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Pesquisa : D02.455.426.559.847.181 [Categoria DeCS]
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[PMID]:28278671
[Au] Autor:Todorova M; Trendafilova A; Ivanova V; Danova K; Dimitrov D
[Ad] Endereço:a Institute of Organic Chemistry with Centre of Phytochemistry , Bulgarian Academy of Sciences , Sofia , Bulgaria.
[Ti] Título:Essential oil composition of Inula britannica L. from Bulgaria.
[So] Source:Nat Prod Res;31(14):1693-1696, 2017 Jul.
[Is] ISSN:1478-6427
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The separately distilled flowers (F) and leaves' (L) essential oils of Inula britannica L. were investigated using capillary gas chromatography-flame ionization detector (GC-FID) and gas chromatography-mass spectrometry (GC-MS). A total of 83 constituents, representing 96.91% (F) and 96.73% (L) of the total oils, were registered. The oils were rich in terpenoids (57.85% and 77.28%), of which sesquiterpenoids dominated. The main constituents of the essential oils were viridiflorol (7.17%-8.20%) and himachalol (3.45%-8.71%) followed by 6,10,14-trimethyl-2-pentadecanone (5.43%-2.95%), 13-tetradecanolide (3.93%-4.87%) and 3-methyl-4-propyl-2,5-furandione (4.06%-0.29%).
[Mh] Termos MeSH primário: Inula/química
Óleos Voláteis/análise
Óleos Vegetais/análise
[Mh] Termos MeSH secundário: Benzocicloeptenos/análise
Benzocicloeptenos/isolamento & purificação
Bulgária
Flores/química
Cromatografia Gasosa-Espectrometria de Massas/métodos
Óleos Voláteis/química
Folhas de Planta/química
Óleos Vegetais/química
Sesquiterpenos/análise
Sesquiterpenos/isolamento & purificação
Terpenos/análise
Terpenos/isolamento & purificação
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Benzocycloheptenes); 0 (Oils, Volatile); 0 (Plant Oils); 0 (Sesquiterpenes); 0 (Terpenes); 1891-45-8 (himachalol); HN71V2CRMY (viridiflorol)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170311
[St] Status:MEDLINE
[do] DOI:10.1080/14786419.2017.1285295


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[PMID]:28119166
[Au] Autor:Vogel KR; Ainslie GR; Roullet JB; McConnell A; Gibson KM
[Ad] Endereço:Department of Pharmacotherapy, College of Pharmacy, Washington State University, Spokane, WA, United States.
[Ti] Título:In vitro toxicological evaluation of NCS-382, a high-affinity antagonist of γ-hydroxybutyrate (GHB) binding.
[So] Source:Toxicol In Vitro;40:196-202, 2017 Apr.
[Is] ISSN:1879-3177
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:γ-Hydroxybutyric acid (GHB), a minor metabolite of the inhibitory neurotransmitter GABA, can accumulate to significant concentrations in the heritable disorder of GABA degradation, succinic semialdehyde dehydrogenase (SSADH) deficiency (SSADHD). Moreover, GHB may be employed in therapeutic settings (treatment of narcolepsy), as well as instances of illicit activity, including acquaintance sexual assault and the induction of euphoria. High-affinity binding sites for GHB in the brain have been identified, although the absolute identity of these receptors remains unclear. Pharmacological antagonism of GHB binding may have multiple instances of therapeutic relevance. The high affinity GHB receptor antagonist, NCS-382 (6,7,8,9-tetrahydro-5-hydroxy-5H-benzo-cyclohept-6-ylideneacetic acid) has not been piloted in humans. To address the potential clinical utility of NCS-382, we have piloted initial studies of its toxicology in HepG2 and primary hepatocyte cells. At high dose (0.5mM), NCS-382 showed no capacity for inhibition of microsomal CYPs (CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6 and 3A4) and minimal potential for activation of xenobiotic nuclear receptors. Additional cellular integrity and functional assays (viability, oxidative stress, apoptosis, ATP production) revealed little evidence for cytotoxicity, and a low degree of dysregulation of >370 genes actively engaged in the mediation of cellular toxicity. In vitro testing indicates a low probability of cellular toxicity associated with NCS-382.
[Mh] Termos MeSH primário: Benzocicloeptenos/farmacologia
Hidroxibutiratos/metabolismo
Receptores de Superfície Celular/antagonistas & inibidores
[Mh] Termos MeSH secundário: Sobrevivência Celular/efeitos dos fármacos
Células Cultivadas
Inibidores das Enzimas do Citocromo P-450/farmacologia
Sistema Enzimático do Citocromo P-450/genética
Sistema Enzimático do Citocromo P-450/metabolismo
Interações Medicamentosas
Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos
Células Hep G2
Hepatócitos/efeitos dos fármacos
Seres Humanos
Microssomos Hepáticos/efeitos dos fármacos
Microssomos Hepáticos/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (4-hydroxybutyric acid receptor); 0 (Benzocycloheptenes); 0 (Cytochrome P-450 Enzyme Inhibitors); 0 (Hydroxybutyrates); 0 (Receptors, Cell Surface); 131733-92-1 (NCS 382); 30IW36W5B2 (4-hydroxybutyric acid); 9035-51-2 (Cytochrome P-450 Enzyme System)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170726
[Lr] Data última revisão:
170726
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170126
[St] Status:MEDLINE


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[PMID]:27389179
[Au] Autor:Tong LS; Shao AW; Ou YB; Guo ZN; Manaenko A; Dixon BJ; Tang J; Lou M; Zhang JH
[Ad] Endereço:1 Department of Anesthesiology, School of Medicine, Loma Linda University, CA, USA.
[Ti] Título:Recombinant Gas6 augments Axl and facilitates immune restoration in an intracerebral hemorrhage mouse model.
[So] Source:J Cereb Blood Flow Metab;37(6):1971-1981, 2017 Jun.
[Is] ISSN:1559-7016
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Axl, a tyrosine kinase receptor, was recently identified as an essential component regulating innate immune response. Suppressor of cytokine signaling 1 and suppressor of cytokine signaling 3 are potent Axl-inducible negative inflammatory regulators. This study investigated the role of Axl signaling pathway in immune restoration in an autologous blood-injection mouse model of intracerebral hemorrhage. Recombinant growth arrest-specific 6 (Gas6) and R428 were administrated as specific agonist and antagonist. In vivo knockdown of Axl or suppressor of cytokine signaling 1 and suppressor of cytokine signaling 3 by siRNA was applied. After intracerebral hemorrhage, the expression of endogenous Axl, soluble Axl, and Gas6 was increased, whereas the expression of suppressor of cytokine signaling 1 and suppressor of cytokine signaling 3 was inhibited. Recombinant growth arrest-specific 6 administration alleviated brain edema and improved neurobehavioral performances. Moreover, enhanced Axl phosphorylation with cleavage of soluble Axl (sAxl), and an upregulation of suppressor of cytokine signaling 1 and suppressor of cytokine signaling 3 were observed. In vivo knockdown of Axl and R428 administration both abolished the effect of recombinant growth arrest-specific 6 on brain edema and also decreased the expression suppressor of cytokine signaling 1 and suppressor of cytokine signaling 3. In vivo knockdown of suppressor of cytokine signaling 1 and suppressor of cytokine signaling 3 aggravated cytokine releasing despite of recombinant growth arrest-specific 6. In conclusion, Axl plays essential role in immune restoration after intracerebral hemorrhage. And recombinant growth arrest-specific 6 attenuated brain injury after intracerebral hemorrhage, probably by enhancing Axl phosphorylation and production of suppressor of cytokine signaling 1 and suppressor of cytokine signaling 3.
[Mh] Termos MeSH primário: Hemorragia Cerebral/tratamento farmacológico
Imunidade Inata/efeitos dos fármacos
Peptídeos e Proteínas de Sinalização Intercelular/uso terapêutico
Proteínas Proto-Oncogênicas/agonistas
Receptores Proteína Tirosina Quinases/agonistas
[Mh] Termos MeSH secundário: Administração Intranasal
Animais
Comportamento Animal/efeitos dos fármacos
Benzocicloeptenos/farmacologia
Hemorragia Cerebral/imunologia
Hemorragia Cerebral/metabolismo
Citocinas/secreção
Modelos Animais de Doenças
Peptídeos e Proteínas de Sinalização Intercelular/genética
Peptídeos e Proteínas de Sinalização Intercelular/metabolismo
Masculino
Camundongos Endogâmicos
Camundongos Knockout
Proteínas Proto-Oncogênicas/antagonistas & inibidores
Proteínas Proto-Oncogênicas/genética
Receptores Proteína Tirosina Quinases/antagonistas & inibidores
Receptores Proteína Tirosina Quinases/genética
Proteínas Recombinantes
Triazóis/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Benzocycloheptenes); 0 (Cytokines); 0 (Intercellular Signaling Peptides and Proteins); 0 (Proto-Oncogene Proteins); 0 (R428 compound); 0 (Recombinant Proteins); 0 (Triazoles); 0 (growth arrest-specific protein 6); EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases); EC 2.7.10.1 (axl receptor tyrosine kinase)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170811
[Lr] Data última revisão:
170811
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160709
[St] Status:MEDLINE
[do] DOI:10.1177/0271678X16658490


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[PMID]:28025482
[Au] Autor:von Mässenhausen A; Brägelmann J; Billig H; Thewes B; Queisser A; Vogel W; Kristiansen G; Schröck A; Bootz F; Brossart P; Kirfel J; Perner S
[Ad] Endereço:Section of Prostate Cancer Research, University Hospital of Bonn, 53127 Bonn, Germany. anne.vonmaessenhausen@gmail.com.
[Ti] Título:Implication of the Receptor Tyrosine Kinase AXL in Head and Neck Cancer Progression.
[So] Source:Int J Mol Sci;18(1), 2016 Dec 22.
[Is] ISSN:1422-0067
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:Head and neck squamous cell carcinoma (HNSCC) remains a clinical challenge and identification of novel therapeutic targets is necessary. The receptor tyrosine kinase AXL has been implicated in several tumor entities and a selective AXL small molecule inhibitor (BGB324) is currently being tested in clinical trials for patients suffering from non-small cell lung cancer or acute myeloid leukemia. Our study investigates AXL expression during HNSCC progression and its use as a potential therapeutic target in HNSCC. AXL protein expression was determined in a HNSCC cohort ( = 364) using immunohistochemical staining. For functional validation, AXL was either overexpressed or inhibited with BGB324 in HNSCC cell lines to assess proliferation, migration and invasion. We found AXL protein expression increasing during tumor progression with highest expression levels in recurrent tumors. In HNSCC cell lines in vitro, AXL overexpression increased migration as well as invasion. Both properties could be reduced through treatment with BGB324. In contrast, proliferation was neither affected by AXL overexpression nor by inhibition with BGB324. Our patient-derived data and in vitro results show that, in HNSCC, AXL is important for the progression to more advanced tumor stages. Moreover, they suggest that AXL could be a target for precision medicine approaches in this dismal tumor entity.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Benzocicloeptenos/farmacologia
Carcinoma/metabolismo
Neoplasias de Cabeça e Pescoço/metabolismo
Inibidores de Proteínas Quinases/farmacologia
Proteínas Proto-Oncogênicas/metabolismo
Receptores Proteína Tirosina Quinases/metabolismo
Triazóis/farmacologia
[Mh] Termos MeSH secundário: Benzocicloeptenos/toxicidade
Linhagem Celular Tumoral
Movimento Celular/efeitos dos fármacos
Proliferação Celular/efeitos dos fármacos
Seres Humanos
Proteínas Proto-Oncogênicas/antagonistas & inibidores
Receptores Proteína Tirosina Quinases/antagonistas & inibidores
Triazóis/toxicidade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Benzocycloheptenes); 0 (Protein Kinase Inhibitors); 0 (Proto-Oncogene Proteins); 0 (R428 compound); 0 (Triazoles); EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases); EC 2.7.10.1 (axl receptor tyrosine kinase)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:170411
[Lr] Data última revisão:
170411
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161228
[St] Status:MEDLINE


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[PMID]:27597997
[Au] Autor:Sundaram K; Rahman MA; Mitra S; Knoell DL; Woodiga SA; King SJ; Wewers MD
[Ad] Endereço:Pulmonary, Allergy, Critical Care and Sleep Medicine, Davis Heart and Lung Research Institute, Department of Internal Medicine, Ohio State University Medical Center, Columbus, Ohio, United States of America.
[Ti] Título:IκBζ Regulates Human Monocyte Pro-Inflammatory Responses Induced by Streptococcus pneumoniae.
[So] Source:PLoS One;11(9):e0161931, 2016.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Pneumococcal lung infections represent a major cause of death worldwide. Single nucleotide polymorphisms (SNPs) in the NFKBIZ gene, encoding the transcription factor IκBζ, are associated with increased susceptibility to invasive pneumococcal disease. We hence analyzed how IκBζ might regulate inflammatory responses to pneumococcal infection. We first demonstrate that IκBζ is expressed in human blood monocytes but not in bronchial epithelial cells, in response to wild type pneumococcal strain D39. D39 transiently induced IκBζ in a dose dependent manner, with subsequent induction of downstream molecules involved in host defense. Of these molecules, IκBζ knockdown reduced the expression of IL-6 and GMCSF. Furthermore, IκBζ overexpression increased the activity of IL-6 and GMCSF promoters, supporting the knockdown findings. Pneumococci lacking either pneumolysin or capsule still induced IκBζ. While inhibition of TLR1/TLR2 blocked D39 induced IκBζ expression, TLR4 inhibition did not. Blockade of p38 MAP kinase and NFκB suppressed D39 induced IκBζ. Overall, our data demonstrates that IκBζ regulates monocyte inflammatory responses to Streptococcus pneumoniae by promoting the production of IL-6 and GMCSF.
[Mh] Termos MeSH primário: Células Epiteliais/imunologia
Interações Hospedeiro-Patógeno
Proteínas I-kappa B/imunologia
Monócitos/imunologia
Proteínas Nucleares/imunologia
Streptococcus pneumoniae/fisiologia
[Mh] Termos MeSH secundário: Benzocicloeptenos/farmacologia
Brônquios/efeitos dos fármacos
Brônquios/imunologia
Brônquios/microbiologia
Células Epiteliais/efeitos dos fármacos
Células Epiteliais/microbiologia
Regulação da Expressão Gênica
Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética
Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia
Seres Humanos
Proteínas I-kappa B/antagonistas & inibidores
Proteínas I-kappa B/genética
Interleucina-6/genética
Interleucina-6/imunologia
Lipopolissacarídeos/farmacologia
Monócitos/efeitos dos fármacos
Monócitos/microbiologia
NF-kappa B/genética
NF-kappa B/imunologia
Proteínas Nucleares/antagonistas & inibidores
Proteínas Nucleares/genética
Cultura Primária de Células
RNA Interferente Pequeno/genética
RNA Interferente Pequeno/imunologia
Transdução de Sinais
Streptococcus pneumoniae/efeitos dos fármacos
Receptor 1 Toll-Like/antagonistas & inibidores
Receptor 1 Toll-Like/genética
Receptor 1 Toll-Like/imunologia
Receptor 2 Toll-Like/antagonistas & inibidores
Receptor 2 Toll-Like/genética
Receptor 2 Toll-Like/imunologia
Receptor 4 Toll-Like/antagonistas & inibidores
Receptor 4 Toll-Like/genética
Receptor 4 Toll-Like/imunologia
Proteínas Quinases p38 Ativadas por Mitógeno/genética
Proteínas Quinases p38 Ativadas por Mitógeno/imunologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Benzocycloheptenes); 0 (I-kappa B Proteins); 0 (IL6 protein, human); 0 (Interleukin-6); 0 (Lipopolysaccharides); 0 (NF-kappa B); 0 (NFKBIZ protein, human); 0 (Nuclear Proteins); 0 (RNA, Small Interfering); 0 (TLR2 protein, human); 0 (TLR4 protein, human); 0 (Toll-Like Receptor 1); 0 (Toll-Like Receptor 2); 0 (Toll-Like Receptor 4); 83869-56-1 (Granulocyte-Macrophage Colony-Stimulating Factor); EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170802
[Lr] Data última revisão:
170802
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160907
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0161931


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[PMID]:27527804
[Au] Autor:Ott GR; Cheng M; Learn KS; Wagner J; Gingrich DE; Lisko JG; Curry M; Mesaros EF; Ghose AK; Quail MR; Wan W; Lu L; Dobrzanski P; Albom MS; Angeles TS; Wells-Knecht K; Huang Z; Aimone LD; Bruckheimer E; Anderson N; Friedman J; Fernandez SV; Ator MA; Ruggeri BA; Dorsey BD
[Ad] Endereço:Teva Branded Pharmaceutical Products R&D , 145 Brandywine Parkway, West Chester, Pennsylvania 19380, United States.
[Ti] Título:Discovery of Clinical Candidate CEP-37440, a Selective Inhibitor of Focal Adhesion Kinase (FAK) and Anaplastic Lymphoma Kinase (ALK).
[So] Source:J Med Chem;59(16):7478-96, 2016 Aug 25.
[Is] ISSN:1520-4804
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Analogues structurally related to anaplastic lymphoma kinase (ALK) inhibitor 1 were optimized for metabolic stability. The results from this endeavor not only led to improved metabolic stability, pharmacokinetic parameters, and in vitro activity against clinically derived resistance mutations but also led to the incorporation of activity for focal adhesion kinase (FAK). FAK activation, via amplification and/or overexpression, is characteristic of multiple invasive solid tumors and metastasis. The discovery of the clinical stage, dual FAK/ALK inhibitor 27b, including details surrounding SAR, in vitro/in vivo pharmacology, and pharmacokinetics, is reported herein.
[Mh] Termos MeSH primário: Benzamidas/farmacologia
Benzocicloeptenos/farmacologia
Descoberta de Drogas
Quinase 1 de Adesão Focal/antagonistas & inibidores
Inibidores de Proteínas Quinases/farmacologia
Receptores Proteína Tirosina Quinases/antagonistas & inibidores
[Mh] Termos MeSH secundário: Administração Oral
Animais
Benzamidas/administração & dosagem
Benzamidas/química
Benzocicloeptenos/administração & dosagem
Benzocicloeptenos/química
Linhagem Celular Tumoral
Proliferação Celular
Relação Dose-Resposta a Droga
Ensaios de Seleção de Medicamentos Antitumorais
Feminino
Quinase 1 de Adesão Focal/metabolismo
Seres Humanos
Camundongos
Camundongos Nus
Camundongos SCID
Modelos Moleculares
Estrutura Molecular
Neoplasias Experimentais/tratamento farmacológico
Neoplasias Experimentais/patologia
Inibidores de Proteínas Quinases/administração & dosagem
Inibidores de Proteínas Quinases/química
Receptores Proteína Tirosina Quinases/metabolismo
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Benzamides); 0 (Benzocycloheptenes); 0 (CEP-37440); 0 (Protein Kinase Inhibitors); EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases); EC 2.7.10.1 (anaplastic lymphoma kinase); EC 2.7.10.2 (Focal Adhesion Kinase 1); EC 2.7.10.2 (PTK2 protein, human)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170606
[Lr] Data última revisão:
170606
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160817
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jmedchem.6b00487


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[PMID]:27279912
[Au] Autor:Wang C; Jin H; Wang N; Fan S; Wang Y; Zhang Y; Wei L; Tao X; Gu D; Zhao F; Fang J; Yao M; Qin W
[Ad] Endereço:1. State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China;
[Ti] Título:Gas6/Axl Axis Contributes to Chemoresistance and Metastasis in Breast Cancer through Akt/GSK-3ß/ß-catenin Signaling.
[So] Source:Theranostics;6(8):1205-19, 2016.
[Is] ISSN:1838-7640
[Cp] País de publicação:Australia
[La] Idioma:eng
[Ab] Resumo:Chemoresistance in breast cancer has been of great interest in past studies. However, the development of rational therapeutic strategies targeting chemoresistant cells is still a challenge in clinical oncology. By integrating data from global differences of gene expression and phospho-receptor tyrosine kinases between sensitive parental cells (MCF-7) and doxorubicin-resistant cells (MCF-7/ADR), we identified Axl as a potential target for chemoresistance and metastasis in multidrug resistant breast cancer cells. We analyzed Axl expression in 57 breast cancer cell lines and detected a dramatic increase in its expression level in mesenchymal breast cancer cell lines. Axl silencing suppressed invasive and metastatic potentials of chemoresistant breast cancer cells as well as increased elimination of cancer cells when combined with doxorubicin. Furthermore, in preclinical assays, an Axl inhibitor R428 showed increased cell death upon doxorubicin treatment. Additionally, using phospho-kinase array based proteomic analysis, we identified that Akt/GSK-3ß/ß-catenin cascade was responsible for Axl-induced cell invasion. Nuclear translocation of ß-catenin then induced transcriptional upregulation of ZEB1, which in turn regulated DNA damage repair and doxorubicin-resistance in breast cancer cells. Most importantly, Axl was correlated with its downstream targets in tumor samples and was associated with poor prognosis in breast cancer patients. These results demonstrate that Gas6/Axl axis confers aggressiveness in breast cancer and may represent a therapeutic target for chemoresistance and metastasis.
[Mh] Termos MeSH primário: Neoplasias da Mama/patologia
Resistência a Medicamentos
Peptídeos e Proteínas de Sinalização Intercelular/metabolismo
Metástase Neoplásica/patologia
Proteínas Proto-Oncogênicas/biossíntese
Receptores Proteína Tirosina Quinases/biossíntese
[Mh] Termos MeSH secundário: Animais
Antineoplásicos/administração & dosagem
Antineoplásicos/metabolismo
Benzocicloeptenos/administração & dosagem
Benzocicloeptenos/metabolismo
Linhagem Celular Tumoral
Doxorrubicina/administração & dosagem
Doxorrubicina/metabolismo
Perfilação da Expressão Gênica
Inativação Gênica
Glicogênio Sintase Quinase 3 beta/metabolismo
Xenoenxertos
Seres Humanos
Camundongos Endogâmicos BALB C
Camundongos Nus
Inibidores de Proteínas Quinases/metabolismo
Proteínas Proto-Oncogênicas c-akt/metabolismo
Transdução de Sinais
Resultado do Tratamento
Triazóis/administração & dosagem
Triazóis/metabolismo
beta Catenina/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Benzocycloheptenes); 0 (Intercellular Signaling Peptides and Proteins); 0 (Protein Kinase Inhibitors); 0 (Proto-Oncogene Proteins); 0 (R428 compound); 0 (Triazoles); 0 (beta Catenin); 0 (growth arrest-specific protein 6); 80168379AG (Doxorubicin); EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases); EC 2.7.10.1 (axl receptor tyrosine kinase); EC 2.7.11.1 (Glycogen Synthase Kinase 3 beta); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171016
[Lr] Data última revisão:
171016
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160610
[St] Status:MEDLINE
[do] DOI:10.7150/thno.15083


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[PMID]:27009091
[Au] Autor:Salem I; Alsalahi M; Chervoneva I; Aburto LD; Addya S; Ott GR; Ruggeri BA; Cristofanilli M; Fernandez SV
[Ad] Endereço:Department of Medical Oncology, Thomas Jefferson University, Philadelphia, PA, USA.
[Ti] Título:The effects of CEP-37440, an inhibitor of focal adhesion kinase, in vitro and in vivo on inflammatory breast cancer cells.
[So] Source:Breast Cancer Res;18(1):37, 2016 Mar 24.
[Is] ISSN:1465-542X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Inflammatory breast cancer (IBC) is an aggressive type of advanced breast cancer with a poor prognosis. We recently found that focal adhesion kinase 1 (FAK1) is upregulated and phosphorylated (active) in IBC. In this study, we investigated the effect of CEP-37440, a dual inhibitor of FAK1 and anaplastic lymphoma kinase (ALK), using human IBC cell lines and preclinical models of IBC. METHODS: Cell proliferation assays were performed in the presence of several concentrations of CEP-37440 using IBC and triple-negative breast cancer non-IBC cell lines. In vitro, we studied the expression of total FAK1, phospho-FAK1 (Tyr 397), total ALK and phospho-ALK (Tyr 1604). In vivo, we tested CEP-37440 using FC-IBC02, SUM149, and SUM190 IBC xenograft mouse models. RESULTS: CEP-37440 at low concentration decreased the proliferation of the IBC cell lines FC-IBC02, SUM190, and KPL4, while not affecting the proliferation of normal breast epithelial cells. At higher concentration, CEP-37440 was also able to inhibit the proliferation of the IBC cell line MDA-IBC03 and the triple-negative non-IBC cell lines MDA-MB-231 and MDA-MB-468; the IBC cell line SUM149 showed a slight response to the drug. CEP-37440 decreased the cell proliferation of FC-IBC02, SUM190, and KPL4 by blocking the autophosphorylation kinase activity of FAK1 (Tyr 397). None of the cells evaluated expressed ALK. In vivo, after 7 weeks of CEP-37440 treatment, the SUM190, FC-IBC02, and SUM149 breast tumor xenografts were smaller in mice treated with 55 mg/kg bid CEP-37440 compared to the controls; the tumor growth inhibition (TGI) was 79.7 %, 33 %, and 23 %, respectively. None of the FC-IBC02 breast xenografts mice treated with CEP-37440 developed brain metastasis while 20 % of the mice in the control group developed brain metastasis. Expression array analyses in FC-IBC02 cells showed that CEP-37440 affects the expression of genes related to apoptosis, interferon signaling, and cytokines. CONCLUSIONS: CEP-37440 is effective against some IBC cells that express phospho-FAK1 (Tyr 397), and its antiproliferative activity is related to its ability to decrease phospho-FAK1. Our results suggest that combinational therapies could be more effective than using CEP-37440 as a single agent.
[Mh] Termos MeSH primário: Benzamidas/administração & dosagem
Benzocicloeptenos/administração & dosagem
Inibidores Enzimáticos/administração & dosagem
Proteína-Tirosina Quinases de Adesão Focal/genética
Neoplasias Inflamatórias Mamárias/tratamento farmacológico
Neoplasias de Mama Triplo Negativas/tratamento farmacológico
[Mh] Termos MeSH secundário: Animais
Apoptose/efeitos dos fármacos
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Feminino
Proteína-Tirosina Quinases de Adesão Focal/antagonistas & inibidores
Proteína-Tirosina Quinases de Adesão Focal/biossíntese
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos
Seres Humanos
Neoplasias Inflamatórias Mamárias/genética
Neoplasias Inflamatórias Mamárias/patologia
Camundongos
Receptores Proteína Tirosina Quinases/biossíntese
Receptores Proteína Tirosina Quinases/genética
Neoplasias de Mama Triplo Negativas/genética
Neoplasias de Mama Triplo Negativas/patologia
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Benzamides); 0 (Benzocycloheptenes); 0 (CEP-37440); 0 (Enzyme Inhibitors); EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases); EC 2.7.10.1 (anaplastic lymphoma kinase); EC 2.7.10.2 (Focal Adhesion Protein-Tyrosine Kinases)
[Em] Mês de entrada:1610
[Cu] Atualização por classe:170526
[Lr] Data última revisão:
170526
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160325
[St] Status:MEDLINE
[do] DOI:10.1186/s13058-016-0694-4


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[PMID]:26863403
[Au] Autor:Klaeger S; Gohlke B; Perrin J; Gupta V; Heinzlmeir S; Helm D; Qiao H; Bergamini G; Handa H; Savitski MM; Bantscheff M; Médard G; Preissner R; Kuster B
[Ad] Endereço:Chair of Proteomics and Bioanalytics, Technical University of Munich , Freising, Germany.
[Ti] Título:Chemical Proteomics Reveals Ferrochelatase as a Common Off-target of Kinase Inhibitors.
[So] Source:ACS Chem Biol;11(5):1245-54, 2016 05 20.
[Is] ISSN:1554-8937
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Many protein kinases are valid drug targets in oncology because they are key components of signal transduction pathways. The number of clinical kinase inhibitors is on the rise, but these molecules often exhibit polypharmacology, potentially eliciting desired and toxic effects. Therefore, a comprehensive assessment of a compound's target space is desirable for a better understanding of its biological effects. The enzyme ferrochelatase (FECH) catalyzes the conversion of protoporphyrin IX into heme and was recently found to be an off-target of the BRAF inhibitor Vemurafenib, likely explaining the phototoxicity associated with this drug in melanoma patients. This raises the question of whether FECH binding is a more general feature of kinase inhibitors. To address this, we applied a chemical proteomics approach using kinobeads to evaluate 226 clinical kinase inhibitors for their ability to bind FECH. Surprisingly, low or submicromolar FECH binding was detected for 29 of all compounds tested and isothermal dose response measurements confirmed target engagement in cells. We also show that Vemurafenib, Linsitinib, Neratinib, and MK-2461 reduce heme levels in K562 cells, verifying that drug binding leads to a loss of FECH activity. Further biochemical and docking experiments identified the protoporphyrin pocket in FECH as one major drug binding site. Since the genetic loss of FECH activity leads to photosensitivity in humans, our data strongly suggest that FECH inhibition by kinase inhibitors is the molecular mechanism triggering photosensitivity in patients. We therefore suggest that a FECH assay should generally be part of the preclinical molecular toxicology package for the development of kinase inhibitors.
[Mh] Termos MeSH primário: Ferroquelatase/antagonistas & inibidores
Ferroquelatase/metabolismo
Inibidores de Proteínas Quinases/farmacologia
[Mh] Termos MeSH secundário: Benzocicloeptenos/farmacologia
Linhagem Celular Tumoral
Ferroquelatase/química
Heme/metabolismo
Seres Humanos
Imidazóis/farmacologia
Indóis/farmacologia
Simulação de Acoplamento Molecular
Ligação Proteica
Proteômica
Pirazinas/farmacologia
Piridinas/farmacologia
Quinolinas/farmacologia
Sulfonamidas/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (3-(8-amino-1-(2-phenylquinolin-7-yl)imidazo(1,5-a)pyrazin-3-yl)-1-methylcyclobutanol); 0 (5H-benzo(4,5)cyclohepta(1,2-b)pyridin-5-one); 0 (Benzocycloheptenes); 0 (Imidazoles); 0 (Indoles); 0 (N-(4-(3-chloro-4-(2-pyridinylmethoxy)anilino)-3-cyano-7-ethoxy-6-quinolyl)-4-(dimethylamino)-2-butenamide); 0 (Protein Kinase Inhibitors); 0 (Pyrazines); 0 (Pyridines); 0 (Quinolines); 0 (Sulfonamides); 207SMY3FQT (vemurafenib); 42VZT0U6YR (Heme); EC 4.99.1.1 (Ferrochelatase)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:170404
[Lr] Data última revisão:
170404
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160211
[St] Status:MEDLINE
[do] DOI:10.1021/acschembio.5b01063


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[PMID]:26672458
[Au] Autor:Itoh N; Takagi S; Miki A; Kurokawa J
[Ad] Endereço:Biotechnology Research Center and Department of Biotechnology, Toyama Prefectural University, 5180 Kurokawa, Imizu, Toyama 939-0398, Japan. Electronic address: nbito@pu-toyama.ac.jp.
[Ti] Título:Characterization and cloning of laccase gene from Hericium coralloides NBRC 7716 suitable for production of epitheaflagallin 3-O-gallate.
[So] Source:Enzyme Microb Technol;82:125-132, 2016 Jan.
[Is] ISSN:1879-0909
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Epitheaflagallin 3-O-gallate (ETFGg) is a minor polyphenol found in black tea extract, which has good physiological functions. It is synthesized from epigallocatechin gallate (EGCg) with gallic acid via laccase oxidation. Various basidiomycetes and fungi were screened to find a suitable laccase for the production of ETFGg. A basidiomycete, Hericium coralloides NBRC 7716, produced an appropriate extracellular laccase. The purified laccase produced twice the level of ETFGg compared with commercially available laccase from Trametes sp. The enzyme, termed Lcc2, is a monomeric protein with an apparent molecular mass of 67.2 kDa. The N-terminal amino acid sequence of Lcc2 is quite different from laccase isolated from the fruiting bodies of Hericium. Lcc2 showed similar substrate specificity to known laccases and could oxidize various phenolic substrates, including pyrogallol, gallic acid, and 2,6-dimethoxyphenol. The full-length lcc2 gene was obtained by PCR using degenerate primers, which were designed based on the N-terminal amino acid sequence of Lcc2 and conserved copper-binding sites of laccases, and 5'-, and 3'-RACE PCR with mRNA. The Lcc2 gene showed homology with Lentinula edodes laccase (sharing 77% amino acid identity with Lcc6). We successfully produced extracellular Lcc2 using a heterologous expression system with Saccharomyces cerevisiae. Moreover, it was confirmed that the recombinant laccase generates similar levels of ETFGg as the native enzyme.
[Mh] Termos MeSH primário: Basidiomycota/enzimologia
Proteínas Fúngicas/genética
Lacase/genética
Polifenóis/biossíntese
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Basidiomycota/genética
Benzocicloeptenos
Catequina/análogos & derivados
Catequina/metabolismo
Clonagem Molecular
Proteínas Fúngicas/isolamento & purificação
Proteínas Fúngicas/metabolismo
Ácido Gálico/metabolismo
Genes Fúngicos
Temperatura Alta
Concentração de Íons de Hidrogênio
Lacase/isolamento & purificação
Lacase/metabolismo
Dados de Sequência Molecular
Estrutura Molecular
Oxirredução
Fenóis/metabolismo
Fosfoglicerato Quinase/genética
Estabilidade Proteica
Proteínas Recombinantes de Fusão/genética
Proteínas Recombinantes de Fusão/isolamento & purificação
Proteínas Recombinantes de Fusão/metabolismo
Saccharomyces cerevisiae
Especificidade por Substrato
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Benzocycloheptenes); 0 (Fungal Proteins); 0 (Phenols); 0 (Polyphenols); 0 (Recombinant Fusion Proteins); 0 (epitheaflagallin 3-O-gallate); 632XD903SP (Gallic Acid); 8R1V1STN48 (Catechin); BQM438CTEL (epigallocatechin gallate); EC 1.10.3.2 (Laccase); EC 2.7.2.3 (Phosphoglycerate Kinase)
[Em] Mês de entrada:1610
[Cu] Atualização por classe:170807
[Lr] Data última revisão:
170807
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151218
[St] Status:MEDLINE



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