Base de dados : MEDLINE
Pesquisa : D03.633.100.733 [Categoria DeCS]
Referências encontradas : 2431 [refinar]
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[PMID]:27773673
[Au] Autor:Xiao D; Yue M; Su H; Ren P; Jiang J; Li F; Hu Y; Du H; Liu H; Qing G
[Ad] Endereço:Zhongnan Hospital of Wuhan University, Wuhan 430071, China; Medical Research Institute, Wuhan University, Wuhan 430071, China.
[Ti] Título:Polo-like Kinase-1 Regulates Myc Stabilization and Activates a Feedforward Circuit Promoting Tumor Cell Survival.
[So] Source:Mol Cell;64(3):493-506, 2016 Nov 03.
[Is] ISSN:1097-4164
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:MYCN amplification in human cancers predicts poor prognosis and resistance to therapy. However, pharmacological strategies that directly target N-Myc, the protein encoded by MYCN, remain elusive. Here, we identify a molecular mechanism responsible for reciprocal activation between Polo-like kinase-1 (PLK1) and N-Myc. PLK1 specifically binds to the SCF ubiquitin ligase, phosphorylates it, and promotes its autopolyubiquitination and proteasomal degradation, counteracting Fbw7-mediated degradation of N-Myc and additional substrates, including cyclin E and Mcl1. Stabilized N-Myc in turn directly activates PLK1 transcription, constituting a positive feedforward regulatory loop that reinforces Myc-regulated oncogenic programs. Inhibitors of PLK1 preferentially induce potent apoptosis of MYCN-amplified tumor cells from neuroblastoma and small cell lung cancer and synergistically potentiate the therapeutic efficacies of Bcl2 antagonists. These findings reveal a PLK1-Fbw7-Myc signaling circuit that underlies tumorigenesis and validate PLK1 inhibitors, alone or with Bcl2 antagonists, as potential effective therapeutics for MYC-overexpressing cancers.
[Mh] Termos MeSH primário: Neoplasias Encefálicas/genética
Proteínas de Ciclo Celular/genética
Proteínas F-Box/genética
Retroalimentação Fisiológica
Regulação Neoplásica da Expressão Gênica
Proteína Proto-Oncogênica N-Myc/genética
Neuroblastoma/genética
Proteínas Serina-Treonina Quinases/genética
Proteínas Proto-Oncogênicas/genética
Ubiquitina-Proteína Ligases/genética
[Mh] Termos MeSH secundário: Animais
Antineoplásicos/farmacologia
Neoplasias Encefálicas/tratamento farmacológico
Neoplasias Encefálicas/mortalidade
Neoplasias Encefálicas/patologia
Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia
Proteínas de Ciclo Celular/antagonistas & inibidores
Proteínas de Ciclo Celular/metabolismo
Linhagem Celular Tumoral
Sinergismo Farmacológico
Proteínas F-Box/metabolismo
Proteína 7 com Repetições F-Box-WD
Seres Humanos
Camundongos Nus
Proteína Proto-Oncogênica N-Myc/antagonistas & inibidores
Proteína Proto-Oncogênica N-Myc/metabolismo
Neuroblastoma/tratamento farmacológico
Neuroblastoma/mortalidade
Neuroblastoma/patologia
Neurônios/efeitos dos fármacos
Neurônios/metabolismo
Neurônios/patologia
Proteínas Serina-Treonina Quinases/antagonistas & inibidores
Proteínas Serina-Treonina Quinases/metabolismo
Proteínas Proto-Oncogênicas/antagonistas & inibidores
Proteínas Proto-Oncogênicas/metabolismo
Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores
Proteínas Proto-Oncogênicas c-bcl-2/genética
Proteínas Proto-Oncogênicas c-bcl-2/metabolismo
Pteridinas/farmacologia
RNA Interferente Pequeno/genética
RNA Interferente Pequeno/metabolismo
Transdução de Sinais
Sulfonamidas/farmacologia
Análise de Sobrevida
Transcrição Genética
Carga Tumoral/efeitos dos fármacos
Ubiquitina-Proteína Ligases/metabolismo
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (BCL2 protein, human); 0 (BI 6727); 0 (Bridged Bicyclo Compounds, Heterocyclic); 0 (Cell Cycle Proteins); 0 (F-Box Proteins); 0 (F-Box-WD Repeat-Containing Protein 7); 0 (FBXW7 protein, human); 0 (MYCN protein, human); 0 (N-Myc Proto-Oncogene Protein); 0 (Proto-Oncogene Proteins); 0 (Proto-Oncogene Proteins c-bcl-2); 0 (Pteridines); 0 (RNA, Small Interfering); 0 (Sulfonamides); EC 2.3.2.27 (Ubiquitin-Protein Ligases); EC 2.7.11.1 (Protein-Serine-Threonine Kinases); EC 2.7.11.1 (polo-like kinase 1); N54AIC43PW (venetoclax)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:180114
[Lr] Data última revisão:
180114
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161105
[St] Status:MEDLINE


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[PMID]:29220793
[Au] Autor:Zhan MM; Yang Y; Luo J; Zhang XX; Xiao X; Li S; Cheng K; Xie Z; Tu Z; Liao C
[Ad] Endereço:School of Biological and Medical Engineering, Hefei University of Technology, Hefei, Anhui 230009, PR China.
[Ti] Título:Design, synthesis, and biological evaluation of novel highly selective polo-like kinase 2 inhibitors based on the tetrahydropteridin chemical scaffold.
[So] Source:Eur J Med Chem;143:724-731, 2018 Jan 01.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:Polo-like kinase 2 (Plk2) is a potential target for the treatment of cancer, which displays an important role in tumor cell proliferation and survival. In this report, according to the analysis of critical amino acid residue differences among Plk1, Plk2 and Plk3, and structure-based drug design strategies, two novel series of selective Plk2 inhibitors based on tetrahydropteridin chemical scaffold were designed and synthesized to target two specific residues, Lys86 and Tyr161 of Plk2. All compounds were evaluated for their inhibitory activity against Plk1-Plk3 and the cellular inhibition activity on six different human cancer cell lines. All efforts led to the identification of the most potent compounds C2 (3.40 nM against Plk2) and C21 (4.88 nM against Plk2) from the first and second series of selective Plk2 inhibitors respectively. Additionally, the selectivity of C21 over Plk1/3 was significantly increased with the selectivity indexes of 12.57 and 910.06. Moreover, most of our compounds exhibited antitumor activity in the nanomolar range in the MTT assay, indicating that our compounds, especially C2 and C21 could be promising Plk2 inhibitors for further anticancer research.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Desenho de Drogas
Inibidores de Proteínas Quinases/farmacologia
Proteínas Serina-Treonina Quinases/antagonistas & inibidores
Pteridinas/farmacologia
[Mh] Termos MeSH secundário: Antineoplásicos/síntese química
Antineoplásicos/química
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Relação Dose-Resposta a Droga
Ensaios de Seleção de Medicamentos Antitumorais
Seres Humanos
Estrutura Molecular
Inibidores de Proteínas Quinases/síntese química
Inibidores de Proteínas Quinases/química
Proteínas Serina-Treonina Quinases/metabolismo
Pteridinas/síntese química
Pteridinas/química
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Protein Kinase Inhibitors); 0 (Pteridines); EC 2.7.11.- (PLK2 protein, human); EC 2.7.11.1 (Protein-Serine-Threonine Kinases)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180110
[Lr] Data última revisão:
180110
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171209
[St] Status:MEDLINE


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[PMID]:29176894
[Au] Autor:Levillain F; Poquet Y; Mallet L; Mazères S; Marceau M; Brosch R; Bange FC; Supply P; Magalon A; Neyrolles O
[Ad] Endereço:Institut de Pharmacologie et de Biologie Structurale, Université de Toulouse, CNRS, UPS, Toulouse, France.
[Ti] Título:Horizontal acquisition of a hypoxia-responsive molybdenum cofactor biosynthesis pathway contributed to Mycobacterium tuberculosis pathoadaptation.
[So] Source:PLoS Pathog;13(11):e1006752, 2017 Nov.
[Is] ISSN:1553-7374
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The unique ability of the tuberculosis (TB) bacillus, Mycobacterium tuberculosis, to persist for long periods of time in lung hypoxic lesions chiefly contributes to the global burden of latent TB. We and others previously reported that the M. tuberculosis ancestor underwent massive episodes of horizontal gene transfer (HGT), mostly from environmental species. Here, we sought to explore whether such ancient HGT played a part in M. tuberculosis evolution towards pathogenicity. We were interested by a HGT-acquired M. tuberculosis-specific gene set, namely moaA1-D1, which is involved in the biosynthesis of the molybdenum cofactor. Horizontal acquisition of this gene set was striking because homologues of these moa genes are present all across the Mycobacterium genus, including in M. tuberculosis. Here, we discovered that, unlike their paralogues, the moaA1-D1 genes are strongly induced under hypoxia. In vitro, a M. tuberculosis moaA1-D1-null mutant has an impaired ability to respire nitrate, to enter dormancy and to survive in oxygen-limiting conditions. Conversely, heterologous expression of moaA1-D1 in the phylogenetically closest non-TB mycobacterium, Mycobacterium kansasii, which lacks these genes, improves its capacity to respire nitrate and grants it with a marked ability to survive oxygen depletion. In vivo, the M. tuberculosis moaA1-D1-null mutant shows impaired survival in hypoxic granulomas in C3HeB/FeJ mice, but not in normoxic lesions in C57BL/6 animals. Collectively, our results identify a novel pathway required for M. tuberculosis resistance to host-imposed stress, namely hypoxia, and provide evidence that ancient HGT bolstered M. tuberculosis evolution from an environmental species towards a pervasive human-adapted pathogen.
[Mh] Termos MeSH primário: Coenzimas/biossíntese
Transferência Genética Horizontal
Metaloproteínas/biossíntese
Mycobacterium tuberculosis/genética
Mycobacterium tuberculosis/metabolismo
Oxigênio/metabolismo
Tuberculose/microbiologia
[Mh] Termos MeSH secundário: Animais
Proteínas de Bactérias/genética
Proteínas de Bactérias/metabolismo
Feminino
Regulação Bacteriana da Expressão Gênica
Seres Humanos
Hipóxia/metabolismo
Hipóxia/microbiologia
Camundongos
Camundongos Endogâmicos C57BL
Mycobacterium/genética
Mycobacterium/metabolismo
Nitratos/metabolismo
Pteridinas
Tuberculose/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Bacterial Proteins); 0 (Coenzymes); 0 (Metalloproteins); 0 (Nitrates); 0 (Pteridines); 73508-07-3 (molybdenum cofactor); S88TT14065 (Oxygen)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180109
[Lr] Data última revisão:
180109
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171128
[St] Status:MEDLINE
[do] DOI:10.1371/journal.ppat.1006752


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[PMID]:28789892
[Au] Autor:Li Q; Yang HK; Sun Q; You WW; Zhao PL
[Ad] Endereço:Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Science, Southern Medical University, Guangzhou 510515, PR China.
[Ti] Título:Design, synthesis and antiproliferative activity of novel substituted 2-amino-7,8-dihydropteridin-6(5H)-one derivatives.
[So] Source:Bioorg Med Chem Lett;27(17):3954-3958, 2017 09 01.
[Is] ISSN:1464-3405
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Based on our previous work, a series of novel 2-amino-7,8-dihydropteridin-6(5H)-one derivatives were designed and synthesized via a ring-closing strategy. Biological evaluation with four human cancer cell lines (BT549, T47D, MDA-MB-468, and MDA-MB-231) showed that most of these compounds possessed moderate to potent antiproliferative activities. The most promising compound 8-benzyl-2-(phenethylamino)-7,8-dihydropteridin-6(5H)-one (6q) possessing IC values of 7.75, 6.37, and 10.73µM against MDA-MB-468, T47D, and BT549, respectively, which were 49, 11, and 8 folds more active than the positive control fluorouracil. Moreover, fluorescence-activated cell sorting analysis revealed that compound 6q displayed a significant effect on G1 cell-cycle arrest in a concentration-dependent manner in T47D cells. The initial structure-activity relationship studies indicated that linker-length of amine chain in C-2 position of pyrimidine ring played a crucial role in modulating the antitumor activity, which could be of help in the rational design of dihydropteridin-6(5H)-ones as novel anticancer drugs.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Desenho de Drogas
Pteridinas/farmacologia
[Mh] Termos MeSH secundário: Antineoplásicos/síntese química
Antineoplásicos/química
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Relação Dose-Resposta a Droga
Ensaios de Seleção de Medicamentos Antitumorais
Seres Humanos
Estrutura Molecular
Pteridinas/síntese química
Pteridinas/química
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Pteridines)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171125
[Lr] Data última revisão:
171125
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170810
[St] Status:MEDLINE


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[PMID]:28766335
[Au] Autor:Bühning M; Friemel M; Leimkühler S
[Ad] Endereço:Department of Molecular Enzymology, Institute of Biochemistry and Biology, University of Potsdam , D-14476 Potsdam, Germany.
[Ti] Título:Functional Complementation Studies Reveal Different Interaction Partners of Escherichia coli IscS and Human NFS1.
[So] Source:Biochemistry;56(34):4592-4605, 2017 Aug 29.
[Is] ISSN:1520-4995
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The trafficking and delivery of sulfur to cofactors and nucleosides is a highly regulated and conserved process among all organisms. All sulfur transfer pathways generally have an l-cysteine desulfurase as an initial sulfur-mobilizing enzyme in common, which serves as a sulfur donor for the biosynthesis of sulfur-containing biomolecules like iron-sulfur (Fe-S) clusters, thiamine, biotin, lipoic acid, the molybdenum cofactor (Moco), and thiolated nucleosides in tRNA. The human l-cysteine desulfurase NFS1 and the Escherichia coli homologue IscS share a level of amino acid sequence identity of ∼60%. While E. coli IscS has a versatile role in the cell and was shown to have numerous interaction partners, NFS1 is mainly localized in mitochondria with a crucial role in the biosynthesis of Fe-S clusters. Additionally, NFS1 is also located in smaller amounts in the cytosol with a role in Moco biosynthesis and mcm s U34 thio modifications of nucleosides in tRNA. NFS1 and IscS were conclusively shown to have different interaction partners in their respective organisms. Here, we used functional complementation studies of an E. coli iscS deletion strain with human NFS1 to dissect their conserved roles in the transfer of sulfur to a specific target protein. Our results show that human NFS1 and E. coli IscS share conserved binding sites for proteins involved in Fe-S cluster assembly like IscU, but not with proteins for tRNA thio modifications or Moco biosynthesis. In addition, we show that human NFS1 was almost fully able to complement the role of IscS in Moco biosynthesis when its specific interaction partner protein MOCS3 from humans was also present.
[Mh] Termos MeSH primário: Liases de Carbono-Enxofre
Coenzimas
Escherichia coli
Teste de Complementação Genética
Metaloproteínas
Pteridinas
[Mh] Termos MeSH secundário: Sítios de Ligação
Liases de Carbono-Enxofre/genética
Liases de Carbono-Enxofre/metabolismo
Coenzimas/biossíntese
Coenzimas/genética
Escherichia coli/enzimologia
Escherichia coli/genética
Seres Humanos
Metaloproteínas/biossíntese
Metaloproteínas/genética
Nucleotidiltransferases/metabolismo
RNA Bacteriano/genética
RNA Bacteriano/metabolismo
RNA de Transferência/metabolismo
Sulfurtransferases/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Coenzymes); 0 (Metalloproteins); 0 (Pteridines); 0 (RNA, Bacterial); 73508-07-3 (molybdenum cofactor); 9014-25-9 (RNA, Transfer); EC 2.7.7.- (MOCS3 protein, human); EC 2.7.7.- (Nucleotidyltransferases); EC 2.8.1.- (Sulfurtransferases); EC 4.4.- (Carbon-Sulfur Lyases); EC 4.4.1.- (NFS1 protein, human); EC 4.4.1.- (cysteine desulfurase)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170831
[Lr] Data última revisão:
170831
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170803
[St] Status:MEDLINE
[do] DOI:10.1021/acs.biochem.7b00627


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[PMID]:28650996
[Au] Autor:Duncan C; Jamieson FB; Troudt J; Izzo L; Bielefeldt-Ohmann H; Izzo A; Mehaffy C
[Ad] Endereço:Public Health Ontario, Toronto, ON, Canada.
[Ti] Título:Whole transcriptomic and proteomic analyses of an isogenic M. tuberculosis clinical strain with a naturally occurring 15 Kb genomic deletion.
[So] Source:PLoS One;12(6):e0179996, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Tuberculosis remains one of the most difficult to control infectious diseases in the world. Many different factors contribute to the complexity of this disease. These include the ability of the host to control the infection which may directly relate to nutritional status, presence of co-morbidities and genetic predisposition. Pathogen factors, in particular the ability of different Mycobacterium tuberculosis strains to respond to the harsh environment of the host granuloma, which includes low oxygen and nutrient availability and the presence of damaging radical oxygen and nitrogen species, also play an important role in the success of different strains to cause disease. In this study we evaluated the impact of a naturally occurring 12 gene 15 Kb genomic deletion on the physiology and virulence of M. tuberculosis. The strains denominated ON-A WT (wild type) and ON-A NM (natural mutant) were isolated from a previously reported TB outbreak in an inner city under-housed population in Toronto, Canada. Here we subjected these isogenic strains to transcriptomic (via RNA-seq) and proteomic analyses and identified several gene clusters with differential expression in the natural mutant, including the DosR regulon and the molybdenum cofactor biosynthesis genes, both of which were found in lower abundance in the natural mutant. We also demonstrated lesser virulence of the natural mutant in the guinea pig animal model. Overall, our findings suggest that the ON-A natural mutant is less fit to cause disease, but nevertheless has the potential to cause extended transmission in at-risk populations.
[Mh] Termos MeSH primário: Deleção de Genes
Genoma Bacteriano
Mycobacterium tuberculosis/genética
[Mh] Termos MeSH secundário: Animais
Proteínas de Bactérias/biossíntese
Proteínas de Bactérias/genética
Coenzimas/biossíntese
Coenzimas/genética
Modelos Animais de Doenças
Perfilação da Expressão Gênica
Cobaias
Seres Humanos
Metabolismo dos Lipídeos/genética
Metaloproteínas/biossíntese
Metaloproteínas/genética
Família Multigênica
Mycobacterium tuberculosis/metabolismo
Mycobacterium tuberculosis/patogenicidade
Proteínas Quinases/genética
Proteômica
Pteridinas
Regulon
Tuberculose Pulmonar/microbiologia
Virulência/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Bacterial Proteins); 0 (Coenzymes); 0 (Metalloproteins); 0 (Pteridines); 73508-07-3 (molybdenum cofactor); EC 2.7.- (Protein Kinases); EC 2.7.3.- (DosR protein, Mycobacterium tuberculosis)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170918
[Lr] Data última revisão:
170918
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170627
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0179996


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[PMID]:28599981
[Au] Autor:Theodosakis N; Micevic G; Langdon CG; Ventura A; Means R; Stern DF; Bosenberg MW
[Ad] Endereço:Department of Pathology, Yale School of Medicine, New Haven, Connecticut, USA.
[Ti] Título:p90RSK Blockade Inhibits Dual BRAF and MEK Inhibitor-Resistant Melanoma by Targeting Protein Synthesis.
[So] Source:J Invest Dermatol;137(10):2187-2196, 2017 Oct.
[Is] ISSN:1523-1747
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Despite improvements in survival in metastatic melanoma with combined BRAF and mitogen-activated protein kinase/extracellular signal-regulated kinase inhibitor treatment, the overwhelming majority of patients eventually acquire resistance to both agents. Consequently, new targets for therapy in resistant tumors are currently being evaluated. Previous studies have identified p90 subfamily of ribosomal S6 kinase (p90RSK) family kinases as key factors for growth and proliferation, as well as protein synthesis via assembly of the 7-methyl-guanosine triphosphate cap-dependent translation complex. We sought to evaluate inhibitors of p90RSK family members: BI-D1870 and BRD7389, for their ability to inhibit both proliferation and protein synthesis in patient-derived melanoma cell lines with acquired resistance to combined treatment with the BRAF inhibitor vemurafenib and the mitogen-activated protein kinase/extracellular signal-regulated kinase inhibitor selumetinib. We found that the RSK inhibitors blocked cell proliferation and protein synthesis in multiple dual-resistant melanoma lines. In addition, single agent RSK inhibitor treatment was effective in drug-naïve lines, two of which are innately vemurafenib resistant. We also used Reverse Phase Protein Array screening to identify differential protein expression that correlates with BI-D1870 sensitivity, and identified prognostic biomarkers for survival in human melanoma patients. These findings establish p90RSK inhibition as a therapeutic strategy in treatment-resistant melanoma and provide insight into the mechanism of action.
[Mh] Termos MeSH primário: Resistência a Medicamentos Antineoplásicos/efeitos dos fármacos
MAP Quinase Quinase 1/biossíntese
Melanoma/metabolismo
Proteínas Proto-Oncogênicas B-raf/biossíntese
[Mh] Termos MeSH secundário: Apoptose
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Seres Humanos
MAP Quinase Quinase 1/efeitos dos fármacos
Melanoma/tratamento farmacológico
Melanoma/patologia
Inibidores de Proteínas Quinases/farmacologia
Proteínas Proto-Oncogênicas B-raf/efeitos dos fármacos
Pteridinas
Proteínas Quinases S6 Ribossômicas 90-kDa/antagonistas & inibidores
Proteínas Quinases S6 Ribossômicas 90-kDa/metabolismo
Transdução de Sinais
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (BI D1870); 0 (Protein Kinase Inhibitors); 0 (Pteridines); EC 2.7.11.1 (BRAF protein, human); EC 2.7.11.1 (Proto-Oncogene Proteins B-raf); EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 90-kDa); EC 2.7.12.2 (MAP Kinase Kinase 1)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171103
[Lr] Data última revisão:
171103
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170611
[St] Status:MEDLINE


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[PMID]:28585214
[Au] Autor:Engin AB; Engin A
[Ad] Endereço:Faculty of Pharmacy, Department of Toxicology, Gazi University, Hipodrom, Ankara, Turkey. abengin@gmail.com.
[Ti] Título:The Interactions Between Kynurenine, Folate, Methionine and Pteridine Pathways in Obesity.
[So] Source:Adv Exp Med Biol;960:511-527, 2017.
[Is] ISSN:0065-2598
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Obesity activates both innate and adaptive immune responses in adipose tissue. Elevated levels of eosinophils with depression of monocyte and neutrophil indicate the deficiencies in the immune system of morbidly obese individuals. Actually, adipose tissue macrophages are functional antigen-presenting cells that promote the proliferation of interferon-gamma (IFN-gamma)-producing CD4+ T cells in adipose tissue of obese subjects. Eventually, diet-induced obesity is associated with the loss of tissue homeostasis and development of type 1 inflammatory responses in visceral adipose tissue. Activity of inducible indoleamine 2,3-dioxygenase-1 (IDO-1) plays a major role under pro-inflammatory, IFN-gamma dominated settings. One of the two rate-limiting enzymes which can metabolize tryptophan to kynurenine is IDO-1. Tumor necrosis factor-alpha (TNF-alpha) correlates with IDO-1 in adipose compartments. Actually, IDO-1-mediated tryptophan catabolism due to chronic immune activation is the cause of reduced tryptophan plasma levels and be considered as the driving force for food intake in morbidly obese patients. Thus, decrease in plasma tryptophan levels and subsequent reduction in serotonin (5-HT) production provokes satiety dysregulation that leads to increased caloric uptake and obesity. However, after bariatric surgery, weight reduction does not lead to normalization of IDO-1 activity. Furthermore, there is a connection between arginine and tryptophan metabolic pathways in the generation of reactive nitrogen intermediates. Hence, abdominal obesity is associated with vascular endothelial dysfunction and reduced nitric oxide (NO) availability. IFN-gamma-induced activation of the inducible nitric oxide synthase (iNOS) and dissociation of endothelial adenosine monophosphate activated protein kinase (AMPK)- phosphoinositide 3-kinase (PI3K)-protein kinase B (Akt)- endothelial NO synthase (eNOS) pathway enhances oxidative stress production secondary to high-fat diet. Thus, reduced endothelial NO availability correlates with the increase in plasma non-esterified fatty acids and triglycerides levels. Additionally, in obese patients, folate-deficiency leads to hyperhomocysteinemia. Folic acid confers protection against hyperhomocysteinemia-induced oxidative stress.
[Mh] Termos MeSH primário: Ácido Fólico/metabolismo
Cinurenina/metabolismo
Metionina/metabolismo
Obesidade/metabolismo
Pteridinas/metabolismo
Transdução de Sinais/fisiologia
[Mh] Termos MeSH secundário: Animais
Seres Humanos
Inflamação/metabolismo
Inflamação/patologia
Obesidade/patologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Pteridines); 343-65-7 (Kynurenine); 935E97BOY8 (Folic Acid); AE28F7PNPL (Methionine)
[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:170607
[St] Status:MEDLINE
[do] DOI:10.1007/978-3-319-48382-5_22


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[PMID]:28531794
[Au] Autor:Fernández-Sainz J; Pacheco-Liñán PJ; Granadino-Roldán JM; Bravo I; Garzón A; Rubio-Martínez J; Albaladejo J
[Ad] Endereço:Departamento de Química Física, Facultad de Farmacia, Universidad de Castilla-La Mancha, Paseo de los Estudiantes, s/n, 02071 Albacete, Spain.
[Ti] Título:Binding of the anticancer drug BI-2536 to human serum albumin. A spectroscopic and theoretical study.
[So] Source:J Photochem Photobiol B;172:77-87, 2017 Jul.
[Is] ISSN:1873-2682
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:BI-2536 is a potent Polo-like kinase inhibitor which induces apoptosis in diverse human cancer cell lines. The binding affinity of BI-2536 for human serum albumin (HSA) protein may define its pharmacokinetic and pharmacodynamic profile. We have studied the binding of BI-2536 to HSA by means of different spectroscopic techniques and docking calculations. We have experimentally observed that the affinity of BI-2536 for HSA is higher than that of other common HSA binding drugs. Therefore, it can be postulated that the drug dose should be increased to achieve a certain concentration of free drug in plasma, although BI-2536 could also reach tumour tissues by uptaking HSA/BI-2536 complex. Only a single binding site on HSA has been observed for BI-2536 which seems to correspond to the subdomain IIA pocket. The formation of the HSA/BI-2536 complex is a spontaneous and entropy-driven process that does not cause a significant change of the secondary structure of the protein. Its endothermic character could be related to proton release. Thermodynamic analysis showed that the main protein-drug interactions are of the van der Waals type although the presence of amide and ether groups in BI-2536 could also allow H-bonding with some residues in the subdomain IIA pocket.
[Mh] Termos MeSH primário: Antineoplásicos/metabolismo
Simulação de Acoplamento Molecular
Pteridinas/metabolismo
Albumina Sérica/metabolismo
[Mh] Termos MeSH secundário: Antineoplásicos/química
Sítios de Ligação
Seres Humanos
Ligação Proteica
Estrutura Secundária de Proteína
Pteridinas/química
Teoria Quântica
Albumina Sérica/química
Espectrometria de Fluorescência
Espectroscopia de Infravermelho com Transformada de Fourier
Termodinâmica
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (BI 2536); 0 (Pteridines); 0 (Serum Albumin)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170925
[Lr] Data última revisão:
170925
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170523
[St] Status:MEDLINE


  10 / 2431 MEDLINE  
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[PMID]:28416751
[Au] Autor:Schnerch D; Schüler J; Follo M; Felthaus J; Wider D; Klingner K; Greil C; Duyster J; Engelhardt M; Wäsch R
[Ad] Endereço:Department of Hematology, Oncology and Stem Cell Transplantation, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
[Ti] Título:Proteasome inhibition enhances the efficacy of volasertib-induced mitotic arrest in AML in vitro and prolongs survival in vivo.
[So] Source:Oncotarget;8(13):21153-21166, 2017 Mar 28.
[Is] ISSN:1949-2553
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Elderly and frail patients, diagnosed with acute myeloid leukemia (AML) and ineligible to undergo intensive treatment, have a dismal prognosis. The small molecule inhibitor volasertib induces a mitotic block via inhibition of polo-like kinase 1 and has shown remarkable anti-leukemic activity when combined with low-dose cytarabine. We have demonstrated that AML cells are highly vulnerable to cell death in mitosis yet manage to escape a mitotic block through mitotic slippage by sustained proteasome-dependent slow degradation of cyclin B. Therefore, we tested whether interfering with mitotic slippage through proteasome inhibition arrests and kills AML cells more efficiently during mitosis. We show that therapeutic doses of bortezomib block the slow degradation of cyclin B during a volasertib-induced mitotic arrest in AML cell lines and patient-derived primary AML cells. In a xenotransplant mouse model of human AML, mice receiving volasertib in combination with bortezomib showed superior disease control compared to mice receiving volasertib alone, highlighting the potential therapeutic impact of this drug combination.
[Mh] Termos MeSH primário: Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia
Bortezomib/farmacologia
Leucemia Mieloide Aguda/tratamento farmacológico
Mitose/efeitos dos fármacos
Inibidores de Proteassoma/farmacologia
Pteridinas/farmacologia
[Mh] Termos MeSH secundário: Idoso
Animais
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico
Bortezomib/uso terapêutico
Proteínas de Ciclo Celular/metabolismo
Linhagem Celular Tumoral
Ciclina B/genética
Ciclina B/metabolismo
Citarabina/farmacologia
Citarabina/uso terapêutico
Idoso Fragilizado
Seres Humanos
Camundongos
Camundongos Endogâmicos NOD
Inibidores de Proteassoma/uso terapêutico
Inibidores de Proteínas Quinases/farmacologia
Inibidores de Proteínas Quinases/uso terapêutico
Proteínas Serina-Treonina Quinases/metabolismo
Proteínas Proto-Oncogênicas/metabolismo
Pteridinas/uso terapêutico
Resultado do Tratamento
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (BI 6727); 0 (Cell Cycle Proteins); 0 (Cyclin B); 0 (Proteasome Inhibitors); 0 (Protein Kinase Inhibitors); 0 (Proto-Oncogene Proteins); 0 (Pteridines); 04079A1RDZ (Cytarabine); 69G8BD63PP (Bortezomib); EC 2.7.11.1 (Protein-Serine-Threonine Kinases); EC 2.7.11.1 (polo-like kinase 1)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170524
[Lr] Data última revisão:
170524
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170419
[St] Status:MEDLINE
[do] DOI:10.18632/oncotarget.15503



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