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[PMID]:29385210
[Au] Autor:Eadie LN; Dang P; Goyne JM; Hughes TP; White DL
[Ad] Endereço:Cancer Theme, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, South Australia.
[Ti] Título:ABCC6 plays a significant role in the transport of nilotinib and dasatinib, and contributes to TKI resistance in vitro, in both cell lines and primary patient mononuclear cells.
[So] Source:PLoS One;13(1):e0192180, 2018.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:ATP Binding Cassette family efflux proteins ABCB1 and ABCG2 have previously been demonstrated to interact with Tyrosine Kinase Inhibitors (TKIs); however, evidence for the interaction of other potentially relevant drug transporters with TKIs is lacking. Through Taqman transporter array technology we assessed the impact of nilotinib on mRNA expression of ABC transporters, with ABCC6 identified as a transporter of interest. Additionally, increased expression of ABCC6 mRNA was observed during in vitro development of nilotinib resistance in BCR-ABL1-expressing cell lines. K562 cells exposed to gradually increasing concentrations of nilotinib (to 2 µM) expressed up to 57-fold higher levels of ABCC6 mRNA when compared with control cells (p = 0.002). Analogous results were observed in nilotinib resistant K562-Dox cells (up to 33-fold higher levels of ABCC6, p = 0.002). IC50 experiments were conducted on patient mononuclear cells in the absence and presence of three ABCC6 inhibitors: indomethacin, probenecid and pantoprazole. Results demonstrated that all three inhibitors significantly reduced nilotinib IC50 (p<0.001) indicating ABCC6 is likely involved in nilotinib transport. Cell line data confirmed these findings. Similar results were obtained for dasatinib, but not imatinib. Combined, these studies suggest that nilotinib and dasatinib are likely substrates of ABCC6 and to our knowledge, this is the first report of ABCC6 involvement in TKI transport. In addition, ABCC6 overexpression may also contribute to nilotinib and dasatinib resistance in vitro. With nilotinib and dasatinib now front line therapy options in the treatment of CML, concomitant administration of ABCC6 inhibitors may present an attractive option to enhance TKI efficacy.
[Mh] Termos MeSH primário: Dasatinibe/farmacologia
Leucócitos Mononucleares/efeitos dos fármacos
Proteínas Associadas à Resistência a Múltiplos Medicamentos/fisiologia
Inibidores de Proteínas Quinases/farmacologia
Pirimidinas/farmacologia
[Mh] Termos MeSH secundário: Linhagem Celular
Dasatinibe/farmacocinética
Resistência a Medicamentos Antineoplásicos
Proteínas de Fusão bcr-abl/metabolismo
Seres Humanos
Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética
Inibidores de Proteínas Quinases/farmacocinética
Pirimidinas/farmacocinética
RNA Mensageiro/genética
Reação em Cadeia da Polimerase em Tempo Real
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (4-methyl-N-(3-(4-methylimidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((4-pyridin-3-ylpyrimidin-2-yl)amino)benzamide); 0 (ABCC6 protein, human); 0 (Multidrug Resistance-Associated Proteins); 0 (Protein Kinase Inhibitors); 0 (Pyrimidines); 0 (RNA, Messenger); EC 2.7.10.2 (Fusion Proteins, bcr-abl); RBZ1571X5H (Dasatinib)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180201
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0192180


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[PMID]:29317622
[Au] Autor:Zwama M; Yamasaki S; Nakashima R; Sakurai K; Nishino K; Yamaguchi A
[Ad] Endereço:Laboratory of Cell Membrane Structural Biology, Institute of Scientific and Industrial Research, Osaka University, Ibaraki, Osaka, 567-0047, Japan.
[Ti] Título:Multiple entry pathways within the efflux transporter AcrB contribute to multidrug recognition.
[So] Source:Nat Commun;9(1):124, 2018 01 09.
[Is] ISSN:2041-1723
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:AcrB is the major multidrug exporter in Escherichia coli. Although several substrate-entrances have been identified, the specificity of these various transport paths remains unclear. Here we present evidence for a substrate channel (channel 3)  from the central cavity of the AcrB trimer, which is connected directly to the deep pocket without first passing the switch-loop and the proximal pocket . Planar aromatic cations, such as ethidium, prefer channel 3 to channels 1 and 2. The efflux through channel 3 increases by targeted mutations and is not in competition with the export of drugs such as minocycline and erythromycin through channels 1 and 2. A switch-loop mutant, in which the pathway from the proximal to the deep pocket is hindered, can export only channel 3-utilizing drugs. The usage of multiple entrances thus contributes to the recognition and transport of a wide range of drugs with different physicochemical properties.
[Mh] Termos MeSH primário: Farmacorresistência Bacteriana Múltipla/genética
Proteínas de Escherichia coli/genética
Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética
Transdução de Sinais/genética
[Mh] Termos MeSH secundário: Antibacterianos/farmacologia
Escherichia coli/efeitos dos fármacos
Escherichia coli/genética
Escherichia coli/metabolismo
Proteínas de Escherichia coli/química
Proteínas de Escherichia coli/metabolismo
Etídio/química
Etídio/metabolismo
Testes de Sensibilidade Microbiana
Modelos Moleculares
Proteínas Associadas à Resistência a Múltiplos Medicamentos/química
Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo
Mutação
Domínios Proteicos
Transdução de Sinais/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (AcrB protein, E coli); 0 (Anti-Bacterial Agents); 0 (Escherichia coli Proteins); 0 (Multidrug Resistance-Associated Proteins); EN464416SI (Ethidium)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180226
[Lr] Data última revisão:
180226
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180111
[St] Status:MEDLINE
[do] DOI:10.1038/s41467-017-02493-1


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[PMID]:29342177
[Au] Autor:Szabó E; Türk D; Telbisz Á; Kucsma N; Horváth T; Szakács G; Homolya L; Sarkadi B; Várady G
[Ad] Endereço:Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary.
[Ti] Título:A new fluorescent dye accumulation assay for parallel measurements of the ABCG2, ABCB1 and ABCC1 multidrug transporter functions.
[So] Source:PLoS One;13(1):e0190629, 2018.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:ABC multidrug transporters are key players in cancer multidrug resistance and in general xenobiotic elimination, thus their functional assays provide important tools for research and diagnostic applications. In this study we have examined the potential interactions of three key human ABC multidrug transporters with PhenGreen diacetate (PGD), a cell permeable fluorescent metal ion indicator. The non-fluorescent, hydrophobic PGD rapidly enters the cells and, after cleavage by cellular esterases, in the absence of quenching metal ions, PhenGreen (PG) becomes highly fluorescent. We found that in cells expressing functional ABCG2, ABCB1, or ABCC1 transporters, cellular PG fluorescence is strongly reduced. This fluorescence signal in the presence of specific transporter inhibitors is increased to the fluorescence levels in the control cells. Thus the PG accumulation assay is a new, unique tool for the parallel determination of the function of the ABCG2, ABCB1, and ABCC1 multidrug transporters. Since PG has very low cellular toxicity, the PG accumulation assay also allows the selection, separation and culturing of selected cell populations expressing either of these transporters.
[Mh] Termos MeSH primário: Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo
Corantes Fluorescentes/metabolismo
Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo
Proteínas de Neoplasias/metabolismo
[Mh] Termos MeSH secundário: Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo
Linhagem Celular Tumoral
Citometria de Fluxo
Seres Humanos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (ABCB1 protein, human); 0 (ABCG2 protein, human); 0 (ATP Binding Cassette Transporter, Sub-Family B); 0 (ATP Binding Cassette Transporter, Sub-Family G, Member 2); 0 (Fluorescent Dyes); 0 (Multidrug Resistance-Associated Proteins); 0 (Neoplasm Proteins); Y49M64GZ4Q (multidrug resistance-associated protein 1)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180210
[Lr] Data última revisão:
180210
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180118
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0190629


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[PMID]:29297851
[Au] Autor:Molitor A; James CE; Fanning S; Pagès JM; Davin-Regli A
[Ad] Endereço:1​UMR_MD1, Facultés de Pharmacie and Médecine, Aix-Marseille Univ, Marseille, France.
[Ti] Título:Ram locus is a key regulator to trigger multidrug resistance in Enterobacter aerogenes.
[So] Source:J Med Microbiol;67(2):148-159, 2018 Feb.
[Is] ISSN:1473-5644
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:PURPOSE: Several genetic regulators belonging to AraC family are involved in the emergence of MDR isolates of E. aerogenes due to alterations in membrane permeability. Compared with the genetic regulator Mar, RamA may be more relevant towards the emergence of antibiotic resistance. METHODOLOGY: Focusing on the global regulators, Mar and Ram, we compared the amino acid sequences of the Ram repressor in 59 clinical isolates and laboratory strains of E. aerogenes. Sequence types were associated with their corresponding multi-drug resistance phenotypes and membrane protein expression profiles using MIC and immunoblot assays. Quantitative gene expression analysis of the different regulators and their targets (porins and efflux pump components) were performed. RESULTS: In the majority of the MDR isolates tested, ramR and a region upstream of ramA were mutated but marR or marA were unchanged. Expression and cloning experiments highlighted the involvement of the ram locus in the modification of membrane permeability. Overexpression of RamA lead to decreased porin production and increased expression of efflux pump components, whereas overexpression of RamR had the opposite effects. CONCLUSION: Mutations or deletions in ramR, leading to the overexpression of RamA predominated in clinical MDR E. aerogenes isolates and were associated with a higher-level of expression of efflux pump components. It was hypothesised that mutations in ramR, and the self-regulating region proximal to ramA, probably altered the binding properties of the RamR repressor; thereby producing the MDR phenotype. Consequently, mutability of RamR may play a key role in predisposing E. aerogenes towards the emergence of a MDR phenotype.
[Mh] Termos MeSH primário: Farmacorresistência Bacteriana Múltipla/genética
Enterobacter aerogenes/efeitos dos fármacos
Enterobacter aerogenes/genética
Regulação Bacteriana da Expressão Gênica
Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética
Fatores de Transcrição/genética
[Mh] Termos MeSH secundário: Antibacterianos/farmacologia
Proteínas de Bactérias/genética
Proteínas de Bactérias/metabolismo
Infecções por Enterobacteriaceae/microbiologia
Genes araC
Loci Gênicos
Seres Humanos
Testes de Sensibilidade Microbiana
Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo
Mutação
Porinas/biossíntese
Porinas/genética
Fatores de Transcrição/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anti-Bacterial Agents); 0 (Bacterial Proteins); 0 (Multidrug Resistance-Associated Proteins); 0 (Porins); 0 (RamA protein, Enterobacter aerogenes); 0 (Transcription Factors)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180206
[Lr] Data última revisão:
180206
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180104
[St] Status:MEDLINE
[do] DOI:10.1099/jmm.0.000667


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[PMID]:29208359
[Au] Autor:Dantas N; de Aquino TM; de Araújo-Júnior JX; da Silva-Júnior E; Gomes EA; Gomes AAS; Siqueira-Júnior JP; Mendonça Junior FJB
[Ad] Endereço:Laboratório de Genética de Microorganismo, Departamento de Biologia Molecular/CCEN/Universidade Federal da Paraíba-UFPB, 58051-970 João Pessoa, PB, Brazil.
[Ti] Título:Aminoguanidine hydrazones (AGH's) as modulators of norfloxacin resistance in Staphylococcus aureus that overexpress NorA efflux pump.
[So] Source:Chem Biol Interact;280:8-14, 2018 Jan 25.
[Is] ISSN:1872-7786
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:One of the promising fields for improving the effectiveness of antimicrobial agents is their combination with efflux pump inhibitors (EPIs), which besides expanding the use of existing antibiotics. The goal of this research was to evaluate a series of aminoguanidine hydrazones (AGH's, 1-19) as antibacterial agents and NorA efflux pump inhibitors in Staphylococcus aureus strain SA-1199B. Molecular modeling and docking studies were also performed in order to explain at the molecular level the interactions of the compounds with the generated NorA efflux pump model. The MICs of the antibiotic and ethidium bromide were determined by microdilution assay in absence or presence of a subinhibitory concentration of aminoguanidine hydrazones and macrophages viability was determined through MTT assay. Bioinformatic software Swiss-Model and AutoDock 4.2 were used to perform modeling and docking studies, respectively. As results, all AGH's were able to potentiate the action for the antibiotic norfloxacin, causing MIC's reduction of 16-fold and 32-fold to ethidium bromide. In the cell viability test, the concentration of 10 µg/mL showed better results than 90% and the concentration of 1000 µg/mL showed the lowest viability, reaching a maximum of 50% for the analyzed aminoguanidine hydrazones. Molecular docking studies showed that both norfloxacin and derivative 13 were recognized by the same binding site of NorA pump, suggesting a competitive mechanism. The present work demonstrated for the first time that AGH derivatives have potential to be putative inhibitors of NorA efflux pump, showing a promising activity as an antibacterial drug development.
[Mh] Termos MeSH primário: Antibacterianos/farmacologia
Proteínas de Bactérias/metabolismo
Farmacorresistência Bacteriana/efeitos dos fármacos
Inibidores Enzimáticos/farmacologia
Hidrazonas/química
Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo
Staphylococcus aureus/metabolismo
[Mh] Termos MeSH secundário: Animais
Proteínas de Bactérias/antagonistas & inibidores
Sítios de Ligação
Linhagem Celular
Sobrevivência Celular/efeitos dos fármacos
Inibidores Enzimáticos/química
Inibidores Enzimáticos/toxicidade
Guanidinas/química
Hidrazonas/síntese química
Hidrazonas/farmacologia
Camundongos
Testes de Sensibilidade Microbiana
Simulação de Acoplamento Molecular
Proteínas Associadas à Resistência a Múltiplos Medicamentos/antagonistas & inibidores
Norfloxacino/farmacologia
Estrutura Terciária de Proteína
Staphylococcus aureus/efeitos dos fármacos
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anti-Bacterial Agents); 0 (Bacterial Proteins); 0 (Enzyme Inhibitors); 0 (Guanidines); 0 (Hydrazones); 0 (Multidrug Resistance-Associated Proteins); N0F8P22L1P (Norfloxacin); SCQ4EZQ113 (pimagedine)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180129
[Lr] Data última revisão:
180129
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171207
[St] Status:MEDLINE


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[PMID]:29220791
[Au] Autor:Wang Y; Mowla R; Ji S; Guo L; De Barros Lopes MA; Jin C; Song D; Ma S; Venter H
[Ad] Endereço:Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, Jinan 250012, China.
[Ti] Título:Design, synthesis and biological activity evaluation of novel 4-subtituted 2-naphthamide derivatives as AcrB inhibitors.
[So] Source:Eur J Med Chem;143:699-709, 2018 Jan 01.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:A novel series of 4-substituted 2-naphthamide derivatives were designed, synthesized and evaluated for their biological activity. In particular, the ability of the compounds to potentiate the action of antibiotics, to inhibit Nile Red efflux and to target AcrB specifically was investigated. The results indicated that most of the 4-substituted 2-naphthamide derivatives were able to synergize with the antibiotics tested, and inhibit Nile Red efflux by AcrB in the resistant phenotype. Subsequent exclusion of compounds with off target effects such as outer- or inner membrane permeabilization identified compounds 7c, 7g, 12c, 12i and 13g as efflux pump inhibitors (EPIs). Particularly, compounds 7c, 7g and 12i were found to be the most potent EPIs, which synergized with the two substrates tested at lower concentrations than that of parent A3, demonstrating an improvement in potency as compared to A3. Additionally, when the outer membrane of E. coli was permeabilized, compound 12c displayed a huge increase in efficacy and was able to synergize with erythromycin at a concentration that was 16 times lower than that of the parent A3. Hence we were able to design and synthesize compounds that displayed significant increase in efficacy as EPIs against AcrB.
[Mh] Termos MeSH primário: Amidas/farmacologia
Antibacterianos/farmacologia
Desenho de Drogas
Proteínas de Escherichia coli/antagonistas & inibidores
Escherichia coli/efeitos dos fármacos
Proteínas Associadas à Resistência a Múltiplos Medicamentos/antagonistas & inibidores
[Mh] Termos MeSH secundário: Amidas/síntese química
Amidas/química
Antibacterianos/síntese química
Antibacterianos/química
Relação Dose-Resposta a Droga
Testes de Sensibilidade Microbiana
Estrutura Molecular
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (AcrB protein, E coli); 0 (Amides); 0 (Anti-Bacterial Agents); 0 (Escherichia coli Proteins); 0 (Multidrug Resistance-Associated Proteins)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180110
[Lr] Data última revisão:
180110
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171209
[St] Status:MEDLINE


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[PMID]:27739315
[Au] Autor:Sedláková I; Laco J; Tosner J; Spacek J
[Ti] Título:[Expression of ATP-binding Cassette Proteins Pgp, MRP1, and MRP3 in Malignant and Benign Ovarian Lesions].
[Ti] Título:Exprese ABC transportéru Pgp, MRP1 a MRP3 u maligních a benigních zmen vajecníku..
[So] Source:Klin Onkol;29(5):358-363, 2016.
[Is] ISSN:0862-495X
[Cp] País de publicação:Czech Republic
[La] Idioma:cze
[Ab] Resumo:BACKGROUND: This study was designed to compare the expression of PgP (P-glycoprotein), MRP1 (multidrug related protein), and MRP3 in ovarian cancer patients, patients with benign ovarian tumors, and healthy women, and to evaluate the correlation between the expression of ATP-binding cassette proteins Pgp, MRP1, and MRP3 with stage, grade, and histological type. PATIENTS AND METHODS: Tissue specimens from 212 women who underwent surgery at the Department of Obstetrics and Gynecology at University Hospital Hradec Králové were subjected to immunohistochemical staining for Pgp, MRP1, and MRP3. RESULTS: The expression of Pgp and MRP1 was higher in ovarian tumor cells than in the cells lining the ovarian cyst. The lowest level of expression was found in normal ovarian tissue (p < 0.001). Histological subtype of epithelial ovarian cancer correlated with the expression of PgP, MRP1, and MRP3. The lowest level of Pgp and MRP1 expression was found in endometrioid ovarian cancers (p = 0.151; p = 0.013). Patients with advanced ovarian cancer (FIGO III + IV) had higher MRP1 expression than those with early stage ovarian cancer (median MRP1 FIGO I + II 80%; CI 60-100; FIGO III + IV 100%; CI 90-100; p = 0.100). An association was observed between MRP1 and tumor grade (p < 0.001). CONCLUSION: Pgp and MRP1 expression was higher in ovarian tumor cells than in cells lining the ovarian cyst. The lowest level of expression was found in normal ovarian tissue. ATP-binding cassette proteins play an important role in ovarian cancer pathogenesis.Key words: ATP-binding cassette proteins - ovarian cancer - P-glycoprotein (Pgp) - multidrug related protein 1 (MRP1) - multidrug related protein 3 (MRP3) - drug resistanceThis work was supported by the Czech Ministry of Health NT 14107-3/2013.The authors declare they have no potential confl icts of interest concerning drugs, products, or services used in the study.The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.Submitted: 9. 11. 2015Accepted: 30. 8. 2016.
[Mh] Termos MeSH primário: Biomarcadores Tumorais/metabolismo
Neoplasias do Endométrio/metabolismo
Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo
Neoplasias Ovarianas/metabolismo
[Mh] Termos MeSH secundário: Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo
Neoplasias do Endométrio/patologia
Neoplasias do Endométrio/cirurgia
Feminino
Seres Humanos
Técnicas Imunoenzimáticas
Neoplasias Ovarianas/patologia
Neoplasias Ovarianas/cirurgia
Ovário/metabolismo
Ovário/patologia
Prognóstico
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ABCB1 protein, human); 0 (ATP Binding Cassette Transporter, Sub-Family B); 0 (Biomarkers, Tumor); 0 (Multidrug Resistance-Associated Proteins); 1YV0492L5Z (multidrug resistance-associated protein 3); Y49M64GZ4Q (multidrug resistance-associated protein 1)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171205
[Lr] Data última revisão:
171205
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161015
[St] Status:MEDLINE


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[PMID]:28982859
[Au] Autor:Kishimoto S; Yasuda M; Fukushima S
[Ad] Endereço:Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Kobe Gakuin University, Kobe, Japan skisimot@pharm.kobegakuin.ac.jp.
[Ti] Título:Changes in the Expression of Various Transporters as Influencing Factors of Resistance to Cisplatin.
[So] Source:Anticancer Res;37(10):5477-5484, 2017 10.
[Is] ISSN:1791-7530
[Cp] País de publicação:Greece
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Changes in the expression of transporters have been reported as factors in resistance to cisplatin (CDDP). This study was designed to clarify whether CDDP-resistant strains isolated from a cell line had the same characteristics, and whether these characteristics could be therapeutic targets. MATERIALS AND METHODS: Intracellular platinum levels were determined by the inductively-coupled plasma method. mRNA expression levels were determined using the real-time polymerase chain reaction. RESULTS: Some CDDP-resistant HepG2 cell lines exhibited changes in the expression of copper transporter 1, multidrug resistant protein (MRP)2, and/or MRP3, resulting in decreased intracellular platinum amounts, while others showed no change in platinum accumulation. Expression of these transporters was not necessarily maintained in a constant direction within the cell population isolated from the same origin. CONCLUSION: These results suggest that the CDDP-resistant tumors caused by a decrease in intracellular platinum content consist of a heterogeneous cell population showing expression changes of several transporters.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Carcinoma Hepatocelular/tratamento farmacológico
Cisplatino/farmacologia
Resistência a Medicamentos Antineoplásicos
Neoplasias Hepáticas/tratamento farmacológico
Proteínas de Membrana Transportadoras/efeitos dos fármacos
[Mh] Termos MeSH secundário: Antineoplásicos/metabolismo
Carcinoma Hepatocelular/genética
Carcinoma Hepatocelular/metabolismo
Carcinoma Hepatocelular/patologia
Proteínas de Transporte de Cátions/efeitos dos fármacos
Proteínas de Transporte de Cátions/genética
Proteínas de Transporte de Cátions/metabolismo
Sobrevivência Celular/efeitos dos fármacos
Cisplatino/metabolismo
Relação Dose-Resposta a Droga
Regulação Neoplásica da Expressão Gênica
Células Hep G2
Seres Humanos
Concentração Inibidora 50
Neoplasias Hepáticas/genética
Neoplasias Hepáticas/metabolismo
Neoplasias Hepáticas/patologia
Proteínas de Membrana Transportadoras/genética
Proteínas de Membrana Transportadoras/metabolismo
Proteínas Associadas à Resistência a Múltiplos Medicamentos/efeitos dos fármacos
Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética
Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo
RNA Mensageiro/genética
RNA Mensageiro/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Cation Transport Proteins); 0 (Membrane Transport Proteins); 0 (Multidrug Resistance-Associated Proteins); 0 (RNA, Messenger); 0 (SLC31A1 protein, human); 1YV0492L5Z (multidrug resistance-associated protein 3); 4AF605U6JN (multidrug resistance-associated protein 2); Q20Q21Q62J (Cisplatin)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171016
[Lr] Data última revisão:
171016
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171007
[St] Status:MEDLINE


  9 / 5289 MEDLINE  
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[PMID]:28968471
[Au] Autor:Lin GL; Ting HJ; Tseng TC; Juang V; Lo YL
[Ad] Endereço:Department of Biological Sciences and Technology, National University of Tainan, Tainan, Taiwan.
[Ti] Título:Modulation of the mRNA-binding protein HuR as a novel reversal mechanism of epirubicin-triggered multidrug resistance in colorectal cancer cells.
[So] Source:PLoS One;12(10):e0185625, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:HuR (ELAVL1), a RNA-binding protein, plays a key role in posttranscriptional regulation of multidrug resistance (MDR)-related genes. Among various HuR-regulated oncogenic transcripts, the activation of galectin-3/ß-catenin survival pathway is critical to induce transcription of cyclin D1, P-glycoprotein (P-gp) and/or multidrug resistance-associated proteins (MRPs). In this study, we aim to elucidate the HuR-regulating pathways related to epirubicin-mediated resistance in human colorectal carcinoma cells. The effects and mechanisms of epirubicin treatment on the expressions of upstream survival signals (e.g., ß-catenin) and downstream MDR transporters (e.g., P-gp) and anti-apoptotic pathways (e.g., Bcl-2) were assessed with or without HuR knockdown (siHuR) or overexpression (overHuR; ectopic HuR or pcDNA3/HA-HuR). Our results showed that siHuR decreased transcriptional expressions of galectin-3, ß-catenin, cyclin D1, Bcl-2, P-gp, MRP1, and MRP2 in epirubicin-treated colon cancer cells. Consistently, the co-treatment of epirubicin and siHuR diminished the expressions of galectin-3, ß-catenin, c-Myc, P-gp and MRP1. HuR silencing enhanced the intracellular accumulation of epirubicin in colon cancer cells. On the other hand, overHuR abolished such effects. Furthermore, siHuR significantly intensified epirubicin-mediated apoptosis via increasing reactive oxygen species and thus promoted the cytotoxic effect of epirubicin. The combined treatments of siHuR and epirubicin significantly reduced the expression of Bcl-2, but increased the expression of Bax, as well as activity and expression levels of caspase-3 and -9. In contrast, overHuR abrogated these effects. Our findings provide insight into the mechanisms by which siHuR potentiated epirubicin-induced cytotoxicity via inhibiting galectin-3/ß-catenin signaling, suppressing MDR transporters and provoking apoptosis. To our best knowledge, this is an innovative investigation linking the post-transcriptional control by HuR silencing to survival signaling repression, efflux transporter reversal and apoptosis induction. Our study thus provides a powerful regimen for circumventing MDR in colon cancer cells.
[Mh] Termos MeSH primário: Antibióticos Antineoplásicos/farmacologia
Neoplasias Colorretais/patologia
Resistência a Múltiplos Medicamentos/efeitos dos fármacos
Resistência a Medicamentos Antineoplásicos/efeitos dos fármacos
Proteína Semelhante a ELAV 1/fisiologia
Epirubicina/farmacologia
[Mh] Termos MeSH secundário: Apoptose/efeitos dos fármacos
Western Blotting
Linhagem Celular Tumoral
Neoplasias Colorretais/tratamento farmacológico
Neoplasias Colorretais/metabolismo
Proteína Semelhante a ELAV 1/genética
Inativação Gênica
Seres Humanos
Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética
Espécies Reativas de Oxigênio/metabolismo
Reação em Cadeia da Polimerase em Tempo Real
Reação em Cadeia da Polimerase Via Transcriptase Reversa
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antibiotics, Antineoplastic); 0 (ELAV-Like Protein 1); 0 (Multidrug Resistance-Associated Proteins); 0 (Reactive Oxygen Species); 3Z8479ZZ5X (Epirubicin)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171031
[Lr] Data última revisão:
171031
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171003
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0185625


  10 / 5289 MEDLINE  
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[PMID]:28953988
[Au] Autor:Wang YH; Ke XM; Zhang CH; Yang RP
[Ad] Endereço:Chongqing Academy of Chinese Materia Medica, Chongqing, China.
[Ti] Título:Absorption mechanism of three curcumin constituents through in situ intestinal perfusion method.
[So] Source:Braz J Med Biol Res;50(11):e6353, 2017 Sep 21.
[Is] ISSN:1414-431X
[Cp] País de publicação:Brazil
[La] Idioma:eng
[Ab] Resumo:This study aimed to investigate the absorption mechanism of three curcumin constituents in rat small intestines. Self-emulsification was used to solubilize the three curcumin constituents, and the rat in situ intestinal perfusion method was used to study factors on drug absorption, including drug mass concentration, absorption site, and the different types and concentrations of absorption inhibitors. Within the scope of experimental concentrations, three curcumin constituents were absorbed in rat small intestines through the active transport mechanism.
[Mh] Termos MeSH primário: Adjuvantes Farmacêuticos/farmacologia
Curcumina/análogos & derivados
Curcumina/farmacocinética
Inibidores Enzimáticos/farmacocinética
Absorção Intestinal
Intestino Delgado/metabolismo
[Mh] Termos MeSH secundário: 2,4-Dinitrofenol/farmacocinética
Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores
Animais
Cromatografia Líquida de Alta Pressão/métodos
Curcumina/química
Emulsões
Feminino
Absorção Intestinal/efeitos dos fármacos
Intestino Delgado/efeitos dos fármacos
Masculino
Proteínas Associadas à Resistência a Múltiplos Medicamentos/análise
Proteínas Associadas à Resistência a Múltiplos Medicamentos/antagonistas & inibidores
Imagem de Perfusão/métodos
Probenecid/farmacologia
Ratos Sprague-Dawley
Valores de Referência
Reprodutibilidade dos Testes
Fatores de Tempo
Desacopladores/farmacologia
Verapamil/farmacologia
[Pt] Tipo de publicação:EVALUATION STUDIES; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Abcc2 protein, rat); 0 (Adjuvants, Pharmaceutic); 0 (Emulsions); 0 (Enzyme Inhibitors); 0 (Multidrug Resistance-Associated Proteins); 0 (Uncoupling Agents); 2EFO1BP34R (bis(4-hydroxycinnamoyl)methane); 4AF605U6JN (multidrug resistance-associated protein 2); CJ0O37KU29 (Verapamil); IT942ZTH98 (Curcumin); PO572Z7917 (Probenecid); Q13SKS21MN (2,4-Dinitrophenol); W2F8059T80 (demethoxycurcumin)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171006
[Lr] Data última revisão:
171006
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170928
[St] Status:MEDLINE



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