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Pesquisa : D03.383.663.283.446.520.203 [Categoria DeCS]
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  1 / 1196 MEDLINE  
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[PMID]:28891315
[Au] Autor:Kammari K; Devaraya K; Bommakanti A; Kondapi AK
[Ad] Endereço:Department of Biotechnology & Bioinformatics, School of Life Sciences, University of Hyderabad.
[Ti] Título:Development of pyridine dicoumarols as potent anti HIV-1 leads, targeting HIV-1 associated topoisomeraseIIß kinase.
[So] Source:Future Med Chem;9(14):1597-1609, 2017 Sep.
[Is] ISSN:1756-8927
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:AIM: A structural study of a series of pyridine dicoumarol derivatives with potential activity against a novel Topoisomerase IIß kinase which was identified in the HIV-1 viral lysate, compounds were designed and synthesized based on a 3D-QSAR study. MATERIALS & METHODS: Based on QSAR model we have designed and synthesized a series of pyridine dicoumarol derivatives and characterized by spectral studies, all the molecules are biologically evaluated by kinase assay, cytotoxicity assay, ELISA and PCR method. RESULT: We demonstrated the achievement of water soluble disodium pyridine dicoumarate derivatives showing high anti-HIV-1 activity (IC <25 nM) which provides a crucial point for further development of pyridine dicoumarol series as HIV-1-associated topoisomerase IIß kinase inhibitors for clinical application against AIDS. CONCLUSION: A new class of anti-HIV-1 lead compounds have been designed and tested. Further studies would result in development of  novel and potential drugs.
[Mh] Termos MeSH primário: DNA Topoisomerases Tipo II/metabolismo
Proteínas de Ligação a DNA/metabolismo
Dicumarol/metabolismo
HIV-1/enzimologia
Inibidores da Topoisomerase II/metabolismo
[Mh] Termos MeSH secundário: Fármacos Anti-HIV/química
Fármacos Anti-HIV/metabolismo
Fármacos Anti-HIV/toxicidade
Linhagem Celular
Sobrevivência Celular/efeitos dos fármacos
Proteínas de Ligação a DNA/antagonistas & inibidores
Dicumarol/química
Dicumarol/farmacologia
Desenho de Drogas
Ensaio de Imunoadsorção Enzimática
Proteína do Núcleo p24 do HIV/antagonistas & inibidores
Proteína do Núcleo p24 do HIV/metabolismo
HIV-1/efeitos dos fármacos
Seres Humanos
Piridinas/química
Relação Quantitativa Estrutura-Atividade
Inibidores da Topoisomerase II/química
Inibidores da Topoisomerase II/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anti-HIV Agents); 0 (DNA-Binding Proteins); 0 (HIV Core Protein p24); 0 (Pyridines); 0 (Topoisomerase II Inhibitors); 7QID3E7BG7 (Dicumarol); EC 5.99.1.3 (DNA Topoisomerases, Type II); NH9L3PP67S (pyridine)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170912
[St] Status:MEDLINE
[do] DOI:10.4155/fmc-2017-0091


  2 / 1196 MEDLINE  
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[PMID]:28617852
[Au] Autor:Zhang W; Su J; Xu H; Yu S; Liu Y; Zhang Y; Sun L; Yue Y; Zhou X
[Ad] Endereço:Department of Gynecological Oncology, The First Hospital of Jilin University, Changchun, China.
[Ti] Título:Dicumarol inhibits PDK1 and targets multiple malignant behaviors of ovarian cancer cells.
[So] Source:PLoS One;12(6):e0179672, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Pyruvate dehydrogenase kinase 1 (PDK1) is overexpressed in ovarian cancer and thus is a promising anticancer therapeutic target. Our previous work suggests that coumarin compounds are potential inhibitors of PDKs. In this study, we used the ovarian cancer cell line SKOV3 as the model system and examined whether dicumarol (DIC), a coumarin compound, could inhibit ovarian cancer through targeting PDK1. We showed that DIC potently inhibited the kinase activity of PDK1, shifted the glucose metabolism from aerobic glycolysis to oxidative phosphorylation, generated a higher level of reactive oxygen species (ROS), attenuated the mitochondrial membrane potential (MMP), induced apoptosis, and reduced cell viability in vitro. The same phenotypes induced by DIC also were translated in vivo, leading to significant suppression of xenograft growth. This study not only identifies a novel inhibitor for PDK1, but it also reveals novel anticancer mechanisms of DIC and provides a promising anticancer therapy that targets the Warburg effect.
[Mh] Termos MeSH primário: Dicumarol/farmacologia
Proteínas de Neoplasias/antagonistas & inibidores
Neoplasias Ovarianas/enzimologia
Proteínas Serina-Treonina Quinases/antagonistas & inibidores
[Mh] Termos MeSH secundário: Apoptose/efeitos dos fármacos
Linhagem Celular Tumoral
Sobrevivência Celular/efeitos dos fármacos
Feminino
Glucose/metabolismo
Glicólise/efeitos dos fármacos
Seres Humanos
Membranas Mitocondriais/efeitos dos fármacos
Proteínas de Neoplasias/metabolismo
Neoplasias Ovarianas/tratamento farmacológico
Neoplasias Ovarianas/patologia
Proteínas Serina-Treonina Quinases/metabolismo
Espécies Reativas de Oxigênio/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Neoplasm Proteins); 0 (Reactive Oxygen Species); 7QID3E7BG7 (Dicumarol); EC 2.7.11.1 (Protein-Serine-Threonine Kinases); EC 2.7.11.2 (pyruvate dehydrogenase (acetyl-transferring) kinase); IY9XDZ35W2 (Glucose)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170913
[Lr] Data última revisão:
170913
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170616
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0179672


  3 / 1196 MEDLINE  
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[PMID]:28411284
[Au] Autor:Fiorillo M; Sotgia F; Sisci D; Cappello AR; Lisanti MP
[Ad] Endereço:The Department of Pharmacy, Health and Nutritional Sciences, The University of Calabria, Cosenza, 87100, Italy.
[Ti] Título:Mitochondrial "power" drives tamoxifen resistance: NQO1 and GCLC are new therapeutic targets in breast cancer.
[So] Source:Oncotarget;8(12):20309-20327, 2017 Mar 02.
[Is] ISSN:1949-2553
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Here, we identified two new molecular targets, which are functionally sufficient to metabolically confer the tamoxifen-resistance phenotype in human breast cancer cells. Briefly, ~20 proteins were first selected as potential candidates, based on unbiased proteomics analysis, using tamoxifen-resistant cell lines. Then, the cDNAs of the most promising candidates were systematically transduced into MCF-7 cells. Remarkably, NQO1 and GCLC were both functionally sufficient to autonomously confer a tamoxifen-resistant metabolic phenotype, characterized by i) increased mitochondrial biogenesis, ii) increased ATP production and iii) reduced glutathione levels. Thus, we speculate that pharmacological inhibition of NQO1 and GCLC may be new therapeutic strategies for overcoming tamoxifen-resistance in breast cancer patients. In direct support of this notion, we demonstrate that treatment with a known NQO1 inhibitor (dicoumarol) is indeed sufficient to revert the tamoxifen-resistance phenotype. As such, these findings could have important translational significance for the prevention of tumor recurrence in ER(+) breast cancers, which is due to an endocrine resistance phenotype. Importantly, we also show here that NQO1 has significant prognostic value as a biomarker for the prediction of tumor recurrence. More specifically, higher levels of NQO1 mRNA strongly predict patient relapse in high-risk ER(+) breast cancer patients receiving endocrine therapy (mostly tamoxifen; H.R. > 2.15; p = 0.007).
[Mh] Termos MeSH primário: Antineoplásicos Hormonais/farmacologia
Neoplasias da Mama/tratamento farmacológico
Resistência a Medicamentos Antineoplásicos/genética
Glutamato-Cisteína Ligase/antagonistas & inibidores
NAD(P)H Desidrogenase (Quinona)/antagonistas & inibidores
Tamoxifeno/farmacologia
[Mh] Termos MeSH secundário: Apoptose/efeitos dos fármacos
Biomarcadores Tumorais/genética
Neoplasias da Mama/patologia
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Dicumarol/farmacologia
Inibidores Enzimáticos/farmacologia
Feminino
Glutamato-Cisteína Ligase/genética
Seres Humanos
Células MCF-7
Mitocôndrias/metabolismo
NAD(P)H Desidrogenase (Quinona)/genética
Recidiva Local de Neoplasia/genética
Prognóstico
Proteômica/métodos
RNA Mensageiro/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents, Hormonal); 0 (Biomarkers, Tumor); 0 (Enzyme Inhibitors); 0 (RNA, Messenger); 094ZI81Y45 (Tamoxifen); 7QID3E7BG7 (Dicumarol); EC 1.6.5.2 (NAD(P)H Dehydrogenase (Quinone)); EC 1.6.5.2 (NQO1 protein, human); EC 6.3.2.2 (GCLC protein, human); EC 6.3.2.2 (Glutamate-Cysteine Ligase)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170505
[Lr] Data última revisão:
170505
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170416
[St] Status:MEDLINE
[do] DOI:10.18632/oncotarget.15852


  4 / 1196 MEDLINE  
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[PMID]:28166408
[Au] Autor:Dempah KE; Lubach JW; Munson EJ
[Ad] Endereço:Department of Pharmaceutical Chemistry, University of Kansas , 2095 Constant Drive, Lawrence, Kansas 66047, United States.
[Ti] Título:Characterization of the Particle Size and Polydispersity of Dicumarol Using Solid-State NMR Spectroscopy.
[So] Source:Mol Pharm;14(3):856-865, 2017 Mar 06.
[Is] ISSN:1543-8392
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:A variety of particle sizes of a model compound, dicumarol, were prepared and characterized in order to investigate the correlation between particle size and solid-state NMR (SSNMR) proton spin-lattice relaxation ( H T ) times. Conventional laser diffraction and scanning electron microscopy were used as particle size measurement techniques and showed crystalline dicumarol samples with sizes ranging from tens of micrometers to a few micrometers. Dicumarol samples were prepared using both bottom-up and top-down particle size control approaches, via antisolvent microprecipitation and cryogrinding. It was observed that smaller particles of dicumarol generally had shorter H T times than larger ones. Additionally, cryomilled particles had the shortest H T times encountered (8 s). SSNMR H T times of all the samples were measured and showed as-received dicumarol to have a T of 1500 s, whereas the H T times of the precipitated samples ranged from 20 to 80 s, with no apparent change in the physical form of dicumarol. Physical mixtures of different sized particles were also analyzed to determine the effect of sample inhomogeneity on H T values. Mixtures of cryoground and as-received dicumarol were clearly inhomogeneous as they did not fit well to a one-component relaxation model, but could be fit much better to a two-component model with both fast-and slow-relaxing regimes. Results indicate that samples of crystalline dicumarol containing two significantly different particle size populations could be deconvoluted solely based on their differences in H T times. Relative populations of each particle size regime could also be approximated using two-component fitting models. Using NMR theory on spin diffusion as a reference, and taking into account the presence of crystal defects, a model for the correlation between the particle size of dicumarol and its H T time was proposed.
[Mh] Termos MeSH primário: Dicumarol/química
[Mh] Termos MeSH secundário: Precipitação Química
Espectroscopia de Ressonância Magnética/métodos
Microscopia Eletrônica de Varredura/métodos
Tamanho da Partícula
Prótons
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Protons); 7QID3E7BG7 (Dicumarol)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171024
[Lr] Data última revisão:
171024
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170207
[St] Status:MEDLINE
[do] DOI:10.1021/acs.molpharmaceut.6b01073


  5 / 1196 MEDLINE  
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[PMID]:28159415
[Au] Autor:Xu X; Fang X; Wang J; Zhu H
[Ad] Endereço:School of Chemistry and Chemical Engineering, Yancheng Teachers University, Yancheng, China. Electronic address: xxjyctu@163.com.
[Ti] Título:Identification of novel ROS inducer by merging the fragments of piperlongumine and dicoumarol.
[So] Source:Bioorg Med Chem Lett;27(5):1325-1328, 2017 Mar 01.
[Is] ISSN:1464-3405
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:A series of novel ROS inducers were designed by merging the fragments of piperlongumine and dicoumarol. Most of these derivatives showed potent in vitro activity against three cancer cell lines and good selectivity towards normal lung cells. The most potent and selective compound 3e was proven to exhibit obvious ROS elevation and excellent in vivo antitumor activity with suppressed tumor growth by 48.46% at the dose of 5mg/kg. Supported by these investigation, these findings encourage further investigation around this interesting antitumor chemotype.
[Mh] Termos MeSH primário: Antineoplásicos/síntese química
Antineoplásicos/farmacologia
Dicumarol/química
Dioxolanos/química
Espécies Reativas de Oxigênio
[Mh] Termos MeSH secundário: Células A549
Animais
Antineoplásicos/química
Proliferação Celular/efeitos dos fármacos
Dicumarol/síntese química
Dicumarol/farmacologia
Dioxolanos/síntese química
Dioxolanos/farmacologia
Ensaios de Seleção de Medicamentos Antitumorais
Xenoenxertos
Seres Humanos
Concentração Inibidora 50
Camundongos
Estrutura Molecular
Espécies Reativas de Oxigênio/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Dioxolanes); 0 (Reactive Oxygen Species); 7QID3E7BG7 (Dicumarol); HN39MC8KIO (piperlonguminine)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171017
[Lr] Data última revisão:
171017
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170205
[St] Status:MEDLINE


  6 / 1196 MEDLINE  
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[PMID]:27986568
[Au] Autor:Kolossov VL; Ponnuraj N; Beaudoin JN; Leslie MT; Kenis PJ; Gaskins HR
[Ad] Endereço:Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, United States. Electronic address: viadimer@illinois.edu.
[Ti] Título:Distinct responses of compartmentalized glutathione redox potentials to pharmacologic quinones targeting NQO1.
[So] Source:Biochem Biophys Res Commun;483(1):680-686, 2017 Jan 29.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Deoxynyboquinone (DNQ), a potent novel quinone-based antineoplastic agent, selectively kills solid cancers with overexpressed cytosolic NAD(P)H:quinone oxidoreductase-1 (NQO1) via excessive ROS production. A genetically encoded redox-sensitive probe was used to monitor intraorganellar glutathione redox potentials (E ) as a direct indicator of cellular oxidative stress following chemotherapeutic administration. Beta-lapachone (ß-lap) and DNQ-induced spatiotemporal redox responses were monitored in human lung A549 and pancreatic MIA-PaCa-2 adenocarcinoma cells incubated with or without dicumarol and ES936, potent NQO1 inhibitors. Immediate oxidation of E in both the cytosol and mitochondrial matrix was observed in response to DNQ and ß-lap. The DNQ-induced cytosolic oxidation was fully prevented with NQO1 inhibition, whereas mitochondrial oxidation in A549 was NQO1-independent in contrast to MIA-PaCa-2 cells. However, at pharmacologic concentrations of ß-lap both quinone-based substrates directly oxidized the redox probe, a possible sign of off-target reactivity with cellular thiols. Together, these data provide new evidence that DNQ's direct and discerning NQO1 substrate specificity underlies its pharmacologic potency, while ß-lap elicits off-target responses at its effective doses.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Glutationa/metabolismo
NAD(P)H Desidrogenase (Quinona)/metabolismo
Estresse Oxidativo/efeitos dos fármacos
Quinonas/farmacologia
[Mh] Termos MeSH secundário: Técnicas Biossensoriais
Linhagem Celular Tumoral
Citosol/efeitos dos fármacos
Citosol/metabolismo
Dicumarol/farmacologia
Corantes Fluorescentes/análise
Glutarredoxinas/análise
Glutarredoxinas/genética
Glutationa/análise
Proteínas de Fluorescência Verde/análise
Proteínas de Fluorescência Verde/genética
Seres Humanos
Indolquinonas/farmacologia
Mitocôndrias/efeitos dos fármacos
Mitocôndrias/metabolismo
Imagem Molecular
Sondas Moleculares/genética
Terapia de Alvo Molecular
NAD(P)H Desidrogenase (Quinona)/antagonistas & inibidores
Naftoquinonas/metabolismo
Oxirredução/efeitos dos fármacos
Espécies Reativas de Oxigênio/metabolismo
Especificidade por Substrato
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (5-methoxy-1,2-dimethyl-3-((4-nitrophenoxy)methyl)indole-4,7-dione); 0 (Antineoplastic Agents); 0 (Fluorescent Dyes); 0 (Glutaredoxins); 0 (Indolequinones); 0 (Molecular Probes); 0 (Naphthoquinones); 0 (Quinones); 0 (Reactive Oxygen Species); 0 (deoxynyboquinone); 147336-22-9 (Green Fluorescent Proteins); 4707-32-8 (beta-lapachone); 7QID3E7BG7 (Dicumarol); EC 1.6.5.2 (NAD(P)H Dehydrogenase (Quinone)); EC 1.6.5.2 (NQO1 protein, human); GAN16C9B8O (Glutathione)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170529
[Lr] Data última revisão:
170529
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161218
[St] Status:MEDLINE


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[PMID]:26201483
[Au] Autor:Timson DJ
[Ad] Endereço:School of Biological Sciences, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7BL, United Kingdom.
[Ti] Título:Dicoumarol: A Drug which Hits at Least Two Very Different Targets in Vitamin K Metabolism.
[So] Source:Curr Drug Targets;18(5):500-510, 2017.
[Is] ISSN:1873-5592
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Dicoumarol, a symmetrical biscoumarin can be considered as the "parent" of the widely used anticoagulant drug, warfarin. The discovery of dicoumarol's bioactive properties resulted from an investigation into a mysterious cattle disease in the 1940s. It was then developed as a pharmaceutical, but was superseded in the 1950s by warfarin. Both dicoumarol and warfarin antagonise the blood clotting process through inhibition of vitamin K epoxide reductase (VKOR). This blocks the recycling of vitamin K and prevents the γ-carboxylation of glutamate residues in clotting factors. VKOR is an integral membrane protein and our understanding of the molecular mechanism of action of dicoumarol and warfarin is hampered by the lack of a three dimensional structure. There is consequent controversy about the membrane topology of VKOR, the location of the binding site for coumarin inhibitors and the mechanism of inhibition by these compounds. Dicoumarol (and warfarin) also inhibit a second enzyme, NAD(P)H quinone oxidoreductase 1 (NQO1). This soluble, cytoplasmic enzyme may also play a minor role in the recycling of vitamin K. However, its main cellular roles as an enzyme appear to be detoxification and the prevention of the build-up of reactive oxygen species. NQO1 is well characterised biochemically and structurally. Consequently, structure-based drug design has identified NQO1 inhibitors which have potential for the development of anti-cancer drugs. Many of these compounds are structurally related to dicoumarol and some have reduced "off target" effects. Therefore, it is possible that dicoumarol will become the "parent" of a second group of drugs.
[Mh] Termos MeSH primário: Dicumarol/farmacologia
NAD(P)H Desidrogenase (Quinona)/antagonistas & inibidores
Vitamina K Epóxido Redutases/antagonistas & inibidores
Vitamina K/metabolismo
[Mh] Termos MeSH secundário: Animais
Antineoplásicos/farmacologia
Dicumarol/química
Inibidores Enzimáticos/farmacologia
Seres Humanos
Modelos Moleculares
NAD(P)H Desidrogenase (Quinona)/química
Espécies Reativas de Oxigênio/metabolismo
Relação Estrutura-Atividade
Vitamina K Epóxido Redutases/química
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Enzyme Inhibitors); 0 (Reactive Oxygen Species); 12001-79-5 (Vitamin K); 7QID3E7BG7 (Dicumarol); EC 1.17.4.4 (Vitamin K Epoxide Reductases); EC 1.6.5.2 (NAD(P)H Dehydrogenase (Quinone)); EC 1.6.5.2 (NQO1 protein, human)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170913
[Lr] Data última revisão:
170913
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150724
[St] Status:MEDLINE
[do] DOI:10.2174/1389450116666150722141906


  8 / 1196 MEDLINE  
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[PMID]:27653744
[Au] Autor:He DX; Gu F; Wu J; Gu XT; Lu CX; Mao AQ; Zhang GY; Ding ZY; Wang JK; Hao JJ; Fu L; Ma X
[Ad] Endereço:National Engineering Laboratory for Cereal Fermentation Technology, Jiangnan University, Wuxi 214122, China.
[Ti] Título:Targeting PSG1 to enhance chemotherapeutic efficacy: new application for anti-coagulant the dicumarol.
[So] Source:Clin Sci (Lond);130(24):2267-2276, 2016 Dec 01.
[Is] ISSN:1470-8736
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Chemotherapeutic response is critical for the successful treatment and good prognosis in cancer patients. In this study, we analysed the gene expression profiles of preoperative samples from oestrogen receptor (ER)-negative breast cancer patients with different responses to taxane-anthracycline-based (TA-based) chemotherapy, and identified a group of genes that was predictive. Pregnancy specific beta-1-glycoprotein 1 (PSG1) played a central role within signalling pathways of these genes. Inhibiting PSG1 can effectively reduce chemoresistance via a transforming growth factor-ß (TGF-ß)-related pathway in ER-negative breast cancer cells. Drug screening then identified dicumarol (DCM) to target the PSG1 and inhibit chemoresistance to TA-based chemotherapy in vitro, in vivo, and in clinical samples. Taken together, this study highlights PSG1 as an important mediator of chemoresistance, whose effect could be diminished by DCM.
[Mh] Termos MeSH primário: Anticoagulantes/uso terapêutico
Neoplasias da Mama/genética
Dicumarol/uso terapêutico
Glicoproteínas beta 1 Específicas da Gravidez/antagonistas & inibidores
[Mh] Termos MeSH secundário: Neoplasias da Mama/tratamento farmacológico
Neoplasias da Mama/metabolismo
Hidrocarbonetos Aromáticos com Pontes/uso terapêutico
Linhagem Celular Tumoral
Resistência a Medicamentos Antineoplásicos
Feminino
Seres Humanos
Glicoproteínas beta 1 Específicas da Gravidez/genética
Glicoproteínas beta 1 Específicas da Gravidez/metabolismo
Taxoides/uso terapêutico
Fator de Crescimento Transformador beta/genética
Fator de Crescimento Transformador beta/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anticoagulants); 0 (Bridged-Ring Compounds); 0 (Pregnancy-Specific beta 1-Glycoproteins); 0 (Taxoids); 0 (Transforming Growth Factor beta); 1605-68-1 (taxane); 7QID3E7BG7 (Dicumarol)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170630
[Lr] Data última revisão:
170630
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160923
[St] Status:MEDLINE


  9 / 1196 MEDLINE  
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[PMID]:26969764
[Au] Autor:Wang L; Hu T; Shen J; Zhang L; Li LF; Chan RL; Li MX; Wu WK; Cho CH
[Ad] Endereço:School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China; Beijing Key Laboratory of Drug Targets Research and New Drug Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100050, China. El
[Ti] Título:Miltirone induced mitochondrial dysfunction and ROS-dependent apoptosis in colon cancer cells.
[So] Source:Life Sci;151:224-234, 2016 Apr 15.
[Is] ISSN:1879-0631
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:AIMS: To study the characteristics of miltirone-induced anti-colon cancer effects. MATERIALS AND METHODS: Cell viability was detected using MTT assay. LDH (lactate dehydrogenase) leakage was detected using CytoTox96® non-radioactive cytotoxicity kit. Apoptosis was detected by FCM (flow cytometry). Caspase activation was determined by chemiluminescence or western blotting. AIF (apoptosis-inducing factor) expression in the cell fraction was determined by western blotting. ROS (reactive oxygen species), MMP (mitochondrial membrane potential) and mitochondrial mass were determined by confocal microscope. Intracellular calcium was detected by both FCM and confocal microscope. To determine the roles of ROS and Ca(2+) in the pro-apoptotic activity of miltirone, colon cancer cells were pretreated with kinds of antioxidants, dicoumarol, calpeptin or BAPTA-AM in some cases. KEY FINDINGS: Miltirone exhibited potent cytotoxicity on colon cancer cells with a better selectivity than that of dihydrotanshinone. The pro-apoptotic activity of miltirone was p53- and ROS-dependent. In detail, miltirone induced direct mitochondrial damage, including significant decrease of mitochondrial ROS, MMP, mass and increase of intracellular ROS and Ca(2+). NQO1 (quinone oxidoreductase1) was supposed to be a defender for the cytotoxicity induced by miltirone in colon cancer cells. Furthermore, miltirone induced time- and concentration-dependent translocation of AIF and activation of caspases. SIGNIFICANCE: In this study, ROS- and p53-dependent apoptosis induced by miltirone on colon cancer cells was firstly revealed. Strong positive feedback between mitochondrial dysfunction and accumulation of intracellular Ca(2+) was suggested to be the characteristic of the anti-colon cancer activity of miltirone.
[Mh] Termos MeSH primário: Apoptose/efeitos dos fármacos
Neoplasias do Colo/metabolismo
Neoplasias do Colo/patologia
Mitocôndrias/efeitos dos fármacos
Mitocôndrias/patologia
Fenantrenos/farmacologia
Espécies Reativas de Oxigênio/metabolismo
[Mh] Termos MeSH secundário: Fator de Indução de Apoptose/metabolismo
Cálcio/metabolismo
Caspases/metabolismo
Linhagem Celular Tumoral
Sobrevivência Celular/efeitos dos fármacos
Dicumarol/farmacologia
Seres Humanos
L-Lactato Desidrogenase/metabolismo
Potencial da Membrana Mitocondrial/efeitos dos fármacos
NAD(P)H Desidrogenase (Quinona)
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Apoptosis Inducing Factor); 0 (Phenanthrenes); 0 (Reactive Oxygen Species); 27210-57-7 (miltirone); 7QID3E7BG7 (Dicumarol); EC 1.1.1.27 (L-Lactate Dehydrogenase); EC 1.6.5.2 (NAD(P)H Dehydrogenase (Quinone)); EC 1.6.5.2 (NQO1 protein, human); EC 3.4.22.- (Caspases); SY7Q814VUP (Calcium)
[Em] Mês de entrada:1702
[Cu] Atualização por classe:170912
[Lr] Data última revisão:
170912
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160313
[St] Status:MEDLINE


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[PMID]:26838129
[Au] Autor:Encarnación MC; Palomino-Morales RJ; Fuchs JE; Esperanza PG; Noel MT; Salido E; Timson DJ; Pey AL
[Ad] Endereço:Department of Physical Chemistry, Faculty of Sciences, University of Granada, Granada, Spain.
[Ti] Título:Conformational dynamics is key to understanding loss-of-function of NQO1 cancer-associated polymorphisms and its correction by pharmacological ligands.
[So] Source:Sci Rep;6:20331, 2016 Feb 03.
[Is] ISSN:2045-2322
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Protein dynamics is essential to understand protein function and stability, even though is rarely investigated as the origin of loss-of-function due to genetic variations. Here, we use biochemical, biophysical, cell and computational biology tools to study two loss-of-function and cancer-associated polymorphisms (p.R139W and p.P187S) in human NAD(P)H quinone oxidoreductase 1 (NQO1), a FAD-dependent enzyme which activates cancer pro-drugs and stabilizes several oncosuppressors. We show that p.P187S strongly destabilizes the NQO1 dimer in vitro and increases the flexibility of the C-terminal domain, while a combination of FAD and the inhibitor dicoumarol overcome these alterations. Additionally, changes in global stability due to polymorphisms and ligand binding are linked to the dynamics of the dimer interface, whereas the low activity and affinity for FAD in p.P187S is caused by increased fluctuations at the FAD binding site. Importantly, NQO1 steady-state protein levels in cell cultures correlate primarily with the dynamics of the C-terminal domain, supporting a directional preference in NQO1 proteasomal degradation and the use of ligands binding to this domain to stabilize p.P187S in vivo. In conclusion, protein dynamics are fundamental to understanding loss-of-function in p.P187S, and to develop new pharmacological therapies to rescue this function.
[Mh] Termos MeSH primário: Dicumarol/farmacologia
Flavina-Adenina Dinucleotídeo/farmacologia
NAD(P)H Desidrogenase (Quinona)/química
NAD(P)H Desidrogenase (Quinona)/genética
Neoplasias/genética
Polimorfismo de Nucleotídeo Único
[Mh] Termos MeSH secundário: Sítios de Ligação/efeitos dos fármacos
Células CACO-2
Cristalografia por Raios X
Estabilidade Enzimática/efeitos dos fármacos
Células HCT116
Células HeLa
Seres Humanos
NAD(P)H Desidrogenase (Quinona)/metabolismo
Ligação Proteica/efeitos dos fármacos
Conformação Proteica/efeitos dos fármacos
Multimerização Proteica
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
146-14-5 (Flavin-Adenine Dinucleotide); 7QID3E7BG7 (Dicumarol); EC 1.6.5.2 (NAD(P)H Dehydrogenase (Quinone)); EC 1.6.5.2 (NQO1 protein, human)
[Em] Mês de entrada:1701
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160204
[St] Status:MEDLINE
[do] DOI:10.1038/srep20331



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