Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.868
Filtrar
1.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(11): 1073-1076, 2019 Nov 10.
Artigo em Chinês | MEDLINE | ID: mdl-31703128

RESUMO

OBJECTIVE: To assess the association of single nucleotide polymorphisms of multidrug resistance gene 1 (MDR1) with refractory epilepsy in children. METHODS: Peripheral blood samples were collected from 200 children with epilepsy and 100 healthy controls. Genomic DNA was extracted and subjected to PCR amplification, agarose gel electrophoresis and target site sequencing. Genotypes of rs1922242, rs2235048, rs10808072, rs868755 and rs1202184 loci of the MDR1 gene were analyzed. RESULTS: No significant difference was found in genotypic distribution and allelic frequencies of the rs1922242, rs2235048, rs10808072 and rs868755 loci between the drug-resistant and drug-sensitive groups. For the rs1202184 locus, a significant difference in genotypic distribution was found (P=0.008). No significant difference was found in the frequencies of various haplotypes between the two groups. CONCLUSION: Genotypes of the rs1202184 locus of the MDR1 gene are associated with refractory epilepsy in children, for which the AA genotype plays a dominant role.


Assuntos
Epilepsia Resistente a Medicamentos/genética , Polimorfismo de Nucleotídeo Único , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Estudos de Casos e Controles , Criança , Frequência do Gene , Genótipo , Haplótipos , Humanos
2.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao ; 41(5): 595-600, 2019 Oct 30.
Artigo em Chinês | MEDLINE | ID: mdl-31699188

RESUMO

Objective To explore the role of multidrug resistance gene-1(MDR1)gene in methotrexate(MTX)resistance in patients with rheumatoid arthritis(RA).Methods Fibroblast-like synoviocytes(FLS)from RA patients were infected with recombinant adenovirus Ad-EGFP-MDR1 in vitro to obtain MDR1 over-expressed RA FLS.The transcription level of MDR1 gene and the expression level of its coding product P-glycoprotein(P-gp) rotein were detected by real-time PCR and Western blot analysis.The efflux function was verified by rhodamine 123 efflux assay.The resistance to MTX was detected by MTT assay.Results RA FLS were infected with recombinant adenovirus Ad-EGFP-MDR1;72 hours later,the particles size in MDR1 over-expressed RA FLS increased,the cell volume became larger,and the growth rate decreased.The transcription level of MDR1(1.4325±0.3924 vs.0.0650±0.0070;t=6.035,P=0.004),the expression level of P-gp protein(1.8667±0.2857 vs. 0.9367±0.0551;t=5.536,P=0.005),and the ability of extracellular rhodamine 123(979.43±196.81 vs.1680.06±147.04;t=-4.940,P=0.008) in MDR1 over-expressed RA FLS were significantly higher than those of negative virus control RA-FLS,and the survival rate of MDR1 over-expressed RA FLS was significantly increased at each concentration of MTX(P<0.05).Conclusion The high expression of MDR1 can affect the efflux ability to MTX by up-regulating the expression of P-gp,thus enhancing the drug resistance to MTX in RA FLS.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Resistência a Medicamentos , Fibroblastos/efeitos dos fármacos , Metotrexato/farmacologia , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Artrite Reumatoide/genética , Células Cultivadas , Humanos , Membrana Sinovial/citologia
3.
Vet Parasitol ; 273: 24-31, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31442889

RESUMO

Haemonchus contortus, one of the most pathogenic of all small ruminant parasites, have developed resistance to all used anthelmintics. Detoxification enzymes, e.g. cytochromes P450 (CYPs) and efflux transporters P-glycoproteins (P-gps), which represent the main defense system against harmful xenobiotics, have been suggested to contribute to drug resistance development. The present study was designed to compare the constitutive expression of individual CYPs and P-gps in females and males of H. contortus adults and to follow up on the changes in expression of these genes in nematodes exposed to sub-lethal concentrations of ivermectin (IVM), which might occur during inaccurate treatment. The adults of inbred susceptible-Edinburgh strain (ISE, MHco3) of H. contortus were used for this purpose. The nematodes were incubated ex vivo with or without IVM (1, 10 and 100 nM) in culture medium for 4, 12 and 24 h. After incubation, total RNA was isolated and expression levels of individual CYPs and P-gps were analyzed using qPCR. Our results showed a great variability in the constitutive expression of individual CYPs and P-gps in H. contortus adults. The constitutive expression as well as the inducibility of CYPs and P-gps significantly differed in males and females. Contact of adult nematodes with sub-lethal IVM concentrations led to only minor changes in expression of CYPs, while expression of several P-gps, particularly pgp-9.2 in males and pgp-10, pgp-11 in females was increased significantly in IVM-exposed nematodes. In conclusion, inaccurate treatment of sheep with IVM might contribute to drug resistance development via increased expression of efflux transporters in H. contortus adults.


Assuntos
Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Sistema Enzimático do Citocromo P-450/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Haemonchus/efeitos dos fármacos , Ivermectina/farmacologia , Animais , Resistência a Medicamentos/genética , Feminino , Haemonchus/genética , Masculino
4.
DNA Cell Biol ; 38(8): 808-813, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31335167

RESUMO

This study aims to investigate whether a relationship exists between the C3435T polymorphism of ABCB1 gene and poststroke depression (PSD). A total of 82 PSD patients and 115 nondepression patient (NPSD) controls were included in this study. All patients were evaluated using the Hamilton Rating Scale for Depression to determine the severity of depression and complete the packet. PSD patients were diagnosed in accordance with the DSM-V criteria. The C3435T polymorphism of ABCB1 was genotyped through fluorescence in situ hybridization and chromosome karyotype analysis system. The PSD (n = 82) and NPSD groups (n = 115) had a total prevalence rate of 41.6%. The prevalence of PSD in men was 58.5%, whereas that in women was 41.5%, and no statistically significant difference existed between the two groups (χ2 = 1.009; p = 0.315). The CC, CT, and TT frequencies of the PSD group were 26.8%, 47.6%, and 25.6%, respectively, whereas those of the NPSD group were 42.6%, 45.2%, and 12.2%, respectively. Based on the CC genotype, the relative risk of homozygous mutant TT was 3.341 (χ2 = 7.869; p = 0.005; OR = 3.341), and the T allele frequency in the PSD group was 49.4% higher than that in the NPSD group. The locus gene frequency was 34.8%, and the relative risk of allele T relative to allele C was 1.830 (χ2 = 8.381; p = 0.004; OR = 1.830). A certain correlation exists between the C3435T gene polymorphism and PSD in the Han population in South Anhui Province, China, and further studies are needed to confirm our findings.


Assuntos
Depressão/genética , Polimorfismo Genético , Acidente Vascular Cerebral/psicologia , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Grupo com Ancestrais do Continente Asiático/genética , China , Depressão/etiologia , Feminino , Frequência do Gene , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Acidente Vascular Cerebral/complicações
5.
Anticancer Res ; 39(7): 3633-3639, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31262889

RESUMO

BACKGROUND/AIM: The aim of this study was to analyze the effect of DL-methadone on enhancing the action of the chemotherapeutic drugs cisplatin, doxorubicin, 5-fluoruracil (5-FU) and paclitaxel on head and neck squamous carcinoma (HNSCC) cell lines. MATERIALS AND METHODS: The chemotherapeutic drugs were applied alone or in combination with DL-methadone and cytotoxicity was analyzed by XTT assays. Expression of the µ-opioid receptor and the drug transporter p-glycoprotein were analyzed by qRT-PCR. RESULTS: The effect of DL-methadone strongly depended on the respective chemotherapeutic agent. The basic expression of the µ-opioid receptor was not associated with the effect of DL-methadone, rather its induction by chemotherapeutic drugs. Expression or expression induction of p-glycoprotein was higher in weak-responder cell lines. CONCLUSION: Enhancement of the toxicity of chemotherapeutic drugs by DL-methadone depends on the drug and on the cell line used.


Assuntos
Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Metadona/farmacologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Linhagem Celular Tumoral , Cisplatino/farmacologia , Doxorrubicina/farmacologia , Fluoruracila/farmacologia , Neoplasias de Cabeça e Pescoço/genética , Humanos , Paclitaxel/farmacologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética
6.
Clin Chim Acta ; 495: 598-605, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31181191

RESUMO

Low phospholipid-associated cholelithiasis (LPAC) is characterized by the association of ABCB4 mutations and low biliary phospholipid concentration with symptomatic and recurring cholelithiasis. In the present study, we reported a case of a 63-year-old woman, who presented a biliary pain beginning at the age of 30, recurrent after cholecystectomy, along with "comet-tail shadows" revealed by ultrasonography thus, fulfilling the diagnosis of LPAC. This disease evolved into a cholangiocarcinoma. To understand the molecular basis of this phenotype, we performed the ABCB4 gene sequencing, followed by in silico analysis and Q-RT-PCR assay. The results displayed a homozygous missense sequence variation (c.140G > A, p.Arg47Gln), predicted as pathogenic according to MutPred. Accordingly, this gave rise to a decreased hepatic ABCB4 mRNA level and structural alterations of the mutated protein. Eventually, we reported, here, the first description of an ABCB4 missense mutation (p.Arg47Gln) at homozygous state in a Tunisian LPAC syndrome. An elucidation of its functional consequences was performed. Besides, this case suggests that the delayed diagnosis of LPAC syndrome and the lack of UDCA treatment may contribute in the development of complications, such as cholangiocarcinoma.


Assuntos
Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Colangiocarcinoma/complicações , Colelitíase/complicações , Colelitíase/genética , Homozigoto , Subfamília B de Transportador de Cassetes de Ligação de ATP/química , Sequência de Aminoácidos , Sequência de Bases , Simulação por Computador , Feminino , Humanos , Pessoa de Meia-Idade , Modelos Moleculares , Conformação Proteica
7.
Nat Commun ; 10(1): 2820, 2019 06 27.
Artigo em Inglês | MEDLINE | ID: mdl-31249297

RESUMO

Bats are unusual mammals, with the ability to fly, and long lifespans. In addition, bats have a low incidence of cancer, but the mechanisms underlying this phenomenon remain elusive. Here we discovered that bat cells are more resistant than human and mouse cells to DNA damage induced by genotoxic drugs. We found that bat cells accumulate less chemical than human and mouse cells, and efficient drug efflux mediated by the ABC transporter ABCB1 underlies this improved response to genotoxic reagents. Inhibition of ABCB1 triggers an accumulation of doxorubicin, DNA damage, and cell death. ABCB1 is expressed at higher levels in several cell lines and tissues derived from bats compared to humans. Furthermore, increased drug efflux and high expression of ABCB1 are conserved across multiple bat species. Our findings suggest that enhanced efflux protects bat cells from DNA damage induced by genotoxic compounds, which may contribute to their low cancer incidence.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Quirópteros/genética , Quirópteros/metabolismo , Dano ao DNA/efeitos dos fármacos , Mutagênicos/toxicidade , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Animais , Morte Celular/efeitos dos fármacos , Linhagem Celular , Doxorrubicina/toxicidade , Humanos , Camundongos
8.
Medicine (Baltimore) ; 98(19): e15593, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31083246

RESUMO

RATIONALE: Neonatal cholestasis is one of the most serious diseases in infancy. Progressive familial intrahepatic cholestasis (PFIC) is a disease that leads to intrahepatic cholestasis. It is one of the common causes of neonatal cholestasis in addition to biliary atresia (BA). The differential diagnosis of neonatal cholestasis is clinically challenging for pediatricians. PATIENT CONCERNS: A 4-month-old female presented with severe jaundice, pruritus, and pale stool for 20 days. Abnormally strong echoes near the portal area, an abnormally small gallbladder with an irregularly stiff wall, and splenomegaly were identified on abdominal ultrasound. Blood tests showed elevated alanine aminotransferase, total bilirubin, conjugated bilirubin, gamma-glutamyltranspeptidase, and total bile acid levels. DIAGNOSIS: Intraoperative cholangiography showed BA. ABCB4 gene mutation IVS13+6G>A/G was confirmed by genetic testing. The patient was diagnosed with BA combined with PFIC3. INTERVENTIONS: Kasai portoenterostomy and ursodeoxycholic acid were used for treatment. OUTCOMES: Her clinical symptoms and blood tests improved gradually. No recurrence was noted during 1 year of follow-up. LESSONS: Additional examinations, such as genetic testing, should be considered in patients with BA who had refractory jaundice after Kasai portoenterostomy in order to exclude intrahepatic cholestasis.


Assuntos
Subfamília B de Transportador de Cassetes de Ligação de ATP/deficiência , Atresia Biliar/complicações , Atresia Biliar/diagnóstico , Colestase Intra-Hepática/complicações , Colestase Intra-Hepática/diagnóstico , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Atresia Biliar/genética , Atresia Biliar/terapia , Biomarcadores/sangue , Colestase Intra-Hepática/genética , Colestase Intra-Hepática/terapia , Diagnóstico Diferencial , Feminino , Humanos , Lactente , Icterícia/diagnóstico , Icterícia/etiologia , Icterícia/genética , Icterícia/terapia
9.
Med Oncol ; 36(6): 55, 2019 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-31089832

RESUMO

Individual diversity in plasma concentrations of lenalidomide occurs despite dosage modifications based on creatinine clearance (CCr), which can lead to unexpected toxicity. We have previously identified a cutoff value of area under the concentration-time curve (AUC0-24) for lenalidomide to avoid severe toxicity. Here, we investigated the association between ABCB1 polymorphisms and pharmacokinetics of lenalidomide in patients with multiple myeloma (MM) treated with lenalidomide and dexamethasone. Plasma concentrations of lenalidomide were analyzed using liquid chromatography-tandem mass spectrometry. Genotyping for ABCB1 1236C>T, 2677G>A/T, and 3435C>T polymorphisms was performed, and the effects of ABCB1 polymorphisms on AUC0-24 for lenalidomide were compared in 36 patients with MM who were administered lenalidomide according to the drug label based on CCr. Genotyping analysis showed that although there were no differences in AUC0-24 in 1236C>T and 2677G>A/T polymorphisms. AUC0-24 was significantly higher in patients with the T allele of 3435C>T (n = 15) than in those without (n = 21) (median 6324.6 ng h/mL vs. 2857.4 ng h/mL, p = 0.028). The AUC0-24 value exceeded the aforementioned cutoff value in 95% of the patients with the T allele of 3435C>T but in 60% with C/C genotype (p = 0.013). Multivariate logistic analysis confirmed the significance of T allele of ABCB1 3435C>T as a factor due to which the AUC0-24 cutoff value was exceeded (hazard ratio of 15.0, p = 0.019). We show that lenalidomide pharmacokinetics is influenced by the ABCB1 3435C>T polymorphism, which could be useful to individualize dosage design and reduce unexpected toxicity.


Assuntos
Lenalidomida/farmacocinética , Lenalidomida/toxicidade , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Creatinina/urina , Feminino , Genótipo , Humanos , Fatores Imunológicos/farmacocinética , Fatores Imunológicos/uso terapêutico , Fatores Imunológicos/toxicidade , Lenalidomida/uso terapêutico , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
10.
J Korean Med Sci ; 34(12): e100, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30940996

RESUMO

Background: Increased expression of MDR1 gene is one of the major mechanisms responsible for multidrug resistance in cancer cells. Two alternative promoters, upstream and downstream, are responsible for transcription of MDR1 gene in the human. However, the molecular mechanism regarding the transactivation of MDR1 upstream promoter (USP) has not been determined. Methods: Dual-luciferase reporter gene assays were used to assess the effect of Nkx-2.5 on MDR1 USP activity using reporter plasmids for human MDR1 USP and its mutants. MDR1 mRNA level was examined by quantitative real-time PCR. The direct binding of Nkx-2.5 to the USP of MDR1 was evaluated by promoter enzyme immunoassays and chromatin immunoprecipitation assays. Results: Nkx-2.5 significantly stimulates the transactivation of MDR1 USP and increases MDR1 mRNA expression in MCF7 breast cancer cells. Reporter gene assays with deleted MDR1 USPs showed that the Nkx-2.5-binding site is located between positions -71 and +12. Mutation of the Nkx-2.5-binding site at nucleotide +4 to +10 markedly reduced the Nkx-2.5-mediated activation of MDR1 USP activity. A promoter binding immunoassay and a chromatin immunoprecipitation assay revealed that Nkx-2.5 binds directly to the region +4/+10 of human MDR1 USP. Conclusion: The results in the present study show Nkx-2.5 is a positive regulator for the transactivation of MDR1 USP in MCF7 breast cancer cells. Our findings will help elucidate the regulatory mechanism responsible for the multidrug resistant cancer phenotype.


Assuntos
Proteína Homeobox Nkx-2.5/metabolismo , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Regulação Neoplásica da Expressão Gênica , Genes Reporter , Proteína Homeobox Nkx-2.5/antagonistas & inibidores , Proteína Homeobox Nkx-2.5/genética , Humanos , Células MCF-7 , Regiões Promotoras Genéticas , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Ativação Transcricional
11.
DNA Cell Biol ; 38(5): 485-490, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30977678

RESUMO

P-glycoprotein (P-gp), encoded by the ABCB1 (ATP-binding cassette transporter superfamily B member 1) gene, is a transport protein involved in the efflux and distribution of the osteosarcoma drugs methotrexate, doxorubicin, actinomycin D, and etoposide. In vivo studies indicate a close relationship between the ABCB1 (C1236T) single-nucleotide polymorphism (SNP) and the efficacy of these drugs. The purpose of this research was to elucidate the effect of ABCB1 (C1236T) polymorphism on P-gp-mediated efflux of osteosarcoma drugs. Two stable recombinant Caco-2 cell lines were generated by transfection with either the wild-type ABCB11236C allele or the ABCB11236T variant allele. The two cell lines were compared in terms of drug resistance, intracellular accumulation, and efflux of methotrexate, doxorubicin, actinomycin D, and etoposide. Accumulation of methotrexate, doxorubicin, actinomycin D, and etoposide was significantly lower in cells overexpressing wild-type P-gp than in untransfected control cells, indicating that these drugs are substrates of P-gp. Actinomycin D accumulated to similar extents in cells overexpressing wild-type or variant P-gp. Methotrexate and etoposide were transported to a greater extent by variant P-gp than wild-type protein. Conversely, doxorubicin was transported to a greater extent by wild-type P-gp. The ABCB1 (C1236T) polymorphism affects P-gp-mediated transport of osteosarcoma drugs in a drug-specific way. These studies support the importance of the ABCB1 (C1236T) SNP for P-gp activity and its potential to explain the alterations in drug response.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Dactinomicina/metabolismo , Etoposídeo/metabolismo , Metotrexato/metabolismo , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Células CACO-2 , Doxorrubicina/metabolismo , Resistência a Múltiplos Medicamentos/genética , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Polimorfismo de Nucleotídeo Único/genética
12.
Anticancer Res ; 39(4): 1711-1718, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30952710

RESUMO

BACKGROUND/AIM: Osteosarcoma (OS) is a diagnosed primary cancer of the bone. Despite the great advances that have been made during the past decades in OS therapy, drug resistance and tumor recurrence are still major problems. It is urgent to find novel strategies to overcome drug resistance in order to prolong the survival time of OS patients. MATERIALS AND METHODS: Cell viability was investigated by the cell count kit-8 (CCK-8) and colony formation assays. P-Glycoprotein (P-gp) expression was analyzed by RT-qPCR and western blot. A xenograft mouse model was used to identify the synergistic efficacy of a P-gp inhibitor with cisplatin. Student's t-test was used to determine statistically significant differences. RESULTS: P-gp expression levels were associated with cisplatin efficacy in OS patients. OS cells with higher P-gp expression were more resistant to cisplatin. Knockdown or inhibition of P-gp sensitized OS cells to cisplatin. CONCLUSION: Down-regulating the expression of P-gp in OS maybe a promising strategy to overcome cisplatin resistance.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Ósseas/tratamento farmacológico , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos , Osteossarcoma/tratamento farmacológico , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Animais , Neoplasias Ósseas/genética , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Camundongos Nus , Osteossarcoma/genética , Osteossarcoma/metabolismo , Osteossarcoma/patologia , Fatores de Tempo , Carga Tumoral/efeitos dos fármacos , Regulação para Cima , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Int J Mol Sci ; 20(8)2019 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-31022961

RESUMO

Background: Chronic obstructive pulmonary disease (COPD) is a common, preventable, and manageable lung disease characterized by large heterogeneity in disease presentation and grades impairment. Inhaled corticosteroids (ICS) are commonly used to manage COPD/COPD-exacerbation. The patient's response is characterized by interindividual variability without disease progression/survival modification. Objectives: We hypothesize that a therapeutic intervention may be more effective if single nucleotide polymorphisms (SNPs) are investigated. Methods: In 71 COPD patients under pulmonary rehabilitation, a small number of powerful SNPs, selected according to current literature, were analyzed; namely the glucocorticoid receptor gene NR3C1 (rs6190/rs6189/rs41423247), the glucocorticoid-induced transcript 1 gene (GLCCI1 rs37972), and the related co-chaperone FKBP5 gene (rs4713916). MDR1 rs2032582 was also evaluated. Lung function outcomes were assessed. Results: A significant association with functional outcomes, namely FEV1 (forced expiration volume/one second) and 6MWD (six-minutes walking distance), was found for rs4713916 and weakly for rs37972. The genotype rs4713916(GA) and, in a lesser extent, the genotype rs37972(TT), were more favorable than the wild-type. Conclusions: Our study supports a possible picture of pharmacogenomic control for COPD intervention. rs4713916 and, possibly, rs37972 may be useful predictors of clinical outcome. These results may help to tailor an optimal dose for individual COPD patients based on their genetic makeup.


Assuntos
Corticosteroides/uso terapêutico , Polimorfismo de Nucleotídeo Único , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/genética , Proteínas de Ligação a Tacrolimo/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Administração por Inalação , Corticosteroides/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Receptores de Glucocorticoides/genética , Resultado do Tratamento
14.
Oncol Rep ; 41(6): 3179-3188, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30942458

RESUMO

Multidrug resistance (MDR) is a major reason for the failure of acute myeloid leukemia (AML) therapy. Agents that reverse MDR and sensitize AML cells to chemotherapy are of great clinical significance. The present study developed Adriamycin (Adr)­resistant cell lines, namely K562/Adr200 and K562/Adr500, which exhibited MDR. The upregulation of ATP­binding cassette subfamily B member 1 (ABCB1) was confirmed as the mechanism of resistance by reverse transcription­quantitative polymerase chain reaction and western blot analyses. Subsequently, the role of the mammalian target of rapamycin (mTOR) kinase inhibitor, WYE­354, in sensitizing the K562/Adr200 and K562/Adr500 cell lines to Adr was evaluated. At sub­cytotoxic concentrations, WYE­354 increased Adr cytotoxicity in the K562/Adr200 and K562/Adr500 cells. WYE­354 restored Adr sensitivity in the resistant cells by inhibiting ABCB1­mediated substrate efflux, thereby leading to an accumulation of Adr, an increase in Adr­mediated G2/M cell cycle arrest and the induction of apoptosis. Furthermore, WYE­354 stimulated the ATPase activity of ABCB1, which was consistent with in silico predictions using a human ABCB1 mouse homology model, indicating that WYE­354 is a potent substrate of ABCB1. WYE­354 did not regulate the expression of ABCB1 at the concentrations used in the present study. These findings indicate that WYE­354 may be a competitive inhibitor of ABCB1­mediated efflux and a potential candidate in combination with standard chemotherapy for overcoming MDR. Further clinical investigations are warranted to validate this combination in vivo.


Assuntos
Doxorrubicina/administração & dosagem , Leucemia Mieloide Aguda/tratamento farmacológico , Purinas/administração & dosagem , Subfamília B de Transportador de Cassetes de Ligação de ATP/antagonistas & inibidores , Subfamília B de Transportador de Cassetes de Ligação de ATP/química , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Adenosina Trifosfatases/química , Animais , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Resistência a Múltiplos Medicamentos/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Células K562 , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Camundongos , Especificidade por Substrato , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/genética
15.
Mol Med Rep ; 19(5): 4433-4440, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30942454

RESUMO

MicroRNAs (miRNAs) are post­transcriptional regulators that mediate the initiation and progression of human cancer. Growing evidence suggests that deregulation of miRNA expression levels underlies chemo­resistance. To investigate whether miRNA­302a (miR­302a) is involved in mediating chemo­resistance to paclitaxel in prostate cancer, a series of in vitro analyses were performed in paclitaxel­resistant prostate cancer PC­3PR cells and non­resistant prostate cancer PC­3 cells. It was demonstrated that the expression of miR­302a was upregulated in PC­3PR cells. Notably, ectopic expression of miR­302a also increased resistance to paclitaxel in wild­type PC­3 cells. By contrast, silencing of miR­302a in PC­3PR cells sensitized the cells to paclitaxel. Gene and protein expression analyses suggested that the miR­302a target gene breast cancer resistance protein (BCRP) may mediate chemo­resistance to paclitaxel in PC­3PR cells. In conclusion, the data suggested that elevated miR­302a levels, in part, mediate sensitivity to paclitaxel in prostate cancer through the aberrant regulation of its downstream targets, AOF2, BCRP and permeability glycoprotein 1. These data have implications for the development of novel therapeutics in prostate cancer that may improve sensitivity to chemotherapeutics.


Assuntos
Resistencia a Medicamentos Antineoplásicos , MicroRNAs/metabolismo , Subfamília B de Transportador de Cassetes de Ligação de ATP/química , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/química , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Antagomirs/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Histona Desmetilases/química , Histona Desmetilases/genética , Histona Desmetilases/metabolismo , Humanos , Pontos de Checagem da Fase M do Ciclo Celular/efeitos dos fármacos , Masculino , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Proteínas de Neoplasias/química , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Paclitaxel/farmacologia , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Regulação para Cima
16.
Pharmacol Rep ; 71(3): 385-392, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31003147

RESUMO

BACKGROUND: Effective immunosuppression through optimization of trough levels tacrolimus reduces post-transplant mortality rate in liver transplant cases. METHODS: Meta-analysis was carried out to evaluate how donor/recipient CYP3A5 (n = 678) and recipient ABCB1 (n = 318) genotypes influence tacrolimus pharmacokinetics till one-month of transplantation. RESULTS: The donor CYP3A5*3/*3 genotype exhibited higher concentration/dose (C/D) ratio of tacrolimus in week 1 (mean difference: 65.04, 95% CI: 15.30-114.79 ng/ml/mg/kg), week 2 (mean difference: 21.7, 95% CI: 12.6-30.9 ng/ml/mg/kg) and week 4 (mean difference: 43.28, 95% CI: 17.09 - 69.49 ng/ml/mg/kg) compared to *1/*1 and *1/*3 genotypes. The recipient CYP3A5 *3/*3 genotype did not showed significant difference in tacrolimus C/D ratio in week 1 compared to other two genotypes. However, week 2 (mean difference: 44.16, 95% CI: 3.68-84.65 ng/ml/mg/kg) and week 4 (mean difference: 43.74, 95% CI: 12.50-75.00 ng/ml/mg/kg) availability was higher in *3/*3 mutant recipients. However, the recipient ABCB1 3435 C > T polymorphism has no significant influence on tacrolimus pharmacokinetics till one month of transplant. CONCLUSIONS: The donor and recipient CYP3A5*3 polymorphism influences tacrolimus pharmacokinetics in the first month post-transplantation, whereas the association with recipient ABCB1 3435 C > T is inconclusive.


Assuntos
Citocromo P-450 CYP3A/genética , Tacrolimo/farmacocinética , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Genótipo , Rejeição de Enxerto/metabolismo , Humanos , Imunossupressão/métodos , Transplante de Fígado/métodos , Polimorfismo Genético/genética , Doadores de Tecidos
17.
BMB Rep ; 52(5): 330-335, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30982500

RESUMO

Hepatitis B virus (HBV) encoding the HBV x protein (HBx) is a known causative agent of hepatocellular carcinoma (HCC). Its pathogenic activities in HCC include interference with several signaling pathways associated with cell proliferation and apoptosis. Mutant C-terminal-truncated HBx isoforms are frequently found in human HCC and have been shown to enhance proliferation and invasiveness leading to HCC malignancy. We investigated the molecular mechanism of the reduced doxorubicin cytotoxicity by C-terminal truncated HBx. Cells transfected with C-terminal truncated HBx exhibited reduced cytotoxicity to doxorubicin compared to those transfected with full-length HBx. The doxorubicin resistance of cells expressing C-terminal truncated HBx correlated with upregulation of the ATP binding cassette subfamily B member 1(ABCB1) transporter, resulting in the enhanced efflux of doxorubicin. Inhibiting the activity of ABCB1 and silencing ABCB1 expression by small interfering ribonucleic acid (siRNA) increased the cytotoxicity of doxorubicin. These results indicate that elevated ABCB1 expression induced by C-terminal truncation of HBx was responsible for doxorubicin resistance in HCC. Hence, co-treatment with an ABCB1 inhibitor and an anticancer agent may be effective for the treatment of patients with liver cancer containing the C-terminal truncated HBx. [BMB Reports 2019; 52(5): 330-335].


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/metabolismo , Doxorrubicina/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Transativadores/metabolismo , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Antibióticos Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos , Humanos , Neoplasias Hepáticas/genética , Transdução de Sinais , Transativadores/genética , Ativação Transcricional , Regulação para Cima
18.
Med Sci Monit ; 25: 2959-2965, 2019 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-31007253

RESUMO

BACKGROUND The aim of this study was to investigate the genomic alterations of renal cell carcinoma (RCC) in Chinese patients and to evaluate the correlations between significantly mutated genes and tumor mutation burden (TMB) levels in RCC. MATERIAL AND METHODS Two batch of specimens were collected from patients with RCC. Cohort 1 enrolled 17 RCC patients. Specimens and clinicopathological data were collected and the duration of disease-free survival were evaluated with a follow-up from 2 weeks to longer than 1 year. Cohort 2 collected 70 clear cell RCC (ccRCC) tissues and blood specimens. Next-generation sequencing were used to detect the genomic variations in those specimens in both cohorts and TMB in cohort 2. Clinicopathological features of the 2 cohorts were collected and the χ² test or Fisher's exact test was used for categorical variables stratified by TMB values. RESULTS Our present study demonstrated that the top 3 most frequent aberrated genes in Chinese ccRCC patients were ABCB1, UGT1A1, and VHL, with percentages of 50.00%, 42.86%, and 34.52% respectively. And only 1 gene, which was ABCB1, showed statistically significant difference (P=0.047) stratified by TMB levels. In addition, 6 oncogenic pathways were involved in ccRCC cases in the 2 cohorts. Only 5 out of the 8 most common altered genes of RCC from COSMIC or TCGA databases were detected in our study. CONCLUSIONS The genomic alterations of Chinese RCC patients were different from that in TCGA and COSMIC. No significant genomic alterations were found correlating to TMB levels in ccRCC. Non-silent mutation of VHL may be a predictor for the outcome of ccRCC treated with axitinib.


Assuntos
Carcinoma de Células Renais/genética , Regulação Neoplásica da Expressão Gênica/genética , Genoma Humano/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Grupo com Ancestrais do Continente Asiático/genética , Carcinoma de Células Renais/patologia , China , Estudos de Coortes , Intervalo Livre de Doença , Feminino , Perfilação da Expressão Gênica/métodos , Genômica/métodos , Glucuronosiltransferase/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Mutação/genética , Proteína Supressora de Tumor Von Hippel-Lindau/genética
19.
Nat Commun ; 10(1): 1295, 2019 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-30894541

RESUMO

ABCB1 encodes Multidrug Resistance protein (MDR1), an ATP-binding cassette member involved in the cellular efflux of chemotherapeutic drugs. Here we report that ovarian and breast samples from chemotherapy treated patients are positive for multiple transcriptional fusions involving ABCB1, placing it under the control of a strong promoter while leaving its open reading frame intact. We identified 15 different transcriptional fusion partners involving ABCB1, as well as patients with multiple distinct fusion events. The partner gene selected depended on its structure, promoter strength, and chromosomal proximity to ABCB1. Fusion positivity was strongly associated with the number of lines of MDR1-substrate chemotherapy given. MDR1 inhibition in a fusion positive ovarian cancer cell line increased sensitivity to paclitaxel more than 50-fold. Convergent evolution of ABCB1 fusion is therefore frequent in chemotherapy resistant recurrent ovarian cancer. As most currently approved PARP inhibitors (PARPi) are MDR1 substrates, prior chemotherapy may precondition resistance to PARPi.


Assuntos
Neoplasias da Mama/genética , Cistadenocarcinoma Seroso/genética , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica , Proteínas de Fusão Oncogênica/genética , Neoplasias Ovarianas/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Estudos de Coortes , Cistadenocarcinoma Seroso/tratamento farmacológico , Cistadenocarcinoma Seroso/metabolismo , Cistadenocarcinoma Seroso/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Gradação de Tumores , Proteínas de Fusão Oncogênica/metabolismo , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Paclitaxel/uso terapêutico , Poli(ADP-Ribose) Polimerases/genética , Poli(ADP-Ribose) Polimerases/metabolismo , Regiões Promotoras Genéticas , Recidiva , Transcrição Genética
20.
Gene ; 698: 92-99, 2019 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-30836117

RESUMO

BACKGROUND: Metadherin (MTDH) is an oncogene that has been overexpressed in numerous types of malignancies including colorectal cancer (CRC). However, few investigations associated with the biological behavior of MTDH in CRC have been performed. The aim of the present study was to investigate the effect of modification of MTDH gene expression (knockdown and overexpression) on the biological behavior of CRC in vitro. METHODS: MTDH gene expression was analyzed in two CRC cell lines (Caco-2 and HCT116) by qPCR. MTDH was down-regulated via siRNA-mediated knockdown of human MTDH in HCT116 cells, which express high endogenous levels of MTDH gene. Also, MTDH gene was up-regulated via transfection of Caco-2 cells, which express low endogenous levels of MTDH gene, with a plasmid carrying human MTDH gene. RESULTS: Knockdown of MTDH gene expression significantly decreased the gene expression of multidrug resistance gene (MDR1), Snail and NF-κB p65, but increased the gene expression of E-cadherin. Furthermore, MTDH-knockdown significantly decreased anaerobic glycolysis (glucose consumption and lactate production), cell proliferation ability and transformation into cancer stem cell. Moreover, up-regulation of MTDH gene significantly increased the gene expression of MDR1, Snail and NF-κB p65, deceased the gene expression of E-cadherin, enhanced cell proliferation, and anaerobic glycolysis and activated transformation into cancer stem cells. CONCLUSIONS: MTDH has an important role in promoting CRC aggravation. Also, inhibition of MTDH expression may attenuate the carcinogenic behavior of CRC cells. Furthermore, MTDH-associated NF-κB p65 signaling pathways may be involved in mediating the biological behavior of CRC.


Assuntos
Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular/metabolismo , Neoplasias Colorretais/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Células CACO-2 , Caderinas/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Neoplasias do Colo/genética , Regulação para Baixo , Expressão Gênica , Regulação Neoplásica da Expressão Gênica/genética , Técnicas de Silenciamento de Genes/métodos , Células HCT116 , Humanos , Células-Tronco Neoplásicas/metabolismo , Transdução de Sinais , Fatores de Transcrição da Família Snail/genética , Fator de Transcrição RelA/genética , Regulação para Cima
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA