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[PMID]:28877265
[Au] Autor:Cheng B; Morales LD; Zhang Y; Mito S; Tsin A
[Ad] Endereço:Department of Biomedical Science, School of Medicine, University of Texas Rio Grande Valley, Edinburg, Texas, United States of America.
[Ti] Título:Niclosamide induces protein ubiquitination and inhibits multiple pro-survival signaling pathways in the human glioblastoma U-87 MG cell line.
[So] Source:PLoS One;12(9):e0184324, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Glioblastoma is the most common and lethal malignant primary brain tumor for which the development of efficacious chemotherapeutic agents remains an urgent need. The anti-helminthic drug niclosamide, which has long been in use to treat tapeworm infections, has recently attracted renewed interest due to its apparent anticancer effects in a variety of in vitro and in vivo cancer models. However, the mechanism(s) of action remains to be elucidated. In the present study, we found that niclosamide induced cell toxicity in human glioblastoma cells corresponding with increased protein ubiquitination, ER stress and autophagy. In addition, niclosamide treatment led to down-regulation of Wnt/ß-catenin, PI3K/AKT, MAPK/ERK, and STAT3 pro-survival signal transduction pathways to further reduce U-87 MG cell viability. Taken together, these results provide new insights into the glioblastoma suppressive capabilities of niclosamide, showing that niclosamide can target multiple major cell signaling pathways simultaneously to effectively promote cell death in U-87 MG cells. Niclosamide constitutes a new prospect for a therapeutic treatment against human glioblastoma.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Neoplasias Encefálicas/metabolismo
Glioblastoma/metabolismo
Niclosamida/farmacologia
Ubiquitinação
[Mh] Termos MeSH secundário: Anti-Helmínticos/química
Apoptose
Neoplasias Encefálicas/tratamento farmacológico
Cadaverina/análogos & derivados
Cadaverina/química
Linhagem Celular Tumoral
Proliferação Celular
Sobrevivência Celular
Ensaios de Seleção de Medicamentos Antitumorais
Glioblastoma/tratamento farmacológico
Seres Humanos
Fator de Transcrição STAT3/metabolismo
Transdução de Sinais
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anthelmintics); 0 (Antineoplastic Agents); 0 (STAT3 Transcription Factor); 0 (STAT3 protein, human); 8KK8CQ2K8G (Niclosamide); I9N81SC5HD (monodansylcadaverine); L90BEN6OLL (Cadaverine)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171023
[Lr] Data última revisão:
171023
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170907
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0184324


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[PMID]:28813646
[Au] Autor:Kim MO; Choe MH; Yoon YN; Ahn J; Yoo M; Jung KY; An S; Hwang SG; Oh JS; Kim JS
[Ad] Endereço:Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul, South Korea; Molecular-Targeted Drug Research Center and Korea Institute for Skin and Clinical Sciences, Konkuk University, Seoul, South Korea.
[Ti] Título:Antihelminthic drug niclosamide inhibits CIP2A and reactivates tumor suppressor protein phosphatase 2A in non-small cell lung cancer cells.
[So] Source:Biochem Pharmacol;144:78-89, 2017 Nov 15.
[Is] ISSN:1873-2968
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Protein phosphatase 2A (PP2A) is a critical tumor suppressor complex responsible for the inactivation of various oncogenes. Recently, PP2A reactivation has emerged asan anticancer strategy. Cancerous inhibitor of protein phosphatase 2A (CIP2A), an endogenous inhibitor of PP2A, is upregulated in many cancer cells, including non-small cell lung cancer (NSCLC) cells. We demonstrated that the antihelminthic drug niclosamide inhibited the expression of CIP2A and reactivated the tumor suppressor PP2A in NSCLC cells. We performed a drug-repurposing screen and identified niclosamide asa CIP2A suppressor in NSCLC cells. Niclosamide inhibited cell proliferation, colony formation, and tumor sphere formation, and induced mitochondrial dysfunction through increased mitochondrial ROS production in NSCLC cells; however, these effects were rescued by CIP2A overexpression, which indicated that the antitumor activity of niclosamide was dependent on CIP2A. We found that niclosamide increased PP2A activity through CIP2A inhibition, which reduced the phosphorylation of several oncogenic proteins. Moreover, we found that a niclosamide analog inhibited CIP2A expression and increased PP2A activity in several types of NSCLC cells. Finally, we showed that other well-known PP2A activators, including forskolin and FTY720, did not inhibit CIP2A and that their activities were not dependent on CIP2A. Collectively, our data suggested that niclosamide effectively suppressed CIP2A expression and subsequently activated PP2A in NSCLC cells. This provided strong evidence for the potential use of niclosamide asa PP2A-activating drug in the clinical treatment of NSCLC.
[Mh] Termos MeSH primário: Anti-Helmínticos/farmacologia
Autoantígenos/metabolismo
Carcinoma Pulmonar de Células não Pequenas/metabolismo
Neoplasias Pulmonares/metabolismo
Proteínas de Membrana/metabolismo
Niclosamida/farmacologia
Proteína Fosfatase 2/metabolismo
[Mh] Termos MeSH secundário: Anti-Helmínticos/uso terapêutico
Antinematódeos/farmacologia
Antinematódeos/uso terapêutico
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico
Linhagem Celular Tumoral
Sobrevivência Celular/efeitos dos fármacos
Sobrevivência Celular/fisiologia
Relação Dose-Resposta a Droga
Seres Humanos
Neoplasias Pulmonares/tratamento farmacológico
Potencial da Membrana Mitocondrial/efeitos dos fármacos
Proteínas de Membrana/antagonistas & inibidores
Niclosamida/uso terapêutico
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anthelmintics); 0 (Antinematodal Agents); 0 (Autoantigens); 0 (KIAA1524 protein, human); 0 (Membrane Proteins); 8KK8CQ2K8G (Niclosamide); EC 3.1.3.16 (Protein Phosphatase 2)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171019
[Lr] Data última revisão:
171019
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170817
[St] Status:MEDLINE


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[PMID]:28632878
[Au] Autor:De Filippo E; Manga P; Schiedel AC
[Ad] Endereço:Pharmaceutical Chemistry I, PharmaCenter Bonn, University of Bonn, Bonn, Germany.
[Ti] Título:Identification of Novel G Protein-Coupled Receptor 143 Ligands as Pharmacologic Tools for Investigating X-Linked Ocular Albinism.
[So] Source:Invest Ophthalmol Vis Sci;58(7):3118-3126, 2017 Jun 01.
[Is] ISSN:1552-5783
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Purpose: GPR143 regulates melanosome biogenesis and organelle size in pigment cells. The mechanisms underlying receptor function remain unclear. G protein-coupled receptors (GPCRs) are excellent pharmacologic targets; thus, we developed and applied a screening approach to identify potential GPR143 ligands and chemical modulators. Methods: GPR143 interacts with ß-arrestin; we therefore established a ß-arrestin recruitment assay to screen for compounds that modulate activity. Because GPR143 is localized intracellularly, screening with the wild-type receptor would be restricted to agents absorbed by the cell. For the screen we used a mutant receptor, which shows similar basal activity as the wild type but traffics to the plasma membrane. We tested two compound libraries and investigated validated hits for their effects on melanocyte pigmentation. Results: GPR143, which showed high constitutive activity in the ß-arrestin assay, was inhibited by several compounds. The three validated inhibitors (pimozide, niclosamide, and ethacridine lactate) were assessed for impact on melanocytes. Pigmentation and expression of tyrosinase, a key melanogenic enzyme, were reduced by all compounds. Because GPR143 appears to be constitutively active, these compounds may turn off its activity. Conclusions: X-linked ocular albinism type I, characterized by developmental eye defects, results from GPR143 mutations. Identifying pharmacologic agents that modulate GPR143 activity will contribute significantly to our understanding of its function and provide novel tools with which to study GPCRs in melanocytes and retinal pigment epithelium. Pimozide, one of three GPR143 inhibitors identified in this study, maybe be a good lead structure for development of more potent compounds and provide a platform for design of novel therapeutic agents.
[Mh] Termos MeSH primário: Albinismo Ocular/genética
Proteínas do Olho/genética
Doenças Genéticas Ligadas ao Cromossomo X/genética
Glicoproteínas de Membrana/genética
Mutação
RNA/genética
[Mh] Termos MeSH secundário: Albinismo Ocular/tratamento farmacológico
Albinismo Ocular/metabolismo
Células Cultivadas
Análise Mutacional de DNA
Etacridina/farmacologia
Éxons
Proteínas do Olho/antagonistas & inibidores
Proteínas do Olho/metabolismo
Doenças Genéticas Ligadas ao Cromossomo X/dietoterapia
Doenças Genéticas Ligadas ao Cromossomo X/metabolismo
Seres Humanos
Ligantes
Glicoproteínas de Membrana/antagonistas & inibidores
Glicoproteínas de Membrana/metabolismo
Niclosamida/farmacologia
Linhagem
Pimozida/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Eye Proteins); 0 (GPR143 protein, human); 0 (Ligands); 0 (Membrane Glycoproteins); 1HIZ4DL86F (Pimozide); 63231-63-0 (RNA); 8KK8CQ2K8G (Niclosamide); WIX85M1A6R (Ethacridine)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170719
[Lr] Data última revisão:
170719
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170621
[St] Status:MEDLINE
[do] DOI:10.1167/iovs.16-21128


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[PMID]:28561092
[Au] Autor:McConville MB; Cohen NM; Nowicki SM; Lantz SR; Hixson JL; Ward AS; Remucal CK
[Ad] Endereço:Environmental Chemistry and Technology Program, University of Wisconsin - Madison, Madison, Wisconsin, USA. remucal@wisc.edu.
[Ti] Título:A field analysis of lampricide photodegradation in Great Lakes tributaries.
[So] Source:Environ Sci Process Impacts;19(7):891-900, 2017 Jul 19.
[Is] ISSN:2050-7895
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The lampricides 3-trifluoromethyl-4-nitrophenol (TFM) and 2',5-dichloro-4'-nitrosalicylanilide (niclosamide) are added to Great Lakes tributaries to target the sea lamprey, an invasive parasitic fish. This study examines the photochemical behavior of the lampricides in Carpenter Creek, Sullivan Creek, and the Manistique River. The observed loss of TFM in Carpenter and Sullivan Creeks (i.e., 34 and 19%) was similar to the loss of bromide in parallel time of passage studies (i.e., 30 and 29%), demonstrating that TFM photodegradation was minimal in both tributaries during the lampricide application. Furthermore, the absence of inorganic and organic photoproducts in the Manistique River demonstrates that TFM and niclosamide photodegradation was minimal in this large tributary, despite its long residence time (i.e., 3.3 days). Kinetic modeling was used to identify environmental variables primarily responsible for the limited photodegradation of TFM in the field compared to estimates from laboratory data. This analysis demonstrates that the lack of TFM photodegradation was attributable to the short residence times in Carpenter and Sullivan Creeks, while depth, time of year, time of day, and cloud cover influenced photochemical fate in the Manistique River. The modeling approach was extended to assess how many of the 140 United States tributaries treated with lampricides in 2015 and 2016 were amenable to TFM photolysis. While >50% removal of TFM due to photolysis could occur in 13 long and shallow tributaries, in most systems lampricides will reach the Great Lakes untransformed.
[Mh] Termos MeSH primário: Niclosamida/análise
Nitrofenóis/análise
Petromyzon/crescimento & desenvolvimento
Fotólise
Rios/química
Poluentes Químicos da Água/análise
[Mh] Termos MeSH secundário: Animais
Monitoramento Ambiental
Great Lakes Region
Espécies Introduzidas
Cinética
Niclosamida/efeitos da radiação
Nitrofenóis/efeitos da radiação
Poluentes Químicos da Água/efeitos da radiação
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Nitrophenols); 0 (Water Pollutants, Chemical); 8KK8CQ2K8G (Niclosamide); 96W52A3IFS (3-trifluoromethyl-4-nitrophenol)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171102
[Lr] Data última revisão:
171102
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170601
[St] Status:MEDLINE
[do] DOI:10.1039/c7em00173h


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[PMID]:28551619
[Au] Autor:Tang Z; Acuña UM; Fernandes NF; Chettiar S; Li PK; DE Blanco EC
[Ad] Endereço:Division of Pharmacy Practice and Science, College of Pharmacy, The Ohio State University, Columbus, OH, U.S.A.
[Ti] Título:Structure-Activity Relationship of Niclosamide Derivatives.
[So] Source:Anticancer Res;37(6):2839-2843, 2017 06.
[Is] ISSN:1791-7530
[Cp] País de publicação:Greece
[La] Idioma:eng
[Ab] Resumo:BACKGROUND/AIM: Cancer is a leading cause of death. Hence, this study aimed at the optimization of niclosamide derivatives for the development of new potential anticancer agents. MATERIALS AND METHODS: Niclosamide derivatives were synthesized and tested against a panel of human cancer cells: MDA and MCF7 breast cancer cells, PC3 and DU-145 prostate cancer cells, Hela cervical cancer cells, and HL-60 acute promyelocytic leukemia cells. They were also tested in nuclear factor-ĸappa B (NFĸB), V-Ki-ras2 Kirsten rat sarcoma viral oncogene (KRAS), and mitochondria transmembrane potential (MTP) assays. RESULTS: N-(3,5-Bis(trifluoromethyl)phenyl)-5-chloro-2-hydroxybenzamide exhibited the most significant cytotoxicity against HL-60 cells, while 5-chloro-N-(2-chlorophenyl)-2-hydroxybenzamide was the most active in the NFĸB assay and 5-chloro-N-(3,5-difluorophenyl)-2-hydroxybenzamide in the MTP assay. 5-chloro-N-(2-chloro-4-(trifluoromethyl) phenyl)-2-hydroxybenzamide and 5-chloro-2-hydroxy-N-(4-hydroxyphenyl)benzamide inhibited both HL-60 cell proliferation and NFĸB. CONCLUSION: In-depth study of the most promising compounds is highly encouraged to further develop into potential anticancer agents those derivatives found to be significantly active.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Niclosamida/análogos & derivados
Niclosamida/farmacologia
[Mh] Termos MeSH secundário: Antineoplásicos/química
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Seres Humanos
Potencial da Membrana Mitocondrial/efeitos dos fármacos
NF-kappa B/antagonistas & inibidores
NF-kappa B/metabolismo
Niclosamida/química
Proteínas Proto-Oncogênicas p21(ras)/antagonistas & inibidores
Proteínas Proto-Oncogênicas p21(ras)/metabolismo
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (KRAS protein, human); 0 (NF-kappa B); 8KK8CQ2K8G (Niclosamide); EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras))
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170821
[Lr] Data última revisão:
170821
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170529
[St] Status:MEDLINE


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[PMID]:28414284
[Au] Autor:Zhirnik AS; Semochkina YP; Moskaleva EY; Krylov NI; Tubasheva IA; Kuznetsov SL; Vorontsov EA
[Ad] Endereço:National Research Centre "Kurchatov Institute", NBICS Centre, Moscow, Russia.
[Ti] Título:[Antineoplastic mechanisms of niclosamide-loaded nanoparticles in human colorectal cancer cells].
[Ti] Título:Molekuliarnye mekhanizmy protivoopukholevoi aktivnosti polimernoi formy niklozamida v otnoshenii kletok kolorektal'nogo raka..
[So] Source:Biomed Khim;63(2):132-138, 2017 Mar.
[Is] ISSN:2310-6972
[Cp] País de publicação:Russia (Federation)
[La] Idioma:rus
[Ab] Resumo:Using poly(lactic-co-glycolic) acid we developed a polymeric form of niclosamide (PFN) and investigated molecular mechanisms underlying its antitumor activity against human colorectal cancer cell lines (SW837, Caco-2, COLO 320 HSR). PFN was shown to be more cytotoxic against cancer cells and less cytotoxic against normal cells (human embryonic lung fibroblasts) as compared to niclosamide. Both niclosamide and its polymeric form caused mitochondrial damage (evaluated as a decrease in rhodamine 123 accumulation) and increased the levels of reactive oxygen species, particularly mitochondrial superoxide, resulting in the oxidative damage to biomolecules. Furthermore, niclosamide and PFN induced G0/G1 cell cycle arrest.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Pontos de Checagem do Ciclo Celular/efeitos dos fármacos
Portadores de Fármacos
Mitocôndrias/efeitos dos fármacos
Nanopartículas/toxicidade
Niclosamida/farmacologia
[Mh] Termos MeSH secundário: Resinas Acrílicas/química
Antineoplásicos/química
Células CACO-2
Linhagem Celular
Linhagem Celular Tumoral
Sobrevivência Celular/efeitos dos fármacos
Composição de Medicamentos/métodos
Fibroblastos/citologia
Fibroblastos/efeitos dos fármacos
Seres Humanos
Ácido Láctico/química
Manitol/química
Mitocôndrias/metabolismo
Mitocôndrias/patologia
Nanopartículas/química
Niclosamida/química
Especificidade de Órgãos
Ácido Poliglicólico/química
Álcool de Polivinil/química
Espécies Reativas de Oxigênio/agonistas
Espécies Reativas de Oxigênio/metabolismo
Rodamina 123/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Acrylic Resins); 0 (Antineoplastic Agents); 0 (Drug Carriers); 0 (Reactive Oxygen Species); 0 (polylactic acid-polyglycolic acid copolymer); 1N3CZ14C5O (Rhodamine 123); 26009-03-0 (Polyglycolic Acid); 33434-24-1 (Eudragit RS); 33X04XA5AT (Lactic Acid); 3OWL53L36A (Mannitol); 8KK8CQ2K8G (Niclosamide); 9002-89-5 (Polyvinyl Alcohol)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170912
[Lr] Data última revisão:
170912
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170418
[St] Status:MEDLINE
[do] DOI:10.18097/PBMC20176302132


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[PMID]:28372221
[Au] Autor:Dong B; Shao X; Lin H; Hu J
[Ad] Endereço:Laboratory of Pesticide Residues and Environmental Toxicology, School of Chemistry and Biological Engineering, University of Science and Technology Beijing, Beijing 100083, PR China. Electronic address: idongbizhang@126.com.
[Ti] Título:Dissipation, residues and risk assessment of metaldehyde and niclosamide ethanolamine in pakchoi after field application.
[So] Source:Food Chem;229:604-609, 2017 Aug 15.
[Is] ISSN:0308-8146
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:A method using LC-MS/MS after QuEChERS preparation for the simultaneous determination of metaldehyde and niclosamide ethanolamine residues in soil and pakchoi has been developed and validated. The mean recoveries were ranged from 90% to 101% with RSDs (relative standard deviations) less than 9.2%. The dissipation results showed that the half-lives of metaldehyde and niclosamide ethanolamine were 2.3-4.3d and 1.7-9.5d, respectively. The terminal residue results indicated that the residues of metaldehyde in pakchoi were lower than the temporary maximum residue limits (MRL) set by China on 1 d after last treatment and the maximum residue of niclosamide ethanolamine in pakchoi was 0.54mg/kg. The risk quotients of metaldehyde and niclosamide ethanolamine were ranged from 0.015 to 0.033 and from 0.00064 to 0.0014, respectively. This work could provide guidance on reasonable use of these molluscicides and aid in the establishment of MRL in China.
[Mh] Termos MeSH primário: Acetaldeído/análogos & derivados
Brassica/química
Etanolamina/química
Niclosamida/química
[Mh] Termos MeSH secundário: Acetaldeído/química
Medição de Risco
Poluentes do Solo/análise
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Soil Pollutants); 4CI033VJYG (metaldehyde); 5KV86114PT (Ethanolamine); 8KK8CQ2K8G (Niclosamide); GO1N1ZPR3B (Acetaldehyde)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170512
[Lr] Data última revisão:
170512
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170405
[St] Status:MEDLINE


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[PMID]:28284560
[Au] Autor:Chen B; Wei W; Ma L; Yang B; Gill RM; Chua MS; Butte AJ; So S
[Ad] Endereço:Institute for Computational Health Sciences and Department of Pediatrics, University of California, San Francisco, California.
[Ti] Título:Computational Discovery of Niclosamide Ethanolamine, a Repurposed Drug Candidate That Reduces Growth of Hepatocellular Carcinoma Cells In Vitro and in Mice by Inhibiting Cell Division Cycle 37 Signaling.
[So] Source:Gastroenterology;152(8):2022-2036, 2017 Jun.
[Is] ISSN:1528-0012
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND & AIMS: Drug repositioning offers a shorter approval process than new drug development. We therefore searched large public datasets of drug-induced gene expression signatures to identify agents that might be effective against hepatocellular carcinoma (HCC). METHODS: We searched public databases of messenger RNA expression patterns reported from HCC specimens from patients, HCC cell lines, and cells exposed to various drugs. We identified drugs that might specifically increase expression of genes that are down-regulated in HCCs and reduce expression of genes up-regulated in HCCs using a nonparametric, rank-based pattern-matching strategy based on the Kolmogorov-Smirnov statistic. We evaluated the anti-tumor activity of niclosamide and its ethanolamine salt (NEN) in HCC cell lines (HepG2, Huh7, Hep3B, Hep40, and PLC/PRF/5), primary human hepatocytes, and 2 mouse models of HCC. In one model of HCC, liver tumor development was induced by hydrodynamic delivery of a sleeping beauty transposon expressing an activated form of Ras (v12) and truncated ß-catenin (N90). In another mouse model, patient-derived xenografts were established by implanting HCC cells from patients into livers of immunocompromised mice. Tumor growth was monitored by bioluminescence imaging. Tumor-bearing mice were fed a regular chow diet or a chow diet containing niclosamide or NEN. In a separate experiment using patient-derived xenografts, tumor-bearing mice were given sorafenib (the standard of care for patients with advanced HCC), NEN, or niclosamide alone; a combination of sorafenib and NEN; or a combination sorafenib and niclosamide in their drinking water, or regular water (control), and tumor growth was monitored. RESULTS: Based on gene expression signatures, we identified 3 anthelmintics that significantly altered the expression of genes that are up- or down-regulated in HCCs. Niclosamide and NEN specifically reduced the viability of HCC cells: the agents were at least 7-fold more cytotoxic to HCCs than primary hepatocytes. Oral administration of NEN to mice significantly slowed growth of genetically induced liver tumors and patient-derived xenografts, whereas niclosamide did not, coinciding with the observed greater bioavailability of NEN compared with niclosamide. The combination of NEN and sorafenib was more effective at slowing growth of patient-derived xenografts than either agent alone. In HepG2 cells and in patient-derived xenografts, administration of niclosamide or NEN increased expression of 20 genes down-regulated in HCC and reduced expression of 29 genes up-regulated in the 274-gene HCC signature. Administration of NEN to mice with patient-derived xenografts reduced expression of proteins in the Wnt-ß-catenin, signal transducer and activator of transcription 3, AKT-mechanistic target of rapamycin, epidermal growth factor receptor-Ras-Raf signaling pathways. Using immunoprecipitation assays, we found NEN to bind cell division cycle 37 protein and disrupt its interaction with heat shock protein 90. CONCLUSIONS: In a bioinformatics search for agents that alter the HCC-specific gene expression pattern, we identified the anthelmintic niclosamide as a potential anti-tumor agent. Its ethanolamine salt, with greater bioavailability, was more effective than niclosamide at slowing the growth of genetically induced liver tumors and patient-derived xenografts in mice. Both agents disrupted interaction between cell division cycle 37 and heat shock protein 90 in HCC cells, with concomitant inhibition of their downstream signaling pathways. NEN might be effective for treatment of patients with HCC.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Carcinoma Hepatocelular/tratamento farmacológico
Proteínas de Ciclo Celular/antagonistas & inibidores
Proliferação Celular/efeitos dos fármacos
Chaperoninas/antagonistas & inibidores
Simulação por Computador
Descoberta de Drogas/métodos
Reposicionamento de Medicamentos
Etanolamina/farmacologia
Neoplasias Hepáticas/tratamento farmacológico
Chaperonas Moleculares/antagonistas & inibidores
Niclosamida/farmacologia
[Mh] Termos MeSH secundário: Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia
Carcinoma Hepatocelular/genética
Carcinoma Hepatocelular/metabolismo
Carcinoma Hepatocelular/patologia
Proteínas de Ciclo Celular/genética
Proteínas de Ciclo Celular/metabolismo
Chaperoninas/genética
Chaperoninas/metabolismo
Biologia Computacional
Bases de Dados Genéticas
Relação Dose-Resposta a Droga
Feminino
Perfilação da Expressão Gênica
Regulação Neoplásica da Expressão Gênica
Proteínas de Choque Térmico HSP90/metabolismo
Células Hep G2
Seres Humanos
Neoplasias Hepáticas/genética
Neoplasias Hepáticas/metabolismo
Neoplasias Hepáticas/patologia
Masculino
Chaperonas Moleculares/genética
Chaperonas Moleculares/metabolismo
Niacinamida/análogos & derivados
Niacinamida/farmacologia
Niclosamida/análogos & derivados
Compostos de Fenilureia/farmacologia
Transdução de Sinais/efeitos dos fármacos
Fatores de Tempo
Transcriptoma
Carga Tumoral/efeitos dos fármacos
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (CDC37 protein, human); 0 (Cdc37 protein, mouse); 0 (Cell Cycle Proteins); 0 (HSP90 Heat-Shock Proteins); 0 (Molecular Chaperones); 0 (Phenylurea Compounds); 25X51I8RD4 (Niacinamide); 5KV86114PT (Ethanolamine); 8KK8CQ2K8G (Niclosamide); 9ZOQ3TZI87 (sorafenib); EC 3.6.1.- (Chaperonins)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170814
[Lr] Data última revisão:
170814
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170313
[St] Status:MEDLINE


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[PMID]:28233680
[Au] Autor:Mook RA; Ren XR; Wang J; Piao H; Barak LS; Kim Lyerly H; Chen W
[Ad] Endereço:Department of Medicine, Duke University Medical Center, Durham, NC 27710, United States. Electronic address: robert.mook@duke.edu.
[Ti] Título:Benzimidazole inhibitors from the Niclosamide chemotype inhibit Wnt/ß-catenin signaling with selectivity over effects on ATP homeostasis.
[So] Source:Bioorg Med Chem;25(6):1804-1816, 2017 Mar 15.
[Is] ISSN:1464-3391
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The Wnt signaling pathway plays a key role in organ and tissue homeostasis, and when dysregulated, can become a major underlying mechanism of disease, particularly cancer. We reported previously that the anthelmintic drug Niclosamide inhibits Wnt/ß-catenin signaling and suppresses colon cancer cell growth in vitro and in vivo. To define Niclosamide's mechanism of Wnt/ß-catenin inhibition, and to improve its selectivity and pharmacokinetic properties as an anticancer treatment, we designed a novel class of benzimidazole inhibitors of Wnt/ß-catenin signaling based on SAR studies of the Niclosamide salicylanilide chemotype. Niclosamide has multiple biological activities. To address selectivity in our design, we interrogated a protonophore SAR model and used the principle of conformational restriction to identify novel Wnt/ß-catenin inhibitors with less effect on ATP cellular homeostasis. These studies led to the identification of 4-chloro-2-(5-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl) phenol (4) and related derivatives with greater selectivity for Wnt/ß-catenin signaling inhibition vs. differential effects on cellular ATP homeostasis. This is the first report that the Wnt signaling inhibitory activity of Niclosamide can be translated into a new chemical class and to show that its effects on ATP homeostasis can be separated from its inhibitory effects on Wnt signaling. These compounds could be useful tools to elucidate the mechanism of Niclosamide's inhibition of Wnt signaling, and aid the discovery of inhibitors with improved pharmacologic properties to treat cancer and diseases in which Niclosamide has important biological activity.
[Mh] Termos MeSH primário: Trifosfato de Adenosina/metabolismo
Benzimidazóis/farmacologia
Niclosamida/farmacologia
Transdução de Sinais/efeitos dos fármacos
Proteínas Wnt/metabolismo
beta Catenina/metabolismo
[Mh] Termos MeSH secundário: Benzimidazóis/química
Linhagem Celular Tumoral
Células HEK293
Homeostase
Seres Humanos
Niclosamida/química
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Benzimidazoles); 0 (Wnt Proteins); 0 (beta Catenin); 8KK8CQ2K8G (Niclosamide); 8L70Q75FXE (Adenosine Triphosphate)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171002
[Lr] Data última revisão:
171002
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170225
[St] Status:MEDLINE


  10 / 582 MEDLINE  
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[PMID]:28138036
[Au] Autor:Wang Y; Wang S; Wu Y; Ren Y; Li Z; Yao X; Zhang C; Ye N; Jing C; Dong J; Zhang K; Sun S; Zhao M; Guo W; Qu X; Qiao Y; Chen H; Kong L; Jin R; Wang X; Zhang L; Zhou J; Shen Q; Zhou X
[Ad] Endereço:Department of Maxillofacial and Otorhinolaryngological Oncology, Tianjin Medical University Cancer Institute and Hospital; Key Laboratory of Cancer Prevention and Therapy, Tianjin Cancer Institute; National Clinical Research Center of Cancer, Tianjin 300060, China.
[Ti] Título:Suppression of the Growth and Invasion of Human Head and Neck Squamous Cell Carcinomas via Regulating STAT3 Signaling and the miR-21/ß-catenin Axis with HJC0152.
[So] Source:Mol Cancer Ther;16(4):578-590, 2017 Apr.
[Is] ISSN:1538-8514
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Signal transducer and activator of transcription 3 (STAT3) is involved in the tumor growth and metastasis of human head and neck squamous cell carcinoma (HNSCC) and is therefore a target with therapeutic potential. In this study, we show that HJC0152, a recently developed anticancer agent and a STAT3 signaling inhibitor, exhibits promising antitumor effects against HNSCC both and via inactivating STAT3 and downstream miR-21/ß-catenin axis. HJC0152 treatment efficiently suppressed HNSCC cell proliferation, arrested the cell cycle at the G -G phase, induced apoptosis, and reduced cell invasion in both SCC25 and CAL27 cell lines. Moreover, HJC0152 inhibited nuclear translocation of phosphorylated STAT3 at Tyr705 and decreased VHL/ß-catenin signaling activity via regulation of miR-21. Loss of function of VHL remarkably compromised the antitumor effect of HJC0152 in both cell lines. In our SCC25-derived orthotopic mouse models, HJC0152 treatment significantly abrogated STAT3/ß-catenin expression , leading to a global decrease of tumor growth and invasion. With its favorable aqueous solubility and oral bioavailability, HJC0152 holds the potential to be translated into the clinic as a promising therapeutic strategy for patients with HNSCC. .
[Mh] Termos MeSH primário: Antineoplásicos/administração & dosagem
Carcinoma de Células Escamosas/tratamento farmacológico
Neoplasias de Cabeça e Pescoço/tratamento farmacológico
MicroRNAs/genética
Fator de Transcrição STAT3/genética
Salicilanilidas/administração & dosagem
beta Catenina/genética
[Mh] Termos MeSH secundário: Animais
Antineoplásicos/química
Antineoplásicos/farmacologia
Carcinoma de Células Escamosas/genética
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Sobrevivência Celular/efeitos dos fármacos
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos
Neoplasias de Cabeça e Pescoço/genética
Seres Humanos
Camundongos
Niclosamida/análogos & derivados
Salicilanilidas/química
Salicilanilidas/farmacologia
Transdução de Sinais/efeitos dos fármacos
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (CTNNB1 protein, human); 0 (MIRN21 microRNA, human); 0 (MicroRNAs); 0 (STAT3 Transcription Factor); 0 (STAT3 protein, human); 0 (Salicylanilides); 0 (beta Catenin); 8KK8CQ2K8G (Niclosamide)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170801
[Lr] Data última revisão:
170801
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170201
[St] Status:MEDLINE
[do] DOI:10.1158/1535-7163.MCT-16-0606



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