzed. On the basis of the analysis of the binding modes of ligands in the active site and the structure-activity relationships, 29,254 new compounds were designed for virtual screening. According to the aforementioned analyses and Lipinski's rule of five, five new compounds (CQMU1901-1905) with potential activity were screened through molecular docking. Among them, CQMU1905 is an attractive molecule composed of 5-fluorouracil (5-FU), 6-mercaptopurine (6-MP), and 5-azacytosine. Interestingly, 5-FU, 6-MP, and 5-azacytidine are often used as anti-metabolic agents in cancer treatment. Compared with existing compounds, CQMU1901-1905 can interact with target proteins more effectively and have good potential for modification, making them worthy of further study.


Assuntos
Receptor do Fator de Crescimento Transformador beta Tipo I/antagonistas & inibidores , Citosina/análogos & derivados , Citosina/química , Citosina/farmacologia , Fluoruracila/química , Fluoruracila/farmacologia , Humanos , Mercaptopurina/química , Mercaptopurina/farmacologia , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade
13.
Mol Cancer Ther ; 18(10): 1887-1895, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31358663

RESUMO

Relapse remains a formidable challenge for acute lymphoblastic leukemia (ALL). Recently, recurrent mutations in NT5C2 were identified as a common genomic lesion unique in relapsed ALL and were linked to acquired thiopurine resistance. However, molecular mechanisms by which NT5C2 regulates thiopurine cytotoxicity were incompletely understood. To this end, we sought to comprehensively characterize the biochemical and cellular effects of NT5C2 mutations. Compared with wild-type NT5C2, mutant proteins showed elevated 5'-nucleotidase activity with a stark preference of thiopurine metabolites over endogenous purine nucleotides, suggesting neomorphic effects specific to thiopurine metabolism. Expression of mutant NT5C2 mutations also significantly reduced thiopurine uptake in vitro with concomitant increase in efflux of 6-mercaptopurine (MP) metabolites, plausibly via indirect effects on drug transporter pathways. Finally, intracellular metabolomic profiling revealed significant shifts in nucleotide homeostasis induced by mutant NT5C2 at baseline; MP treatment also resulted in global changes in metabolomic profiles with completely divergent effects in cells with mutant versus wild-type NT5C2. Collectively, our data indicated that NT5C2 mutations alter thiopurine metabolism and cellular disposition, but also influence endogenous nucleotide homeostasis and thiopurine-induced metabolomic response. These complex mechanisms contributed to NT5C2-mediated drug resistance in ALL and pointed to potential opportunities for therapeutic targeting in relapsed ALL.


Assuntos
5'-Nucleotidase/metabolismo , Resistencia a Medicamentos Antineoplásicos , Mercaptopurina/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/enzimologia , Linhagem Celular Tumoral , Células HEK293 , Humanos , Cinética , Mercaptopurina/química , Mercaptopurina/farmacologia , Metabolômica , Modelos Biológicos , Mutação/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia
14.
Eur Respir J ; 54(3)2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31273046

RESUMO

Pulmonary arterial hypertension (PAH) is a progressive fatal disease characterised by abnormal remodelling of pulmonary vessels, leading to increased vascular resistance and right ventricle failure. This abnormal vascular remodelling is associated with endothelial cell dysfunction, increased proliferation of smooth muscle cells, inflammation and impaired bone morphogenetic protein (BMP) signalling. Orphan nuclear receptor Nur77 is a key regulator of proliferation and inflammation in vascular cells, but its role in impaired BMP signalling and vascular remodelling in PAH is unknown.We hypothesised that activation of Nur77 by 6-mercaptopurine (6-MP) would improve PAH by inhibiting endothelial cell dysfunction and vascular remodelling.Nur77 expression is decreased in cultured pulmonary microvascular endothelial cells (MVECs) and lungs of PAH patients. Nur77 significantly increased BMP signalling and strongly decreased proliferation and inflammation in MVECs. In addition, conditioned medium from PAH MVECs overexpressing Nur77 inhibited the growth of healthy smooth muscle cells. Pharmacological activation of Nur77 by 6-MP markedly restored MVEC function by normalising proliferation, inflammation and BMP signalling. Finally, 6-MP prevented and reversed abnormal vascular remodelling and right ventricle hypertrophy in the Sugen/hypoxia rat model of severe angioproliferative PAH.Our data demonstrate that Nur77 is a critical modulator in PAH by inhibiting vascular remodelling and increasing BMP signalling, and activation of Nur77 could be a promising option for the treatment of PAH.


Assuntos
Proteínas Morfogenéticas Ósseas/metabolismo , Hipertensão Pulmonar/tratamento farmacológico , Mercaptopurina/farmacologia , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/agonistas , Animais , Proliferação de Células , Meios de Cultivo Condicionados , Modelos Animais de Doenças , Progressão da Doença , Células Endoteliais/efeitos dos fármacos , Células HEK293 , Humanos , Inflamação , Pulmão/efeitos dos fármacos , Masculino , Microcirculação , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Remodelação Vascular
15.
Int Forum Allergy Rhinol ; 9(6): 648-655, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30748107

RESUMO

BACKGROUND: Oral steroids are recommended for the treatment of nasal polyps (NPs), but prolonged use is avoided because of side effects. Topical steroids can also control NPs without significant complications; however, the response to this is partially successful, and additional therapies are needed to treat glucocorticoid-resistant NPs. Azathioprine (AZA) and its first metabolite 6-mercaptopurine (6-MP) are important immunosuppressants used for the therapy of various diseases. The aim of this study was to investigate the effects of AZA and 6-MP on inflammatory cytokines in organ-cultured NPs. METHODS: NP explants were cultured using an air-liquid interface method. Cultures were maintained in the absence and presence of steroid, AZA, and 6-MP for 72 hours. Elaboration of cytokines tumor necrosis factor alpha (TNF-α), interleukin (IL)-2, IL-4, IL-5, and IL-13 into the supernatant was quantitated using the enzyme-linked immunosorbent assay (ELISA). The messenger RNA (mRNA) expression levels of TNF-α, IL-2, IL-4, IL-5, and IL-13 in cultured mucosa were measured using real-time polymerase chain reaction. Hematoxylin and eosin staining of cultured mucosa was performed to observe inflammatory cells. Immunohistochemistry was done to evaluate the distribution pattern of inflammatory cytokines in NP explants. RESULTS: On histologic examination, less inflammatory cell infiltration was found in NPs treated by steroid, AZA, and 6-MP than in control, but there was no statistical significance (p = 0.218). On immunohistochemistry, IL-13 showed a steady falling tendency in submucosal glands by steroid, AZA, and 6-MP. Expression of TNF-α, IL-2, IL-4, IL-5, and IL-13 mRNA in the NPs treated by steroid, AZA, and 6-MP were significantly lower than those of the control (p < 0.001 for all). By ELISA, IL-2 and IL-13 were significantly lower with topical steroid, AZA, and 6-MP treatment (p = 0.012 and p < 0.001). CONCLUSION: Topical AZT decreases inflammatory cytokines on human NP explants and this could have future therapeutic implications for NPs.


Assuntos
Azatioprina/farmacologia , Citocinas/metabolismo , Imunossupressores/farmacologia , Pólipos Nasais/patologia , Adolescente , Adulto , Citocinas/genética , Feminino , Humanos , Inflamação , Masculino , Mercaptopurina/farmacologia , Pessoa de Meia-Idade , Mucosa Nasal/efeitos dos fármacos , Mucosa Nasal/metabolismo , Mucosa Nasal/patologia , Pólipos Nasais/metabolismo , Técnicas de Cultura de Órgãos , Adulto Jovem
16.
J Leukoc Biol ; 105(3): 463-472, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30476347

RESUMO

Immune modulating treatments are often associated with immune suppression or an opposing anti-inflammatory paradigm. As such, there is a risk of exposing patients to infections and malignancies. Contrarily, eliciting only mild immune modulation can be insufficient for alleviating immune-mediated damage. Oral immunotherapy is a novel approach that uses the inherent ability of the gut immune system to generate signals that specifically suppress inflammation at affected sites, without inducing generalized immune suppression. Oral immunotherapy is being developed as a method to rebalance systemic immunity and restore balance, getting it back on track, rather than pushing the immune response too much or too little in opposing directions. Here, I review recent preclinical and clinical data examining the technique and describe its primary advantages.


Assuntos
Sistema Imunitário/fisiologia , Imunoterapia , Administração Oral , Animais , Humanos , Imunomodulação , Mercaptopurina/administração & dosagem , Mercaptopurina/farmacologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/metabolismo
17.
PLoS One ; 13(10): e0205175, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30321196

RESUMO

Multidrug resistance protein 4 (MRP4/ABCC4) is an ATP-binding cassette (ABC) transporter. It is associated with multidrug resistance (MDR), which is becoming a growing challenge to the treatment of cancer and infections. In the context of several types of cancer in which MRP4 is overexpressed, MRP4 inhibition manifests striking effects against cancer progression and drug resistance. In this study, we combined ligand-based and structure-based drug design strategy, by searching the SPECS chemical library to find compounds that are most likely to bind to MRP4. Clustering analysis based on a two-dimensional fingerprint was performed to help with visual selection of potential compounds. Cell viability assays with potential inhibitors and the anticancer drug 6-MP were carried out to identify their bioactivity. As a result, 39 compounds were tested and seven of them reached inhibition above 55% with 6-MP. Then compound Cpd23 was discovered to improve HEK293/MRP4 cell sensibility to 6-MP dramatically, and low concentration Cpd23 (5 µM) achieved the equivalent effect of 50 µM MK571. The accumulation of 6-MP was determined by validated high-performance liquid chromatography methods, and pretreatment of the HEK293/MRP4 cells with 50 µM MK571 or Cpd23 resulted in significantly increased accumulation of 6-MP by approximately 1.5 times. This compound was first reported with a novel scaffold compared with previously known MRP4 inhibitors, which is a hopeful molecular tool that can be used for overcoming multidrug resistance research.


Assuntos
Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Mercaptopurina/farmacologia , Proteínas Associadas à Resistência a Múltiplos Medicamentos/antagonistas & inibidores , Antineoplásicos/química , Sobrevivência Celular/efeitos dos fármacos , Desenho Assistido por Computador , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Resistencia a Medicamentos Antineoplásicos/fisiologia , Células HEK293 , Humanos , Modelos Moleculares , Estrutura Molecular , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Relação Estrutura-Atividade
18.
Mater Sci Eng C Mater Biol Appl ; 92: 599-611, 2018 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-30184786

RESUMO

The clinical applications of anticancer drugs are restricted due to the incomplete delivery to the cancerous tissue and the numerous drug resistance mechanisms involved in malignant cells. In this regard, stimuli-responsive nanomaterials offer a promising prospect to deal with these concerns. In the present study, ternary responsive hybrid gold/nanogels (Au/NGs) were synthesized as a new nanoplatform to simultaneously carry two anticancer drugs, i.e., doxorubicin (DOX) and 6-mercaptopurine (MP). For this purpose, these drugs were successfully loaded (the loading capacity of 23% and 11%, respectively) into the hybrid Au/NGs by electrostatic interaction (DOX) and AuS bonds (MP). The triggered drug release ability of hybrid Au/NGs was assessed by comparing the environments of simulated physiological and tumor tissue. The incorporation of disulfide bond linkers, pH sensitive, and thermosensitive polymeric segments endowed the NGs with an excellent property in reducing acidic and hyperthermia environments, which greatly facilitates drug release in tumor cells. Intracellular tracking of DOX@MP-Au/NGs confirmed efficient accumulation and cellular uptake of developed NGs and the cytotoxicity studies showed a pronounced tumor inhibition compared with free DOX@MP. It was concluded that the new ternary-responsive NGs have great potential for co-delivery of DOX and MP and can be used in efficient cancer therapy.


Assuntos
Doxorrubicina , Sistemas de Liberação de Medicamentos , Ouro , Mercaptopurina , Nanopartículas/química , Neoplasias/tratamento farmacológico , Polietilenoglicóis , Doxorrubicina/química , Doxorrubicina/farmacologia , Géis , Ouro/química , Ouro/farmacologia , Humanos , Células MCF-7 , Mercaptopurina/química , Mercaptopurina/farmacologia , Neoplasias/metabolismo , Neoplasias/patologia , Polietilenoglicóis/química , Polietilenoglicóis/farmacologia
19.
Cancer Cell ; 34(1): 136-147.e6, 2018 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-29990496

RESUMO

Activating mutations in the cytosolic 5'-nucleotidase II gene NT5C2 drive resistance to 6-mercaptopurine in acute lymphoblastic leukemia. Here we demonstrate that constitutively active NT5C2 mutations K359Q and L375F reconfigure the catalytic center for substrate access and catalysis in the absence of allosteric activator. In contrast, most relapse-associated mutations, which involve the arm segment and residues along the surface of the inter-monomeric cavity, disrupt a built-in switch-off mechanism responsible for turning off NT5C2. In addition, we show that the C-terminal acidic tail lost in the Q523X mutation functions to restrain NT5C2 activation. These results uncover dynamic mechanisms of enzyme regulation targeted by chemotherapy resistance-driving NT5C2 mutations, with important implications for the development of NT5C2 inhibitor therapies.


Assuntos
5'-Nucleotidase/genética , Antimetabólitos Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Mercaptopurina/farmacologia , Mutação , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , 5'-Nucleotidase/química , 5'-Nucleotidase/metabolismo , Regulação Alostérica , Animais , Domínio Catalítico , Regulação Leucêmica da Expressão Gênica , Células HEK293 , Humanos , Células Jurkat , Camundongos Endogâmicos C57BL , Modelos Moleculares , Leucemia-Linfoma Linfoblástico de Células Precursoras/enzimologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Conformação Proteica em alfa-Hélice , Recidiva , Relação Estrutura-Atividade
20.
World J Gastroenterol ; 24(18): 2036-2046, 2018 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-29760546

RESUMO

AIM: To determine the distribution of anthropometric parameter (AP)-z-scores and characterize associations between medications/serum biomarkers and AP-z-scores in pediatric Crohn's disease (CD). METHODS: CD patients [< chronological age (CA) 21 years] were enrolled in a cross-sectional study. Descriptive statistics were generated for participants' demographic characteristics and key variables of interest. Paired t-tests were used to compare AP-z-scores calculated based on CA (CA z-scores) and bone age (BA) (BA z-scores) for interpretation of AP's. Linear regression was utilized to examine associations between medications and serum biomarkers with AP-z-scores calculated based on CA (n = 82) and BA (n = 49). We reported regression coefficients as well as their corresponding p-values and 95% confidence intervals. RESULTS: Mean CA at the time of the study visit was 15.3 ± 3.5 (SD; range = 4.8-20.7) years. Mean triceps skinfold (P = 0.039), subscapular skinfold (P = 0.002) and mid-arm circumference (MAC) (P = 0.001) BA z-scores were higher than corresponding CA z-scores. Medications were positively associated with subscapular skinfold [adalimumab (P = 0.018) and methotrexate (P = 0.027)] and BMI CA z-scores [adalimumab (P = 0.029)]. Azathioprine/6-mercaptopurine were negatively associated with MAC (P = 0.045), subscapular skinfold (P = 0.014), weight (P = 0.002) and BMI (P = 0.013) CA z-scores. ESR, CRP, and WBC count were negatively associated, while albumin and IGF-1 BA z-scores were positively associated, with specific AP z-scores (P < 0.05). Mean height CA z-scores were higher in females, not males, treated with infliximab (P = 0.038). Hemoglobin (P = 0.018) was positively associated, while platelets (P = 0.005), ESR (P = 0.003) and CRP (P = 0.039) were negatively associated with height CA z-scores in males, not females. CONCLUSION: Our results suggest poor efficacy of thiopurines and a possible sex difference in statural growth response to infliximab in pediatric CD. Prospective longitudinal studies are required.


Assuntos
Antropometria , Azatioprina/uso terapêutico , Doença de Crohn/tratamento farmacológico , Imunossupressores/uso terapêutico , Infliximab/uso terapêutico , Mercaptopurina/uso terapêutico , Adolescente , Adulto , Azatioprina/farmacologia , Biomarcadores/sangue , Composição Corporal/efeitos dos fármacos , Desenvolvimento Ósseo , Criança , Pré-Escolar , Doença de Crohn/sangue , Doença de Crohn/complicações , Estudos Transversais , Feminino , Humanos , Imunossupressores/farmacologia , Infliximab/farmacologia , Masculino , Mercaptopurina/farmacologia , Estado Nutricional/efeitos dos fármacos , Estudos Prospectivos , Fatores Sexuais , Resultado do Tratamento , Adulto Jovem
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA