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[PMID]:28176244
[Au] Autor:Schneider NF; Silva IT; Persich L; de Carvalho A; Rocha SC; Marostica L; Ramos AC; Taranto AG; Pádua RM; Kreis W; Barbosa LA; Braga FC; Simões CM
[Ad] Endereço:Departamento de Ciências Farmacêuticas, Centro de Ciências da Saúde, Universidade Federal de Santa Catarina (UFSC), LVA, CIF, CCS, Florianópolis,, SC, 88040-900, Brazil.
[Ti] Título:Cytotoxic effects of the cardenolide convallatoxin and its Na,K-ATPase regulation.
[So] Source:Mol Cell Biochem;428(1-2):23-39, 2017 Apr.
[Is] ISSN:1573-4919
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Cardenolides are cardiac glycosides, mostly obtained from natural sources. They are well known for their inhibitory action on the Na,K-ATPase, an effect that regulates cardiovascular alterations such as congestive heart failure and atrial arrhythmias. In recent years, they have also sparked new interest in their anticancer potential. In the present study, the cytotoxic effects of the natural cardenolide convallatoxin (CON) were evaluated on non-small cell lung cancer (A549 cells). It was found that CON induced cytostatic and cytotoxic effects in A549 cells, showing essentially apoptotic cell death, as detected by annexin V-propidium iodide double-staining, as well as changes in cell form. In addition, it prompted cell cycle arrest in G2/M and reduced cyclin B1 expression. This compound also increased the number of cells in subG1 in a concentration- and time-dependent manner. At a long term, the reduction of cumulative population doubling was shown along with an increase of ß-galactosidase positive cells and larger nucleus, indicative of senescence. Subsequently, CON inhibited the Na,K-ATPase in A549 cells at nM concentrations. Interestingly, at the same concentrations, CON was unable to directly inhibit the Na,K-ATPase, either in pig kidney or in red blood cells. Additionally, results of docking calculations showed that CON binds with high efficiency to the Na,K-ATPase. Taken together, our data highlight the potent anticancer effects of CON in A549 cells, and their possible link with non-classical inhibition of Na,K-ATPase.
[Mh] Termos MeSH primário: Antineoplásicos Fitogênicos/farmacologia
Carcinoma Pulmonar de Células não Pequenas/metabolismo
Neoplasias Pulmonares/metabolismo
ATPase Trocadora de Sódio-Potássio/metabolismo
Estrofantinas/farmacologia
[Mh] Termos MeSH secundário: Células A549
Animais
Apoptose
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico
Proliferação Celular/efeitos dos fármacos
Sobrevivência Celular/efeitos dos fármacos
Relação Dose-Resposta a Droga
Eritrócitos/efeitos dos fármacos
Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos
Seres Humanos
Rim/efeitos dos fármacos
Rim/enzimologia
Neoplasias Pulmonares/tratamento farmacológico
Simulação de Acoplamento Molecular
ATPase Trocadora de Sódio-Potássio/química
Suínos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents, Phytogenic); 0 (Strophanthins); EC 3.6.3.9 (Sodium-Potassium-Exchanging ATPase); JY264VIR1Y (convallatoxin)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:171030
[Lr] Data última revisão:
171030
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170209
[St] Status:MEDLINE
[do] DOI:10.1007/s11010-016-2914-8


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[PMID]:27662422
[Au] Autor:Kaushik V; Yakisich JS; Azad N; Kulkarni Y; Venkatadri R; Wright C; Rojanasakul Y; Iyer AKV
[Ad] Endereço:Department of Pharmaceutical Sciences, Hampton University School of Pharmacy, Hampton, Virginia.
[Ti] Título:Anti-Tumor Effects of Cardiac Glycosides on Human Lung Cancer Cells and Lung Tumorspheres.
[So] Source:J Cell Physiol;232(9):2497-2507, 2017 Sep.
[Is] ISSN:1097-4652
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Lung cancer is a leading cause of cancer-related death in the United States. Although several drugs have been developed that target individual biomarkers, their success has been limited due to intrinsic or acquired resistance for the specific targets of such drugs. A more effective approach is to target multiple pathways that dictate cancer progression. Cardiac glycosides demonstrate such multimodal effects on cancer cell survival, and our aim was to evaluate the effect of two naturally occurring monosaccaridic cardiac glycosides-Convallatoxin and Peruvoside on lung cancer cells. Although both drugs had significant anti-proliferative effects on H460 and Calu-3 lung cancer cells, Convallatoxin demonstrated twofold higher activity as compared to Peruvoside using both viability and colony forming assays, suggesting a role for the aglycone region in dictating drug potency. The tumor suppressor p53 was found to be important for action of both drugs-p53-underexpressing cells were less sensitive as compared to p53-positive H460 cells. Further, assessment of p53-underexpressing H460 cells showed that drugs were able to arrest cells in the G0/G1 phase of the cell cycle in a dose-dependent manner. Both drugs significantly inhibited migration and invasion of cancer cells and decreased the viability of floating tumorspheres. An assessment of intracellular pathways indicated that both drugs were able to modulate proteins that are involved in apoptosis, autophagy, cell cycle, proliferation, and EMT. Our data suggest, a promising role for cardiac glycosides in lung cancer treatment, and provides impetus for further investigation of the anti-cancer potential of this class of drugs. J. Cell. Physiol. 232: 2497-2507, 2017. © 2016 Wiley Periodicals, Inc.
[Mh] Termos MeSH primário: Antineoplásicos Fitogênicos/farmacologia
Cardenolídeos/farmacologia
Movimento Celular/efeitos dos fármacos
Proliferação Celular/efeitos dos fármacos
Neoplasias Pulmonares/tratamento farmacológico
Estrofantinas/farmacologia
[Mh] Termos MeSH secundário: Apoptose/efeitos dos fármacos
Autofagia/efeitos dos fármacos
Pontos de Checagem do Ciclo Celular/efeitos dos fármacos
Linhagem Celular Tumoral
Sobrevivência Celular/efeitos dos fármacos
Relação Dose-Resposta a Droga
Transição Epitelial-Mesenquimal/efeitos dos fármacos
Seres Humanos
Neoplasias Pulmonares/genética
Neoplasias Pulmonares/metabolismo
Neoplasias Pulmonares/patologia
Invasividade Neoplásica
Esferoides Celulares
Proteína Supressora de Tumor p53/genética
Proteína Supressora de Tumor p53/metabolismo
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents, Phytogenic); 0 (Cardenolides); 0 (Strophanthins); 0 (TP53 protein, human); 0 (Tumor Suppressor Protein p53); CT36KGC6A6 (cannogenin thevetoside); JY264VIR1Y (convallatoxin)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160924
[St] Status:MEDLINE
[do] DOI:10.1002/jcp.25611


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[PMID]:27654292
[Au] Autor:Cohen T; Williams JD; Opperman TJ; Sanchez R; Lurain NS; Tortorella D
[Ad] Endereço:Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
[Ti] Título:Convallatoxin-Induced Reduction of Methionine Import Effectively Inhibits Human Cytomegalovirus Infection and Replication.
[So] Source:J Virol;90(23):10715-10727, 2016 Dec 01.
[Is] ISSN:1098-5514
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Cytomegalovirus (CMV) is a ubiquitous human pathogen that increases the morbidity and mortality of immunocompromised individuals. The current FDA-approved treatments for CMV infection are intended to be virus specific, yet they have significant adverse side effects, including nephrotoxicity and hematological toxicity. Thus, there is a medical need for safer and more effective CMV therapeutics. Using a high-content screen, we identified the cardiac glycoside convallatoxin as an effective compound that inhibits CMV infection. Using a panel of cardiac glycoside variants, we assessed the structural elements critical for anti-CMV activity by both experimental and in silico methods. Analysis of the antiviral effects, toxicities, and pharmacodynamics of different variants of cardiac glycosides identified the mechanism of inhibition as reduction of methionine import, leading to decreased immediate-early gene translation without significant toxicity. Also, convallatoxin was found to dramatically reduce the proliferation of clinical CMV strains, implying that its mechanism of action is an effective strategy to block CMV dissemination. Our study has uncovered the mechanism and structural elements of convallatoxin, which are important for effectively inhibiting CMV infection by targeting the expression of immediate-early genes. IMPORTANCE: Cytomegalovirus is a highly prevalent virus capable of causing severe disease in certain populations. The current FDA-approved therapeutics all target the same stage of the viral life cycle and induce toxicity and viral resistance. We identified convallatoxin, a novel cell-targeting antiviral that inhibits CMV infection by decreasing the synthesis of viral proteins. At doses low enough for cells to tolerate, convallatoxin was able to inhibit primary isolates of CMV, including those resistant to the anti-CMV drug ganciclovir. In addition to identifying convallatoxin as a novel antiviral, limiting mRNA translation has a dramatic impact on CMV infection and proliferation.
[Mh] Termos MeSH primário: Antivirais/farmacologia
Infecções por Citomegalovirus/prevenção & controle
Citomegalovirus/efeitos dos fármacos
Metionina/metabolismo
Estrofantinas/farmacologia
[Mh] Termos MeSH secundário: Antivirais/química
Transporte Biológico Ativo/efeitos dos fármacos
Glicosídeos Cardíacos/química
Glicosídeos Cardíacos/farmacologia
Linhagem Celular
Citomegalovirus/genética
Citomegalovirus/fisiologia
Infecções por Citomegalovirus/metabolismo
Infecções por Citomegalovirus/virologia
Genes Precoces/efeitos dos fármacos
Genes Virais/efeitos dos fármacos
Seres Humanos
Testes de Sensibilidade Microbiana
Modelos Moleculares
Estrutura Molecular
RNA Mensageiro/genética
RNA Mensageiro/metabolismo
RNA Viral/genética
RNA Viral/metabolismo
Estrofantinas/química
Relação Estrutura-Atividade
Replicação Viral/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antiviral Agents); 0 (Cardiac Glycosides); 0 (RNA, Messenger); 0 (RNA, Viral); 0 (Strophanthins); AE28F7PNPL (Methionine); JY264VIR1Y (convallatoxin)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170515
[Lr] Data última revisão:
170515
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160923
[St] Status:MEDLINE


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[PMID]:26252521
[Au] Autor:Schneider NF; Geller FC; Persich L; Marostica LL; Pádua RM; Kreis W; Braga FC; Simões CM
[Ad] Endereço:a Departamento de Ciências Farmacêuticas , Centro de Ciências da Saúde, Universidade Federal de Santa Catarina , Florianópolis , SC , Brazil.
[Ti] Título:Inhibition of cell proliferation, invasion and migration by the cardenolides digitoxigenin monodigitoxoside and convallatoxin in human lung cancer cell line.
[So] Source:Nat Prod Res;30(11):1327-31, 2016 Jun.
[Is] ISSN:1478-6427
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Cardiac glycosides consist of a large family of naturally derived compounds that are clinically used to treat congestive heart failure, and also present anticancer properties. In this study, the cytotoxic effects of two cardenolides, digitoxigenin monodigitoxoside (DGX) and convallatoxin (CON) were screened in four human tumour cell lines. Both compounds showed anti-proliferative effects in all tumour cells, at nanomolar concentrations. Since the human lung cancer cell line A549 was the most sensitive, we investigated the anti-proliferative, anti-migratory and anti-invasive effects of these cardenolides. DGX and CON reduced A549 cell migration, being able to reduce more than 90% of cell invasion. Their effects on the expression of key regulators of metastatic mechanism showed decreased levels of MMP-2, MMP-9 and p-FAK. Both compounds also presented low toxicity for healthy cells. Finally, this work provides the first insights into the effects of these cardenolides on key steps of lung cancer metastasis.
[Mh] Termos MeSH primário: Cardenolídeos/farmacologia
Movimento Celular/efeitos dos fármacos
Proliferação Celular/efeitos dos fármacos
Digitoxigenina/análogos & derivados
Neoplasias Pulmonares/patologia
[Mh] Termos MeSH secundário: Células A549
Glicosídeos Cardíacos/farmacologia
Linhagem Celular Tumoral
Digitoxigenina/farmacologia
Seres Humanos
Metástase Neoplásica/tratamento farmacológico
Estrofantinas/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cardenolides); 0 (Cardiac Glycosides); 0 (Strophanthins); 143-62-4 (Digitoxigenin); 18404-43-8 (digitoxigenin monodigitoxoside); JY264VIR1Y (convallatoxin)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170817
[Lr] Data última revisão:
170817
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150808
[St] Status:MEDLINE
[do] DOI:10.1080/14786419.2015.1055265


  5 / 1164 MEDLINE  
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[PMID]:26592202
[Au] Autor:Okuyama-Dobashi K; Kasai H; Tanaka T; Yamashita A; Yasumoto J; Chen W; Okamoto T; Maekawa S; Watashi K; Wakita T; Ryo A; Suzuki T; Matsuura Y; Enomoto N; Moriishi K
[Ad] Endereço:Department of Microbiology, Faculty of Medicine, University of Yamanashi, Japan.
[Ti] Título:Hepatitis B virus efficiently infects non-adherent hepatoma cells via human sodium taurocholate cotransporting polypeptide.
[So] Source:Sci Rep;5:17047, 2015 Nov 23.
[Is] ISSN:2045-2322
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Sodium taurocholate cotransporting polypeptide (NTCP) has been reported as a functional receptor for hepatitis B virus (HBV) infection. However, HBV could not efficiently infect HepG2 cells expressing NTCP (NTCP-HepG2 cells) under adherent monolayer-cell conditions. In this study, NTCP was mainly detected in the basolateral membrane region, but not the apical site, of monolayer NTCP-HepG2 cells. We hypothesized that non-adherent cell conditions of infection would enhance HBV infectivity. Non-adherent NTCP-HepG2 cells were prepared by treatment with trypsin and EDTA, which did not degrade NTCP in the membrane fraction. HBV successfully infected NTCP-HepG2 cells at a viral dose 10 times lower in non-adherent phase than in adherent phase. Efficient infection of non-adherent NTCP-HepG2 cells with blood-borne or cell-culture-derived HBV was observed and was remarkably impaired in the presence of the myristoylated preS1 peptide. HBV could also efficiently infect HepaRG cells under non-adherent cell conditions. We screened several compounds using our culture system and identified proscillaridin A as a potent anti-HBV agent with an IC50 value of 7.2 nM. In conclusion, non-adherent host cell conditions of infection augmented HBV infectivity in an NTCP-dependent manner, thus providing a novel strategy to identify anti-HBV drugs and investigate the mechanism of HBV infection.
[Mh] Termos MeSH primário: Antivirais/farmacologia
Transportadores de Ânions Orgânicos Dependentes de Sódio/genética
Proscilaridina/farmacologia
Receptores Virais/genética
Simportadores/genética
Internalização do Vírus/efeitos dos fármacos
[Mh] Termos MeSH secundário: Bufanolídeos/farmacologia
Adesão Celular
Digitoxina/farmacologia
Digoxina/farmacologia
Expressão Gênica
Células Hep G2
Vírus da Hepatite B/efeitos dos fármacos
Vírus da Hepatite B/fisiologia
Ensaios de Triagem em Larga Escala
Seres Humanos
Transportadores de Ânions Orgânicos Dependentes de Sódio/antagonistas & inibidores
Transportadores de Ânions Orgânicos Dependentes de Sódio/metabolismo
Ftalazinas/farmacologia
Receptores Virais/antagonistas & inibidores
Receptores Virais/metabolismo
Sinvastatina/farmacologia
Estrofantinas/farmacologia
Simportadores/antagonistas & inibidores
Simportadores/metabolismo
Transgenes
Proteínas do Envelope Viral/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antiviral Agents); 0 (Bufanolides); 0 (L protein, hepatitis B virus); 0 (Organic Anion Transporters, Sodium-Dependent); 0 (Phthalazines); 0 (Receptors, Virus); 0 (Strophanthins); 0 (Symporters); 0 (Viral Envelope Proteins); 145420-23-1 (sodium-bile acid cotransporter); 73K4184T59 (Digoxin); AGG2FN16EV (Simvastatin); E90NZP2L9U (Digitoxin); JY264VIR1Y (convallatoxin); KC6BL281EN (Proscillaridin); U549S98QLW (bufalin); ZQI909440X (azelastine)
[Em] Mês de entrada:1609
[Cu] Atualização por classe:151128
[Lr] Data última revisão:
151128
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151124
[St] Status:MEDLINE
[do] DOI:10.1038/srep17047


  6 / 1164 MEDLINE  
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[PMID]:26384484
[Au] Autor:Kim BY; Lee J; Kim NS
[Ad] Endereço:KM-Convergence Research Division, Korea Institute of Oriental Medicine, 1672 Yuseong-daero, Yuseong-gu, Daejeon, 305-811, Republic of Korea.
[Ti] Título:Helveticoside is a biologically active component of the seed extract of Descurainia sophia and induces reciprocal gene regulation in A549 human lung cancer cells.
[So] Source:BMC Genomics;16:713, 2015 Sep 18.
[Is] ISSN:1471-2164
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Although the pharmacological activities of the seed extract of Descurainia sophia have been proven to be useful against cough, asthma, and edema, the biologically active components, particularly at the molecular level, remain elusive. Therefore, we aimed to identify the active component of an ethanol extract of D. sophia seeds (EEDS) by applying a systematic genomic approach. RESULTS: After treatment with EEDS, the dose-dependently expressed genes in A549 cells were used to query the Connectivity map to determine which small molecules could closely mimic EEDS in terms of whole gene expression. Gene ontology and pathway analyses were also performed to identify the functional involvement of the drug responsive genes. In addition, interaction network and enrichment map assays were implemented to measure the functional network structure of the drug-responsive genes. A Connectivity map analysis of differentially expressed genes resulted in the discovery of helveticoside as a candidate drug that induces a similar gene expression pattern to EEDS. We identified the presence of helveticoside in EEDS and determined that helveticoside was responsible for the dose-dependent gene expression induced by EEDS. Gene ontology and pathway analyses revealed that the metabolism and signaling processes in A549 cells were reciprocally regulated by helveticoside and inter-connected as functional modules. Additionally, in an ontological network analysis, diverse cancer type-related genes were found to be associated with the biological functions regulated by helveticoside. CONCLUSIONS: Using bioinformatic analyses, we confirmed that helveticoside is a biologically active component of EEDS that induces reciprocal regulation of metabolism and signaling processes. Our approach may provide novel insights to the herbal research field for identifying biologically active components from extracts.
[Mh] Termos MeSH primário: Brassicaceae/química
Glicosídeos Digitálicos/farmacologia
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos
Sementes/química
Estrofantinas/farmacologia
[Mh] Termos MeSH secundário: Antineoplásicos/farmacologia
Linhagem Celular Tumoral
Biologia Computacional
Seres Humanos
Neoplasias Pulmonares/tratamento farmacológico
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Digitalis Glycosides); 0 (Strophanthins); 52OAE3C457 (helveticoside)
[Em] Mês de entrada:1607
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150920
[St] Status:MEDLINE
[do] DOI:10.1186/s12864-015-1918-1


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[PMID]:26116597
[Au] Autor:Everett JM; Kojima YA; Davis B; Wahed A; Dasgupta A
[Ad] Endereço:Department of Pathology and Laboratory Medicine, University of Texas-Houston Medical School, Houston TX, USA.
[Ti] Título:The iDigoxin Assay is More Sensitive than LOCI Digoxin Assay for Rapid Detection of Convallatoxin, the Active Cardiac Glycoside of Lily of The Valley.
[So] Source:Ann Clin Lab Sci;45(3):323-6, 2015.
[Is] ISSN:1550-8080
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: Lily of the valley is a poisonous plant due to the presence of the cardiac glycoside convallatoxin. We compared two immunoassays (LOCI digoxin assay and iDigoxin assay) for rapid detection of convallatoxin if present in human serum. MATERIALS AND METHODS: Aliquots of a drug free serum pool and a digoxin serum pool were supplemented with microliter amounts of lily of the valley extract or nanogram to microgram quantities of convallatoxin, followed by measurement of apparent digoxin concentrations using the LOCI and iDigxoin assays. RESULTS: Apparent digoxin concentrations were observed when aliquots of a drug free serum pool were supplemented with convallatoxin or lily of the valley extract using both assays but apparent digoxin concentrations were significantly higher using the iDigoxin assay. In addition, the interference of convallatoxin in serum digoxin measurement was also significantly higher using iDigxoin assay compared to the LOCI digoxin assay. CONCLUSIONS: The iDigxoin assay is more sensitive in detecting convallatoxin in human serum.
[Mh] Termos MeSH primário: Bioensaio/métodos
Glicosídeos Cardíacos/sangue
Digoxina/sangue
Lilium/química
Estrofantinas/sangue
[Mh] Termos MeSH secundário: Seres Humanos
Sensibilidade e Especificidade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cardiac Glycosides); 0 (Strophanthins); 73K4184T59 (Digoxin); JY264VIR1Y (convallatoxin)
[Em] Mês de entrada:1603
[Cu] Atualização por classe:150627
[Lr] Data última revisão:
150627
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150628
[St] Status:MEDLINE


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[PMID]:25446405
[Au] Autor:Gardner TJ; Cohen T; Redmann V; Lau Z; Felsenfeld D; Tortorella D
[Ad] Endereço:Icahn School of Medicine at Mount Sinai, Department of Microbiology, New York, NY 10029, USA.
[Ti] Título:Development of a high-content screen for the identification of inhibitors directed against the early steps of the cytomegalovirus infectious cycle.
[So] Source:Antiviral Res;113:49-61, 2015 Jan.
[Is] ISSN:1872-9096
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Human cytomegalovirus (CMV) is a latent and persistent virus whose proliferation increases morbidity and mortality of immune-compromised individuals. The current anti-CMV therapeutics targeting the viral DNA polymerase or the major immediate-early (MIE) gene locus are somewhat effective at limiting CMV-associated disease. However, due to low bioavailability, severe toxicity, and the development of drug resistant CMV strains following prolonged treatment, current anti-CMV therapeutics are insufficient. To help address this shortfall, we established a high-content assay to identify inhibitors targeting CMV entry and the early steps of infection. The infection of primary human fibroblasts with a variant of the CMV laboratory strain AD169 expressing a chimeric IE2-yellow fluorescence protein (YFP) (AD169IE2-YFP) provided the basis for the high-content assay. The localization of IE2-YFP to the nucleus shortly following an AD169IE2-YFP infection induced a robust fluorescent signal that was quantified using confocal microscopy. The assay was optimized to achieve outstanding assay fitness and high Z' scores. We then screened a bioactive chemical library consisting of 2080 compounds and identified hit compounds based on the decrease of fluorescence signal from IE2-YFP nuclear expression. The hit compounds likely target various cellular processes involved in the early steps of infection including capsid transport, chromatin remodeling, and viral gene expression. Extensive secondary assays confirmed the ability of a hit compound, convallatoxin, to inhibit infection of both laboratory and clinical CMV strains and limit virus proliferation. Collectively, the data demonstrate that we have established a robust high-content screen to identify compounds that limit the early steps of the CMV life cycle, and that novel inhibitors of early infection events may serve as viable CMV therapeutics.
[Mh] Termos MeSH primário: Citomegalovirus/efeitos dos fármacos
Ensaios de Triagem em Larga Escala/métodos
Testes de Sensibilidade Microbiana/métodos
Bibliotecas de Moléculas Pequenas/química
Estrofantinas/farmacologia
Replicação Viral/efeitos dos fármacos
[Mh] Termos MeSH secundário: Linhagem Celular
Núcleo Celular/metabolismo
Citomegalovirus/genética
Citomegalovirus/fisiologia
DNA Viral/metabolismo
Regulação Viral da Expressão Gênica
Seres Humanos
Proteínas Imediatamente Precoces/metabolismo
Transativadores/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (DNA, Viral); 0 (IE2 protein, Cytomegalovirus); 0 (Immediate-Early Proteins); 0 (Small Molecule Libraries); 0 (Strophanthins); 0 (Trans-Activators); JY264VIR1Y (convallatoxin)
[Em] Mês de entrada:1508
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:141203
[St] Status:MEDLINE


  9 / 1164 MEDLINE  
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[PMID]:25730978
[Au] Autor:Pogorelova VN; Panait AI; Pogorelov AG
[Ti] Título:[Nonspecific effect of Na+/K(+)-ATPase inhibition with strophanthin or under hypothermia in rat heart].
[So] Source:Biofizika;59(5):946-50, 2014 Sep-Oct.
[Is] ISSN:0006-3029
[Cp] País de publicação:Russia (Federation)
[La] Idioma:rus
[Ab] Resumo:Electron probe microanalysis was applied to study the kinetics of changes in potassium and sodium concentration in muscle cells of isolated heart from Wistar rat during experimental ischemia. Hypoxic perfusion without glucose was shown to evoke the potassium deficiency and sodium accumulation in cardiac myocells. Short-term action (10 min) of strophanthin (0.1 mM/l) recovered Na/K balance in ischemic myocells. Hypothermic perfusion exhibited the opportunity to conserve the cytoplasmic elemental contents in the state corresponding to the beginning of low temperature (4 degrees C) operation.
[Mh] Termos MeSH primário: Inibidores Enzimáticos/farmacologia
Hipotermia/enzimologia
Miocárdio/metabolismo
Miócitos Cardíacos/enzimologia
ATPase Trocadora de Sódio-Potássio/antagonistas & inibidores
Estrofantinas/farmacologia
[Mh] Termos MeSH secundário: Animais
Hipotermia/patologia
Isquemia Miocárdica/enzimologia
Isquemia Miocárdica/patologia
Miocárdio/patologia
Miócitos Cardíacos/patologia
Ratos
Ratos Wistar
ATPase Trocadora de Sódio-Potássio/metabolismo
[Pt] Tipo de publicação:ENGLISH ABSTRACT; JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Enzyme Inhibitors); 0 (Strophanthins); EC 3.6.3.9 (Sodium-Potassium-Exchanging ATPase)
[Em] Mês de entrada:1503
[Cu] Atualização por classe:150303
[Lr] Data última revisão:
150303
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150304
[St] Status:MEDLINE


  10 / 1164 MEDLINE  
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[PMID]:25264938
[Au] Autor:Gozalpour E; Greupink R; Bilos A; Verweij V; van den Heuvel JJ; Masereeuw R; Russel FG; Koenderink JB
[Ad] Endereço:Department of Pharmacology and Toxicology 149, Radboud University Medical Centre, Radboud Institute for Molecular Life Sciences, PO Box 9101, 6500 HB Nijmegen, The Netherlands.
[Ti] Título:Convallatoxin: a new P-glycoprotein substrate.
[So] Source:Eur J Pharmacol;744:18-27, 2014 Dec 05.
[Is] ISSN:1879-0712
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Digitalis-like compounds (DLCs), such as digoxin and digitoxin that are derived from digitalis species, are currently used to treat heart failure and atrial fibrillation, but have a narrow therapeutic index. Drug-drug interactions at the transporter level are frequent causes of DLCs toxicity. P-glycoprotein (P-gp, ABCB1) is the primary transporter of digoxin and its inhibitors influence pharmacokinetics and disposition of digoxin in the human body; however, the involvement of P-gp in the disposition of other DLCs is currently unknown. In present study, the transport of fourteen DLCs by human P-gp was studied using membrane vesicles originating from human embryonic kidney (HEK293) cells overexpressing P-gp. DLCs were quantified by liquid chromatography-mass spectrometry (LC-MS). The Lily of the Valley toxin, convallatoxin, was identified as a P-gp substrate (Km: 1.1±0.2 mM) in the vesicular assay. Transport of convallatoxin by P-gp was confirmed in rat in vivo, in which co-administration with the P-gp inhibitor elacridar, resulted in increased concentrations in brain and kidney cortex. To address the interaction of convallatoxin with P-gp on a molecular level, the effect of nine alanine mutations was compared with the substrate N-methyl quinidine (NMQ). Phe343 appeared to be more important for transport of NMQ than convallatoxin, while Val982 was particularly relevant for convallatoxin transport. We identified convallatoxin as a new P-gp substrate and recognized Val982 as an important amino acid involved in its transport. These results contribute to a better understanding of the interaction of DLCs with P-gp.
[Mh] Termos MeSH primário: Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo
Estrofantinas/metabolismo
[Mh] Termos MeSH secundário: Animais
Transporte Biológico/fisiologia
Encéfalo/metabolismo
Linhagem Celular
Digoxina/metabolismo
Células HEK293
Seres Humanos
Córtex Renal/metabolismo
Masculino
Proteínas de Membrana Transportadoras/metabolismo
Ratos
Ratos Wistar
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (ATP Binding Cassette Transporter, Sub-Family B); 0 (Membrane Transport Proteins); 0 (Strophanthins); 73K4184T59 (Digoxin); JY264VIR1Y (convallatoxin)
[Em] Mês de entrada:1508
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:140930
[St] Status:MEDLINE



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