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Pesquisa : D03.633.100.810.824.700 [Categoria DeCS]
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[PMID]:28606794
[Au] Autor:Jeon KI; Phipps RP; Sime PJ; Huxlin KR
[Ad] Endereço:Flaum Eye Institute, University of Rochester, Rochester, New York.
[Ti] Título:Antifibrotic Actions of Peroxisome Proliferator-Activated Receptor γ Ligands in Corneal Fibroblasts Are Mediated by ß-Catenin-Regulated Pathways.
[So] Source:Am J Pathol;187(8):1660-1669, 2017 Aug.
[Is] ISSN:1525-2191
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Wound healing after corneal injury typically involves fibrosis, with transforming growth factor ß1 (TGF-ß1) as one of its strongest mediators. A class of small molecules-peroxisome proliferator-activated receptor γ (PPARγ) ligands-exert potent antifibrotic effects in the cornea by blocking phosphorylation of p38 mitogen-activated protein kinase (MAPK). However, why this blocks fibrosis remains unknown. Herein, we show that PPARγ ligands (rosiglitazone, troglitazone, and 15-deoxy-Δ12,14-prostaglandin J2) decrease levels of ß-catenin. We also show that ß-catenin siRNA and the Wingless/integrated (Wnt) inhibitor pyrvinium block the ability of corneal fibroblasts to up-regulate synthesis of α-smooth muscle actin (α-SMA), collagen 1 (COL1), and fibronectin (FN) in response to TGF-ß1. Activation of TGF-ß receptors and p38 MAPK increased glycogen synthase kinase 3ß (GSK3ß) phosphorylation, whereas a chemical inhibitor of p38 MAPK (SB203580) reduced the phosphorylation of GSK3ß, decreasing active ß-catenin levels in both cytoplasmic and nuclear fractions. Finally, lithium chloride, a GSK3 inhibitor, also attenuated the TGF-ß1-induced increase in α-SMA, COL1, and FN expression. All in all, our results suggest that TGF-ß1 stimulation increases active ß-catenin concentration in cultured corneal fibroblasts through p38 MAPK regulation of canonical Wnt/ß-catenin signaling, increasing α-SMA, COL1, and FN synthesis. Thus, PPARγ ligands, by blocking TGF-ß1-induced p38 MAPK phosphorylation, prevent increases in both total and active ß-catenin through p38 MAPK-GSK3ß signaling.
[Mh] Termos MeSH primário: Córnea/efeitos dos fármacos
Fibroblastos/efeitos dos fármacos
PPAR gama/agonistas
beta Catenina/metabolismo
[Mh] Termos MeSH secundário: Actinas/metabolismo
Animais
Gatos
Cromanos/farmacologia
Colágeno Tipo I/metabolismo
Córnea/metabolismo
Fibroblastos/metabolismo
Fibronectinas/metabolismo
Fibrose/metabolismo
Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores
Glicogênio Sintase Quinase 3 beta/metabolismo
Cloreto de Lítio/farmacologia
Fosforilação/efeitos dos fármacos
Prostaglandina D2/análogos & derivados
Prostaglandina D2/farmacologia
Compostos de Pirvínio/farmacologia
Receptores de Fatores de Crescimento Transformadores beta/metabolismo
Transdução de Sinais/efeitos dos fármacos
Tiazolidinedionas/farmacologia
Fator de Crescimento Transformador beta1/farmacologia
Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (15-deoxy-delta(12,14)-prostaglandin J2); 0 (Actins); 0 (Chromans); 0 (Collagen Type I); 0 (Fibronectins); 0 (PPAR gamma); 0 (Pyrvinium Compounds); 0 (Receptors, Transforming Growth Factor beta); 0 (Thiazolidinediones); 0 (Transforming Growth Factor beta1); 0 (beta Catenin); 05V02F2KDG (rosiglitazone); 6B9991FLU3 (pyrvinium); EC 2.7.11.1 (Glycogen Synthase Kinase 3 beta); EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases); G4962QA067 (Lithium Chloride); I66ZZ0ZN0E (troglitazone); RXY07S6CZ2 (Prostaglandin D2)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170912
[Lr] Data última revisão:
170912
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170614
[St] Status:MEDLINE


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[PMID]:28348148
[Au] Autor:Stoddart A; Wang J; Hu C; Fernald AA; Davis EM; Cheng JX; Le Beau MM
[Ad] Endereço:Department of Medicine and.
[Ti] Título:Inhibition of WNT signaling in the bone marrow niche prevents the development of MDS in the MDS mouse model.
[So] Source:Blood;129(22):2959-2970, 2017 Jun 01.
[Is] ISSN:1528-0020
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:There is accumulating evidence that functional alteration(s) of the bone marrow (BM) microenvironment contribute to the development of some myeloid disorders, such as myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). In addition to a cell-intrinsic role of WNT activation in leukemia stem cells, WNT activation in the BM niche is also thought to contribute to the pathogenesis of MDS and AML. We previously showed that the -haploinsufficient mice ( ) model MDS induced by an aberrant BM microenvironment. We sought to determine whether Apc, a multifunctional protein and key negative regulator of the canonical ß-catenin (Ctnnb1)/WNT-signaling pathway, mediates this disease through modulating WNT signaling, and whether inhibition of WNT signaling prevents the development of MDS in mice. Here, we demonstrate that loss of 1 copy of is sufficient to prevent the development of MDS in mice and that altered canonical WNT signaling in the microenvironment is responsible for the disease. Furthermore, the US Food and Drug Administration (FDA)-approved drug pyrvinium delays and/or inhibits disease in mice, even when it is administered after the presentation of anemia. Other groups have observed increased nuclear CTNNB1 in stromal cells from a high frequency of MDS/AML patients, a finding that together with our results highlights a potential new strategy for treating some myeloid disorders.
[Mh] Termos MeSH primário: Genes APC
Síndromes Mielodisplásicas/genética
Síndromes Mielodisplásicas/prevenção & controle
Nicho de Células-Tronco/genética
Via de Sinalização Wnt
[Mh] Termos MeSH secundário: Animais
Modelos Animais de Doenças
Haploinsuficiência
Seres Humanos
Células Mesenquimais Estromais/efeitos dos fármacos
Células Mesenquimais Estromais/metabolismo
Células Mesenquimais Estromais/patologia
Camundongos
Camundongos da Linhagem 129
Camundongos Endogâmicos C57BL
Camundongos Knockout
Síndromes Mielodisplásicas/patologia
Compostos de Pirvínio/farmacologia
Via de Sinalização Wnt/genética
beta Catenina/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (CTNNB1 protein, mouse); 0 (Pyrvinium Compounds); 0 (beta Catenin); 6B9991FLU3 (pyrvinium)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170822
[Lr] Data última revisão:
170822
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170329
[St] Status:MEDLINE
[do] DOI:10.1182/blood-2016-08-736454


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[PMID]:28090074
[Au] Autor:Zhang C; Zhang Z; Zhang S; Wang W; Hu P
[Ad] Endereço:Department of Obstetrics and Gynaecology, Jingzhou Central Hospital, The Second Clinical Medical College, Yangtze University, Jingzhou, Hubei, China (mainland).
[Ti] Título:Targeting of Wnt/ß-Catenin by Anthelmintic Drug Pyrvinium Enhances Sensitivity of Ovarian Cancer Cells to Chemotherapy.
[So] Source:Med Sci Monit;23:266-275, 2017 Jan 16.
[Is] ISSN:1643-3750
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND Aberrant activation of Wnt/ß-catenin has been shown to promote ovarian cancer proliferation and chemoresistance. Pyrvinium, an FDA-approved anthelmintic drug, has been identified as a potent Wnt inhibitor. Pyrvinium may sensitize ovarian cancer cells to chemotherapy. MATERIAL AND METHODS The effect of pyrvinium alone and its combination with paclitaxel in ovarian cancer was investigated using an in vitro culture system and in vivo xenograft models. The mechanisms of its action were also analyzed, focusing on the Wnt/ß-catenin pathway. RESULTS Pyrvinium inhibited growth and induced apoptosis of paclitaxel- and cisplatin-resistant epithelial ovarian cancer cell lines A2278/PTX and SK-OV-3. Its combination with paclitaxel was synergistic in targeting ovarian cancer cells in vitro. In 3 independent ovarian xenograft mouse models, pyrvinium alone inhibited tumor growth. More importantly, we observed significant inhibition of tumor growth throughout the treatment when using pyrvinium and paclitaxel combined. Mechanistically, pyrvinium increased the Wnt-negative regulator axin and decreased the b-catenin levels in ovarian cancer cells. In addition, pyrvinium suppressed Wnt/b-catenin-mediated transcription, as shown by the decreased mRNA levels of MYC, cyclin D, and BCL-9. In contrast, the inhibitory effects of pyrvinium were reversed by ß-catenin stabilization or overexpression, demonstrating that pyrvinium acted on ovarian cancer cells via targeting the Wnt/ß-catenin signaling pathway. CONCLUSIONS We demonstrated that the anthelmintic drug pyrvinium targets ovarian cancer cells through suppressing Wnt/ß-catenin signaling. Our work highlights the therapeutic value of inhibiting Wnt/ß-catenin in ovarian cancer.
[Mh] Termos MeSH primário: Anti-Helmínticos/farmacologia
Antineoplásicos/uso terapêutico
Neoplasias Ovarianas/tratamento farmacológico
Neoplasias Ovarianas/patologia
Compostos de Pirvínio/farmacologia
Via de Sinalização Wnt/efeitos dos fármacos
[Mh] Termos MeSH secundário: Animais
Antineoplásicos/farmacologia
Apoptose/efeitos dos fármacos
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Resistência a Medicamentos Antineoplásicos/efeitos dos fármacos
Sinergismo Farmacológico
Feminino
Seres Humanos
Cloreto de Lítio/farmacologia
Camundongos SCID
Paclitaxel/farmacologia
beta Catenina/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anthelmintics); 0 (Antineoplastic Agents); 0 (Pyrvinium Compounds); 0 (beta Catenin); 6B9991FLU3 (pyrvinium); G4962QA067 (Lithium Chloride); P88XT4IS4D (Paclitaxel)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170627
[Lr] Data última revisão:
170627
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170117
[St] Status:MEDLINE


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[PMID]:27189319
[Au] Autor:Torp-Pedersen A; Jimenez-Solem E; Cejvanovic V; Poulsen HE; Andersen JT
[Ad] Endereço:a Department of Clinical Pharmacology , Copenhagen University Hospital , Bispebjerg , Copenhagen , Denmark.
[Ti] Título:Birth outcomes after exposure to mebendazole and pyrvinium during pregnancy - A Danish nationwide cohort study.
[So] Source:J Obstet Gynaecol;36(8):1020-1025, 2016 Nov.
[Is] ISSN:1364-6893
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Mebendazole and pyrvinium are anthelmintics used to treat infections with pinworms, a common infection in children. Other indications for treatment with mebendazole are infections with soil-transmitted helminths. These infections are rare in Denmark, but affect more than 1.5 billion people worldwide. Limited safety data of anthelmintics during pregnancy exists and the purpose of this study was to investigate the association between exposure to mebendazole or pyrvinium during pregnancy and the adverse pregnancy outcomes: congenital malformations, stillbirths, neonatal mortality and small for gestational age. The Danish Fertility Database was used to identify all births in Denmark from 1997 to 2007. Maternal exposure to anthelmintics was identified through The Danish Prescription Registry. Of 713667 births, 2567 mothers redeemed a prescription for mebendazole; 1588 for pyrvinium. Logistic regression analysis adjusted for potential confounders. We found no association between exposure to mebendazole and major congenital malformations (OR = 0.7 (CI 95% 0.5-1.1)) or other negative birth outcomes and we found no association between exposure to pyrvinium and major congenital malformations (OR = 0.8 (CI 95% 0.4-1.5)) or other negative birth outcomes. No increased risk was found of having negative birth outcomes after exposure at any trimester during pregnancy.
[Mh] Termos MeSH primário: Anti-Helmínticos/uso terapêutico
Exposição Materna
Mebendazol/uso terapêutico
Resultado da Gravidez
Compostos de Pirvínio/uso terapêutico
[Mh] Termos MeSH secundário: Anormalidades Induzidas por Medicamentos/epidemiologia
Adolescente
Adulto
Estudos de Coortes
Dinamarca/epidemiologia
Feminino
Helmintíase/tratamento farmacológico
Seres Humanos
Lactente
Mortalidade Infantil
Recém-Nascido
Recém-Nascido Pequeno para a Idade Gestacional
Meia-Idade
Gravidez
Complicações Parasitárias na Gravidez/tratamento farmacológico
Sistema de Registros
Natimorto/epidemiologia
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anthelmintics); 0 (Pyrvinium Compounds); 6B9991FLU3 (pyrvinium); 81G6I5V05I (Mebendazole)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170626
[Lr] Data última revisão:
170626
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160519
[St] Status:MEDLINE


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[PMID]:27126388
[Au] Autor:Gerstein AC; Rosenberg A; Hecht I; Berman J
[Ad] Endereço:3​Department of Microbiology & Immunology, Medical School, University of Minnesota, MN, USA 2​Department of Genetics, Cell Biology & Development, College of Biological Sciences, University of Minnesota, MN, USA 1​Department of Molecular Microbiology and Biotechnology, George S. Wise Fa
[Ti] Título:diskImageR: quantification of resistance and tolerance to antimicrobial drugs using disk diffusion assays.
[So] Source:Microbiology;162(7):1059-68, 2016 Jul.
[Is] ISSN:1465-2080
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Microbial pathogens represent an increasing threat to human health. Although many infections can be successfully treated and cleared, drug resistance is a widespread problem. The existence of subpopulations of 'tolerant' cells (where a fraction of the population is able to grow above the population resistance level) may increase the rate of treatment failure; yet, existing methods to measure subpopulation effects are cumbersome. Here we describe diskImageR, a computational pipeline that analyses photographs of disk diffusion assays to determine the degree of drug susceptibility [the radius of inhibition, (RAD)], and two aspects of subpopulation growth [the fraction of growth (FoG) within the zone of inhibition, (ZOI), and the rate of change in growth from no drug to inhibitory drug concentrations, (SLOPE)]. diskImageR was used to examine the response of the human fungal pathogen Candida albicans to the antifungal drug fluconazole across different strain backgrounds and growth conditions. Disk diffusion assays performed under Clinical and Laboratory Standards Institute (CLSI) conditions led to more susceptibility and less tolerance than assays performed using rich medium conditions. We also used diskImageR to quantify the effects of three drugs in combination with fluconazole, finding that all three combinations affected tolerance, with the effect of one drug (doxycycline) being very strain dependent. The three drugs had different effects on susceptibility, with doxycycline generally having no effect, chloroquine generally increasing susceptibility and pyrvinium pamoate generally reducing susceptibility. The ability to simultaneously quantitate different aspects of microbial drug responses will facilitate the study of mechanisms of subpopulation responses in the presence of antimicrobial drugs.
[Mh] Termos MeSH primário: Antifúngicos/farmacologia
Candida albicans/efeitos dos fármacos
Candida albicans/crescimento & desenvolvimento
Testes de Sensibilidade a Antimicrobianos por Disco-Difusão/métodos
Software
[Mh] Termos MeSH secundário: Candida albicans/isolamento & purificação
Cloroquina/farmacologia
Doxiciclina/farmacologia
Farmacorresistência Fúngica
Fluconazol/farmacologia
Seres Humanos
Compostos de Pirvínio/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antifungal Agents); 0 (Pyrvinium Compounds); 6B9991FLU3 (pyrvinium); 886U3H6UFF (Chloroquine); 8VZV102JFY (Fluconazole); N12000U13O (Doxycycline)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170907
[Lr] Data última revisão:
170907
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160430
[St] Status:MEDLINE
[do] DOI:10.1099/mic.0.000295


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[PMID]:27032189
[Au] Autor:Nagashima F; Tabuchi Y; Ito T; Harinantenaina L; Asakawa Y
[Ti] Título:Terpenoids, Flavonoids and Acetogenins from Some Malagasy Plants.
[So] Source:Nat Prod Commun;11(2):153-7, 2016 Feb.
[Is] ISSN:1934-578X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Humulanes, drimanes, ent-kaurane, lupane, cycloartane, flavanone, flavones and quinol derivatives were isolated from Malagasy Cussonia vantsilana, Helichrysum gymnocephalum, Phyllarthron madagascariense, Gomphocarpus fructicosus, Cinnamosma sp. and C. fragrans, and their structures elucidated by using extensive NMR analysis. A mixture of a few flavones and/or lupane triterpene showed antimicrobial activity against Mycobacterium smegmatis and Pseudomonas aeruginosa.
[Mh] Termos MeSH primário: Acetogeninas/química
Flavonoides/química
Plantas/química
Terpenos/química
[Mh] Termos MeSH secundário: Madagáscar
Modelos Moleculares
Plantas/classificação
Compostos de Pirvínio
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Acetogenins); 0 (Flavonoids); 0 (Pyrvinium Compounds); 0 (Terpenes); 6B9991FLU3 (pyrvinium)
[Em] Mês de entrada:1605
[Cu] Atualização por classe:160401
[Lr] Data última revisão:
160401
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160402
[St] Status:MEDLINE


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[PMID]:26881712
[Au] Autor:Yang EJ; Wu C; Liu Y; Lv J; Sup Shim J
[Ti] Título:Revisiting Non-Cancer Drugs for Cancer Therapy.
[So] Source:Curr Top Med Chem;16(19):2144-55, 2016.
[Is] ISSN:1873-4294
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Although tremendous effort has been made over the past century to treat cancer effectively, the pace of drug development is far behind the increasing rate of cancer incidence and mortality. There are two major hurdles in anticancer drug development: dose-limiting toxic side effects that reduce either drug effectiveness or the quality of life of patients and complicated drug development processes that are costly and time consuming. Drug repositioning has recently gained increasing attention among cancer researchers as this approach utilizes existing drugs and is significantly cost- and time-effective. Existing drugs, particularly non-cancer drugs, have favorable safety profiles in humans and serve as an ever-increasing source for new anticancer drug discovery. Here we review the recent examples of drug repositioning of existing non-cancer drugs for preclinical and clinical introductions of cancer therapy.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Reposicionamento de Medicamentos/métodos
[Mh] Termos MeSH secundário: Antineoplásicos/química
Antineoplásicos/uso terapêutico
Dissulfiram/química
Dissulfiram/farmacologia
Doxiciclina/química
Doxiciclina/farmacologia
Ensaios de Triagem em Larga Escala
Seres Humanos
Mebendazol/química
Mebendazol/farmacologia
Neoplasias/tratamento farmacológico
Compostos de Pirvínio/química
Compostos de Pirvínio/farmacologia
Triclosan/química
Triclosan/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Pyrvinium Compounds); 4NM5039Y5X (Triclosan); 6B9991FLU3 (pyrvinium); 81G6I5V05I (Mebendazole); N12000U13O (Doxycycline); TR3MLJ1UAI (Disulfiram)
[Em] Mês de entrada:1702
[Cu] Atualização por classe:170208
[Lr] Data última revisão:
170208
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160217
[St] Status:MEDLINE


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[PMID]:26781188
[Au] Autor:Xu L; Zhang L; Hu C; Liang S; Fei X; Yan N; Zhang Y; Zhang F
[Ad] Endereço:Department of Oncology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, P.R. China.
[Ti] Título:WNT pathway inhibitor pyrvinium pamoate inhibits the self-renewal and metastasis of breast cancer stem cells.
[So] Source:Int J Oncol;48(3):1175-86, 2016 Mar.
[Is] ISSN:1791-2423
[Cp] País de publicação:Greece
[La] Idioma:eng
[Ab] Resumo:Acquisition of chemoresistance and metastatic phenotype are the major causes of breast cancer treatment failure and cancer-related mortality. Recently, a plethora of experimental and clinical studies points toward a central role of cancer stem cells (CSCs) in the chemoresistance and metastasis. In the present study, we demonstrated that pyrvinium pamoate (PP), an anthelmintic drug, inhibited proliferation of different subtypes of breast cancer cells (luminal: MCF-7, claudin-low: MDA-MB­231, basal-like: MDA-MB­468 and Her-2 enriched: SkBr-3) as a novel WNT pathway inhibitor. Additionally, PP was also shown to inhibit self-renewal of breast cancer stem cells (BCSCs) and decrease both CD44+CD24-/low and ALDH-positive BCSCs content in a panel of breast cancer cell lines. Besides, the metastatic potential and expression of EMT markers (such as N-cadherin, vimentin, Snail) were also found suppressed by PP. By using a xenograft model, we next tested the efficacy of PP on tumorigenicity of MDA-MB­231, one of the most aggressive breast cancer cell lines, and we observed PP significantly delayed tumor growth in vivo. Moreover, in-depth analysis revealed that PP caused inhibition of WNT pathway activity and stemness regulator expression including NANOG, SOX2 and OCT4, which were inherently upregulated in the BCSCs as compared with the bulk of cells within the tumor. Collectively, our findings provide direct evidence for PP serving as a promising high-yield agent targeting BCSCs and cancer heterogeneity. Therefore, strategies combining PP with standard chemotherapy drugs which fail to eliminate the BCSCs hold promise to overcome BCSCs associated treatment resistance and achieve a better therapeutic outcome.
[Mh] Termos MeSH primário: Neoplasias da Mama/metabolismo
Células-Tronco Neoplásicas/citologia
Compostos de Pirvínio/química
Via de Sinalização Wnt
[Mh] Termos MeSH secundário: Animais
Antineoplásicos/química
Antígeno CD24/metabolismo
Linhagem Celular Tumoral
Movimento Celular
Proliferação Celular
Transição Epitelial-Mesenquimal
Feminino
Seres Humanos
Receptores de Hialuronatos/metabolismo
Células MCF-7
Neoplasias Mamárias Experimentais/metabolismo
Camundongos
Camundongos Endogâmicos NOD
Camundongos SCID
Invasividade Neoplásica
Metástase Neoplásica
Transplante de Neoplasias
Reação em Cadeia da Polimerase
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (CD24 Antigen); 0 (CD44 protein, human); 0 (Hyaluronan Receptors); 0 (Pyrvinium Compounds); 6B9991FLU3 (pyrvinium)
[Em] Mês de entrada:1611
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160120
[St] Status:MEDLINE
[do] DOI:10.3892/ijo.2016.3337


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[PMID]:26707639
[Au] Autor:Xiao M; Zhang L; Zhou Y; Rajoria P; Wang C
[Ad] Endereço:Department of Laboratory Medicine, JingZhou Hospital, Tongji Medical College, Huazhong University of Science and Technology (HUST), Jing Zhou, People's Republic of China.
[Ti] Título:Pyrvinium selectively induces apoptosis of lymphoma cells through impairing mitochondrial functions and JAK2/STAT5.
[So] Source:Biochem Biophys Res Commun;469(3):716-22, 2016 Jan 15.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Targeting mitochondrial respiration has emerged as an attractive therapeutic strategy in blood cancer due to their unique metabolic dependencies. In this study, we show that pyrvinium, a FDA-approved anthelmintic drug, selectively targets lymphoma T-cells though inhibition of mitochondrial functions and JAK2/STAT5. Pyrvinium induces apoptosis of malignant T-cell line Jurkat and primary T-cells from lymphoma patients while sparing T-cells from healthy donors. Increased level of active caspase-3 and decreased levels of Bcl-2 and Mcl-1 were also observed in Jurkat and lymphoma T-cells but not normal T-cells treated with pyrvinium. In addition, pyrvinium impairs mitochondrial functions by inhibit mitochondrial respiration, suppressing mitochondrial respiratory complex I activity, increasing ROS and decreasing ATP levels. However, the effects of pyrvinium were abolished in mitochondrial respiration-deficient Jurkat ρ(0) cells, confirming that pyrvinium acts on lymphoma T-cells via targeting mitochondrial respiration. We further show that lymphoma T-cells derived from patients depend more on mitochondrial respiration than normal T-cells, and this explains the selective toxicity of pyrvinium in lymphoma versus normal T-cells. Finally, we demonstrate that pyrvinium also suppresses JAK2/STAT5 signaling pathway in Jurkat cells. Our study suggests that pyrvinium is a useful addition to T-cell lymphoma treatment, and emphasizes the potential therapeutic value of the differences in the mitochondrial characteristics between malignant and normal T-cells in blood cancer.
[Mh] Termos MeSH primário: Apoptose/efeitos dos fármacos
Janus Quinase 2/metabolismo
Linfoma/tratamento farmacológico
Linfoma/metabolismo
Compostos de Pirvínio/administração & dosagem
Fator de Transcrição STAT5/metabolismo
[Mh] Termos MeSH secundário: Anti-Helmínticos/administração & dosagem
Antineoplásicos/administração & dosagem
Respiração Celular/efeitos dos fármacos
Relação Dose-Resposta a Droga
Seres Humanos
Células Jurkat
Linfoma/patologia
Mitocôndrias
Transdução de Sinais/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Anthelmintics); 0 (Antineoplastic Agents); 0 (Pyrvinium Compounds); 0 (STAT5 Transcription Factor); 6B9991FLU3 (pyrvinium); EC 2.7.10.2 (JAK2 protein, human); EC 2.7.10.2 (Janus Kinase 2)
[Em] Mês de entrada:1605
[Cu] Atualização por classe:160117
[Lr] Data última revisão:
160117
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151229
[St] Status:MEDLINE


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[PMID]:26378050
[Au] Autor:Xiang W; Cheong JK; Ang SH; Teo B; Xu P; Asari K; Sun WT; Than H; Bunte RM; Virshup DM; Chuah C
[Ad] Endereço:Department of Haematology, Singapore General Hospital, Singapore.
[Ti] Título:Pyrvinium selectively targets blast phase-chronic myeloid leukemia through inhibition of mitochondrial respiration.
[So] Source:Oncotarget;6(32):33769-80, 2015 Oct 20.
[Is] ISSN:1949-2553
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The use of BCR-ABL1 tyrosine kinase inhibitors (TKI) has led to excellent clinical responses in patients with chronic phase chronic myeloid leukemia (CML). However these inhibitors have been less effective as single agents in the terminal blast phase (BP). We show that pyrvinium, a FDA-approved anthelminthic drug, selectively targets BP-CML CD34+ progenitor cells. Pyrvinium is effective in inducing apoptosis, inhibiting colony formation and self-renewal capacity of CD34+ cells from TKI-resistant BP-CML patients, while cord blood CD34+ are largely unaffected. The effects of pyrvinium are further enhanced upon combination with dasatinib, a second generation BCR-ABL1 TKI. In a CML xenograft model pyrvinium significantly inhibits tumor growth as a single agent, with complete inhibition in combination with dasatinib. While pyrvinium has been shown to inhibit the Wnt/ß-catenin signalling pathway via activation of casein kinase 1α , we find its activity in CML is not dependent on this pathway. Instead, we show that pyrvinium localizes to mitochondria and induces apoptosis by inhibiting mitochondrial respiration. Our study suggests that pyrvinium is a useful addition to the treatment armamentarium for BP-CML and that targeting mitochondrial respiration may be a potential therapeutic strategy in aggressive leukemia.
[Mh] Termos MeSH primário: Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico
Mitocôndrias/metabolismo
Compostos de Pirvínio/administração & dosagem
[Mh] Termos MeSH secundário: Trifosfato de Adenosina/química
Animais
Antígenos CD34/metabolismo
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico
Apoptose
Crise Blástica/metabolismo
Caseína Quinase I/metabolismo
Linhagem Celular Tumoral
Proliferação Celular
Dasatinibe/administração & dosagem
Dasatinibe/uso terapêutico
Seres Humanos
Concentração Inibidora 50
Células K562
Camundongos
Camundongos SCID
Transplante de Neoplasias
Fosforilação
Compostos de Pirvínio/uso terapêutico
Interferência de RNA
beta Catenina/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antigens, CD34); 0 (Pyrvinium Compounds); 0 (beta Catenin); 6B9991FLU3 (pyrvinium); 8L70Q75FXE (Adenosine Triphosphate); EC 2.7.11.1 (Casein Kinase I); RBZ1571X5H (Dasatinib)
[Em] Mês de entrada:1608
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150918
[St] Status:MEDLINE
[do] DOI:10.18632/oncotarget.5615



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