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Pesquisa : D12.644.360.075.718.968 [Categoria DeCS]
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[PMID]:29372687
[Au] Autor:Stefaniková A; Klacanová K; Pilchová I; Hatok J; Racay P
[Ad] Endereço:1 Department of Medical Biochemistry Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia. racay@jfmed.uniba.sk.
[Ti] Título:Cyclin-dependent kinase 2 inhibitor SU9516 increases sensitivity of colorectal carcinoma cells Caco-2 but not HT29 to BH3 mimetic ABT-737.
[So] Source:Gen Physiol Biophys;36(5):539-547, 2017 Dec.
[Is] ISSN:0231-5882
[Cp] País de publicação:Slovakia
[La] Idioma:eng
[Ab] Resumo:Colorectal carcinoma (CRC) that represents one of the major causes for cancer-related death in humans is often associated with over-expression of anti-apoptotic proteins of Bcl-2 family. The aim of presented study was to determine the effect of ABT-737 inhibitor of anti-apoptotic proteins Bcl-2, Bcl-XL and Bcl-w as well as cyclin-dependent kinase 2 (CDK2) inhibitor SU9516 alone and in combination with ABT-737 on survival of colorectal cell lines HT29 and Caco-2. We have shown that both Caco-2 and HT29 cells that are relatively resistant to ABT-737 are also partially sensitive to SU9516, which increased sensitivity of Caco-2 but not HT29 cells to ABT-737. Increased sensitivity of Caco-2 cells to ABT-737 after addition of SU9516 correlated well with SU9516-induced decrease of Mcl-1 expression while we have not observed downregulation of Mcl-1 after the treatment of HT29 cells with SU9516. Instead of this, we have shown that treatment of HT29 cells with SU9516 is associated with decreased expression of tumour suppressor protein p53. Our findings provide a rationale for clinical use of Bcl-2 family inhibitors in combination with CDK2 inhibitors for treatment of Mcl-1-dependent colorectal tumours associated with expression of Bcl-2, Bcl-XL and Bcl-w proteins. In addition, we have shown potential of CDK2 inhibitors for treatment of tumours expressing R273H mutant p53.
[Mh] Termos MeSH primário: Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem
Compostos de Bifenilo/administração & dosagem
Neoplasias Colorretais/tratamento farmacológico
Neoplasias Colorretais/enzimologia
Quinase 2 Dependente de Ciclina/antagonistas & inibidores
Imidazóis/administração & dosagem
Indóis/administração & dosagem
Nitrofenóis/administração & dosagem
Sulfonamidas/administração & dosagem
[Mh] Termos MeSH secundário: Apoptose/efeitos dos fármacos
Proteína Agonista de Morte Celular de Domínio Interatuante com BH3/química
Compostos de Bifenilo/química
Células CACO-2
Sobrevivência Celular/efeitos dos fármacos
Neoplasias Colorretais/patologia
Relação Dose-Resposta a Droga
Sinergismo Farmacológico
Células HT29
Seres Humanos
Nitrofenóis/química
Piperazinas/administração & dosagem
Piperazinas/química
Sulfonamidas/química
Resultado do Tratamento
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ABT-737); 0 (BH3 Interacting Domain Death Agonist Protein); 0 (BID protein, human); 0 (Biphenyl Compounds); 0 (Imidazoles); 0 (Indoles); 0 (Nitrophenols); 0 (Piperazines); 0 (SU 9516); 0 (Sulfonamides); EC 2.7.11.22 (CDK2 protein, human); EC 2.7.11.22 (Cyclin-Dependent Kinase 2)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180223
[Lr] Data última revisão:
180223
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180127
[St] Status:MEDLINE
[do] DOI:10.4149/gpb_2017030


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[PMID]:29182622
[Au] Autor:Vondálová Blanárová O; Safaríková B; Herudková J; Krkoska M; Tománková S; Kahounová Z; Andera L; Bouchal J; Kharaishvili G; Král M; Sova P; Kozubík A; Hyrslová Vaculová A
[Ad] Endereço:Department of Cytokinetics, Institute of Biophysics, Czech Academy of Sciences, v.v.i., Brno, Czech Republic.
[Ti] Título:Cisplatin or LA-12 enhance killing effects of TRAIL in prostate cancer cells through Bid-dependent stimulation of mitochondrial apoptotic pathway but not caspase-10.
[So] Source:PLoS One;12(11):e0188584, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Searching for new strategies for effective elimination of human prostate cancer cells, we investigated the cooperative cytotoxic action of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and two platinum-based complexes, cisplatin or LA-12, and related molecular mechanisms. We demonstrated a notable ability of cisplatin or LA-12 to enhance the sensitivity of several human prostate cancer cell lines to TRAIL-induced cell death via an engagement of mitochondrial apoptotic pathway. This was accompanied by augmented Bid cleavage, Bak activation, loss of mitochondrial membrane potential, activation of caspase-8, -10, -9, and -3, and XIAP cleavage. RNAi-mediated silencing of Bid or Bak in Bax-deficient DU 145 cells suppressed the drug combination-induced cytotoxicity, further underscoring the involvement of mitochondrial signaling. The caspase-10 was dispensable for enhancement of cisplatin/LA-12 and TRAIL combination-induced cell death and stimulation of Bid cleavage. Importantly, we newly demonstrated LA-12-mediated enhancement of TRAIL-induced cell death in cancer cells derived from human patient prostate tumor specimens. Our results provide convincing evidence that employing TRAIL combined with cisplatin/LA-12 could contribute to more effective killing of prostate cancer cells compared to the individual action of the drugs, and offer new mechanistic insights into their cooperative anticancer action.
[Mh] Termos MeSH primário: Amantadina/análogos & derivados
Apoptose/efeitos dos fármacos
Proteína Agonista de Morte Celular de Domínio Interatuante com BH3/metabolismo
Caspase 10/metabolismo
Cisplatino/farmacologia
Mitocôndrias/efeitos dos fármacos
Compostos Organoplatínicos/farmacologia
Neoplasias da Próstata/patologia
Ligante Indutor de Apoptose Relacionado a TNF/metabolismo
[Mh] Termos MeSH secundário: Amantadina/farmacologia
Seres Humanos
Masculino
Mitocôndrias/metabolismo
Neoplasias da Próstata/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (BH3 Interacting Domain Death Agonist Protein); 0 (BID protein, human); 0 (Organoplatinum Compounds); 0 (TNF-Related Apoptosis-Inducing Ligand); 0 (bis(acetato)(1-adamantylamine)amminedichloroplatinum(IV)); BF4C9Z1J53 (Amantadine); EC 3.4.22.- (Caspase 10); Q20Q21Q62J (Cisplatin)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171226
[Lr] Data última revisão:
171226
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171129
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0188584


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[PMID]:28549584
[Au] Autor:Lan T; Zhao H; Xiang B; Wang J; Liu Y
[Ad] Endereço:Department of Orthodontics, State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China.
[Ti] Título:Suture compression induced midpalatal suture chondrocyte apoptosis with increased caspase-3, caspase-9, Bad, Bak, Bax and Bid expression.
[So] Source:Biochem Biophys Res Commun;489(2):179-186, 2017 Jul 22.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: Previous studies found bone resorption and chondrocytes loss in mouse models of mid-palatal suture when given continuous compressive force, although chondrocytes response remained unknown. Herein, we design this study to determine how continuous compression force induces chondrocytes apoptosis. METHODS: Thirty C57BL/6 male mice (aged 6 weeks) were randomly assigned into controls (not ligated to a spring), blank controls (ligated with no compression) and the compression group (ligated with 20-g compression). After 4 d, palatal tissues were sampled and stained by TB and safranin-O. Tunel staining measured the percentage of apoptotic chondrocytes, and immunohistochemistry was performed to label apoptosis-associated proteins (e.g., Bcl-2, Bcl-xl, Bax, Bak, Bid, Bad, caspase-3, caspase-8 and caspase-9). Intergroup comparison was made by the rank sum test, and P < 0.05 was defined as statistical significance. RESULTS: After 7d of induction, TB and safranin-O staining revealed that the cartilage area in the compression group was significantly decreased, while the control group remained largely unaltered. Tunel staining showed that apoptotic cell numbers in the mid-palatal suture were significantly higher than the control group. Immunohistochemistry showed that mice in the compression group had significantly increased expression of caspase-3, caspase-9, Bad, Bak, Bax and Bid; However, caspase-8 remained unaltered. No expression of Bcl-2 and Bcl-xl was detected. CONCLUSIONS: Continuous compression force induces chondrocytes apoptosis in the mid-palatal suture. This process might be associated with the mitochondrial pathway.
[Mh] Termos MeSH primário: Apoptose
Condrócitos/metabolismo
Condrócitos/patologia
Pressão/efeitos adversos
Suturas/efeitos adversos
Regulação para Cima
[Mh] Termos MeSH secundário: Animais
Proteína Agonista de Morte Celular de Domínio Interatuante com BH3/biossíntese
Caspase 3/biossíntese
Caspase 9/biossíntese
Imuno-Histoquímica
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Fenazinas
Cloreto de Tolônio
Proteína Killer-Antagonista Homóloga a bcl-2/biossíntese
Proteína X Associada a bcl-2/biossíntese
Proteína de Morte Celular Associada a bcl/biossíntese
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (BH3 Interacting Domain Death Agonist Protein); 0 (Bad protein, mouse); 0 (Bak1 protein, mouse); 0 (Bax protein, mouse); 0 (Bid protein, mouse); 0 (Phenazines); 0 (bcl-2 Homologous Antagonist-Killer Protein); 0 (bcl-2-Associated X Protein); 0 (bcl-Associated Death Protein); 15XUH0X66N (Tolonium Chloride); EC 3.4.22.- (Casp3 protein, mouse); EC 3.4.22.- (Casp9 protein, mouse); EC 3.4.22.- (Caspase 3); EC 3.4.22.- (Caspase 9); XTX0YXU2HV (safranine T)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170921
[Lr] Data última revisão:
170921
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170528
[St] Status:MEDLINE


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[PMID]:28529067
[Au] Autor:Yan F; Li X; Li N; Zhang R; Wang Q; Ru Y; Hao X; Ni J; Wang H; Wu G
[Ad] Endereço:Department of Urology, Tang Du Hospital, The Fourth Military Medical University, Shaanxi, Xian, 710038, China; Department of Urology, Xi Jing Hospital, The Fourth Military Medical University, Shaanxi, Xian, 710032, China.
[Ti] Título:Immunoproapoptotic molecule scFv-Fdt-tBid modified mesenchymal stem cells for prostate cancer dual-targeted therapy.
[So] Source:Cancer Lett;402:32-42, 2017 Aug 28.
[Is] ISSN:1872-7980
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:Highly efficient target therapy is urgently needed for prostate cancer with overexpression of γ-seminoprotein (γ-SM). Recent studies indicated that mesenchymal stem cells (MSCs) are attractive candidate for cell-based, targeted therapy due to their tumor tropism. Here we designed a dual-target therapeutic system in which MSCs were engineered to produce and deliver scFv-Fdt-tBid, a novel γ-SM-targeted immunoproapoptotic molecule. Such engineered MSCs (MSC.scFv-Fdt-tBid) would home to tumor sites and release the fusion protein to induce the apoptosis of prostate cancer cells. Our data demonstrated that scFv-Fdt-tBid showed a selective, potent and dose-dependent inhibition for γ-SM-positive cells (LNCaP, C4-2, 22Rv1) rather than γ-SM-negative cells and MSCs. Importantly, MSC.scFv-Fdt-tBid caused cell death through an apoptosis-dependent manner. Further, the tropism of MSC.scFv-Fdt-tBid to prostate cancer was verified both in vitro and in vivo. Finally, the in vivo experiments demonstrated that MSC.scFv-Fdt-tBid significantly inhibited γ-SM-positive tumor growth without toxic side effects. Collectively, this study represented a novel immunoproapoptotic molecule scFv-Fdt-tBid for γ-SM-positive tumors and demonstrated the therapeutic efficiency and safety of scFv-Fdt-tBid-modified MSCs against prostate cancers.
[Mh] Termos MeSH primário: Apoptose
Proteína Agonista de Morte Celular de Domínio Interatuante com BH3/metabolismo
Toxina Diftérica/metabolismo
Terapia Genética/métodos
Imunoterapia/métodos
Calicreínas/metabolismo
Transplante de Células-Tronco Mesenquimais
Células Mesenquimais Estromais/metabolismo
Fragmentos de Peptídeos/metabolismo
Antígeno Prostático Específico/metabolismo
Neoplasias da Próstata/terapia
Anticorpos de Cadeia Única/metabolismo
[Mh] Termos MeSH secundário: Animais
Proteína Agonista de Morte Celular de Domínio Interatuante com BH3/genética
Linhagem Celular Tumoral
Movimento Celular
Técnicas de Cocultura
Toxina Diftérica/genética
Seres Humanos
Calicreínas/imunologia
Masculino
Células Mesenquimais Estromais/imunologia
Camundongos Nus
Invasividade Neoplásica
Fragmentos de Peptídeos/genética
Antígeno Prostático Específico/imunologia
Neoplasias da Próstata/genética
Neoplasias da Próstata/imunologia
Neoplasias da Próstata/metabolismo
Transdução de Sinais
Anticorpos de Cadeia Única/genética
Anticorpos de Cadeia Única/imunologia
Fatores de Tempo
Transfecção
Carga Tumoral
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (BH3 Interacting Domain Death Agonist Protein); 0 (Diphtheria Toxin); 0 (Peptide Fragments); 0 (Single-Chain Antibodies); EC 3.4.21.- (Kallikreins); EC 3.4.21.- (kallikrein-related peptidase 3, human); EC 3.4.21.77 (Prostate-Specific Antigen)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170926
[Lr] Data última revisão:
170926
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170523
[St] Status:MEDLINE


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[PMID]:28416970
[Au] Autor:Sundar IK; Yin Q; Baier BS; Yan L; Mazur W; Li D; Susiarjo M; Rahman I
[Ad] Endereço:Department of Environmental Medicine, University of Rochester Medical Center, Box 850, 601 Elmwood Avenue, Rochester, 14642 NY USA.
[Ti] Título:DNA methylation profiling in peripheral lung tissues of smokers and patients with COPD.
[So] Source:Clin Epigenetics;9:38, 2017.
[Is] ISSN:1868-7083
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Epigenetics changes have been shown to be affected by cigarette smoking. Cigarette smoke (CS)-mediated DNA methylation can potentially affect several cellular and pathophysiological processes, acute exacerbations, and comorbidity in the lungs of patients with chronic obstructive pulmonary disease (COPD). We sought to determine whether genome-wide lung DNA methylation profiles of smokers and patients with COPD were significantly different from non-smokers. We isolated DNA from parenchymal lung tissues of patients including eight lifelong non-smokers, eight current smokers, and eight patients with COPD and analyzed the samples using Illumina's Infinium HumanMethylation450 BeadChip. RESULTS: Our data revealed that the differentially methylated genes were related to top canonical pathways (e.g., G beta gamma signaling, mechanisms of cancer, and nNOS signaling in neurons), disease and disorders (organismal injury and abnormalities, cancer, and respiratory disease), and molecular and cellular functions (cell death and survival, cellular assembly and organization, cellular function and maintenance) in patients with COPD. The genome-wide DNA methylation analysis identified suggestive genes, such as , , , , , and with DNA methylation changes in COPD lung tissues that were further validated by pyrosequencing. Pyrosequencing validation confirmed hyper-methylation in smokers and patients with COPD as compared to non-smokers. However, we did not detect significant differences in DNA methylation for , , and genes in smokers and COPD groups despite the changes observed in the genome-wide analysis. CONCLUSIONS: Our study suggests that DNA methylation in suggestive genes, such as , , and may be used as epigenetic signatures in smokers and patients with COPD if the same is validated in a larger cohort. Future studies are required to correlate DNA methylation status with transcriptomics of selective genes identified in this study and elucidate their role and involvement in the progression of COPD and its exacerbations.
[Mh] Termos MeSH primário: Proteínas Adaptadoras de Transdução de Sinal/genética
Proteína Agonista de Morte Celular de Domínio Interatuante com BH3/genética
Metilação de DNA
Doença Pulmonar Obstrutiva Crônica/genética
Receptores de GABA-A/genética
Fumar/genética
[Mh] Termos MeSH secundário: Idoso
Impressões Digitais de DNA
Feminino
Seres Humanos
Pulmão/metabolismo
Masculino
Meia-Idade
Análise de Sequência de DNA
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adaptor Proteins, Signal Transducing); 0 (BH3 Interacting Domain Death Agonist Protein); 0 (BID protein, human); 0 (GABRB1 protein, human); 0 (NOS1AP protein, human); 0 (Receptors, GABA-A)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:170421
[Lr] Data última revisão:
170421
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170419
[St] Status:MEDLINE
[do] DOI:10.1186/s13148-017-0335-5


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[PMID]:28288819
[Au] Autor:Opydo-Chanek M; Gonzalo O; Marzo I
[Ad] Endereço:Department of Experimental Hematology, Institute of Zoology, Jagiellonian University in Kraków, Poland. Electronic address: malgorzata.opydo-chanek@uj.edu.pl.
[Ti] Título:Multifaceted anticancer activity of BH3 mimetics: Current evidence and future prospects.
[So] Source:Biochem Pharmacol;136:12-23, 2017 Jul 15.
[Is] ISSN:1873-2968
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BH3 mimetics are a novel class of anticancer agents designed to specifically target pro-survival proteins of the Bcl-2 family. Like endogenous BH3-only proteins, BH3 mimetics competitively bind to surface hydrophobic grooves of pro-survival Bcl-2 family members, counteracting their protective effects and thus facilitating apoptosis in cancer cells. Among the small-molecule BH3 mimetics identified, ABT-737 and its analogs, obatoclax as well as gossypol derivatives are the best characterized. The anticancer potential of these compounds applied as a single agent or in combination with chemotherapeutic drugs is currently being evaluated in preclinical studies and in clinical trials. In spite of promising results, the actual mechanisms of their anticancer action remain to be identified. Findings from preclinical studies point to additional activities of BH3 mimetics in cancer cells that are not connected with apoptosis induction. These off-target effects involve induction of autophagy and necrotic cell death as well as modulation of the cell cycle and multiple cell signaling pathways. For the optimization and clinical implementation of BH3 mimetics, a detailed understanding of their role as inhibitors of the pro-survival Bcl-2 proteins, but also of their possible additional effects is required. This review summarizes the most representative BH3 mimetic compounds with emphasis on their off-target effects. Based on the present knowledge on the multifaceted effects of BH3 mimetics on cancer cells, the commentary outlines the potential pitfalls and highlights the considerable promise for cancer treatment with BH3 mimetics.
[Mh] Termos MeSH primário: Antineoplásicos/metabolismo
Antineoplásicos/uso terapêutico
Proteína Agonista de Morte Celular de Domínio Interatuante com BH3/metabolismo
Materiais Biomiméticos/metabolismo
Materiais Biomiméticos/uso terapêutico
[Mh] Termos MeSH secundário: Animais
Previsões
Seres Humanos
Neoplasias/tratamento farmacológico
Neoplasias/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (BH3 Interacting Domain Death Agonist Protein); 0 (BID protein, human)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170613
[Lr] Data última revisão:
170613
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170315
[St] Status:MEDLINE


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[PMID]:28235426
[Au] Autor:Said M; Brouard I; Quintana J; Estévez F
[Ad] Endereço:Departamento de Bioquímica y Biología Molecular, Unidad Asociada al Consejo Superior de Investigaciones Científicas (CSIC), Instituto Universitario de Investigaciones Biomédicas y Sanitarias, Universidad de las Palmas de Gran Canaria, Spain.
[Ti] Título:Antiproliferative activity and apoptosis induction by 3',4'-dibenzyloxyflavonol on human leukemia cells.
[So] Source:Chem Biol Interact;268:13-23, 2017 Apr 25.
[Is] ISSN:1872-7786
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:In this study, we investigated the effects of synthetic 3',4'-dibenzyloxyflavonol on viabilities of eight human tumor cells. It was cytotoxic against leukemia cells (HL-60, U-937, MOLT-3, K-562, NALM-6, Raji), with significant effects against P-glycoprotein-overexpressing K-562/ADR and Bcl-2-overexpressing U-937/Bcl-2 cells, but had no significant cytotoxic effects against quiescent or proliferating human peripheral blood mononuclear cells. The IC value for the leukemia HL-60 cells was 0.8 ± 0.1 µM. This indicates a 60-fold greater toxicity than the naturally occurring flavonol quercetin. Synthetic 3',4'-dibenzyloxyflavonol induced S phase cell cycle arrest and was a potent apoptotic inducer in human leukemia cells. Cell death was (i) mediated by the activation and the cleavage of initiator and executioner caspases; (ii) prevented by the pan-caspase inhibitor z-VAD-fmk; (iii) associated with the release of cytochrome c and with the phosphorylation of members of the mitogen activated protein kinases including p38 , JNK/SAPK and ERK, and (iv) independent of the generation of reactive oxygen species. The synthetic 3',4'-dibenzyloxyflavonol is a potent cytotoxic compound against several human leukemia cells and might be useful in the development of new strategies in the fight against cancer.
[Mh] Termos MeSH primário: Antineoplásicos/uso terapêutico
Apoptose/efeitos dos fármacos
Flavonóis/uso terapêutico
Leucemia/tratamento farmacológico
[Mh] Termos MeSH secundário: Antineoplásicos/síntese química
Proteína Agonista de Morte Celular de Domínio Interatuante com BH3/metabolismo
Inibidores de Caspase/farmacologia
Caspases/metabolismo
Linhagem Celular Tumoral/efeitos dos fármacos
Flavonóis/síntese química
Seres Humanos
Proteínas Quinases Ativadas por Mitógeno/metabolismo
Fosforilação
Espécies Reativas de Oxigênio/metabolismo
Pontos de Checagem da Fase S do Ciclo Celular/efeitos dos fármacos
Proteína X Associada a bcl-2/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (3',4'-dibenzyloxyflavonol); 0 (Antineoplastic Agents); 0 (BAX protein, human); 0 (BH3 Interacting Domain Death Agonist Protein); 0 (BID protein, human); 0 (Caspase Inhibitors); 0 (Flavonols); 0 (Reactive Oxygen Species); 0 (bcl-2-Associated X Protein); EC 2.7.11.24 (Mitogen-Activated Protein Kinases); EC 3.4.22.- (Caspases)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:170425
[Lr] Data última revisão:
170425
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170226
[St] Status:MEDLINE


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[PMID]:28170214
[Au] Autor:Das KK; Shalaby R; García-Sáez AJ
[Ad] Endereço:Interfaculty Institute of Biochemistry, Eberhard Karls University Tübingen , Hoppe-Seyler-Str. 4, 72076 Tübingen, Germany.
[Ti] Título:Determinants of BH3 Sequence Specificity for the Disruption of Bcl-xL/cBid Complexes in Membranes.
[So] Source:ACS Chem Biol;12(4):989-1000, 2017 Apr 21.
[Is] ISSN:1554-8937
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The prosurvival Bcl-2 proteins exhibit a specific pattern of interactions with BH3-only proteins that determines the cellular dependence on apoptotic stress. This specificity is crucial for the development of BH3 mimetics, a class of anticancer molecules based on the BH3 domain with promising activity in clinical trials. Although complex formation mainly takes place in the mitochondrial outer membrane, most studies so far addressed the interaction between BH3 peptides and truncated Bcl-2 proteins in solution. As a consequence, quantitative understanding of the sequence specificity determinants of BH3 peptides in the membrane environment is missing. Here, we tackle this issue by systematically quantifying the ability of BH3 peptides to compete for the complexes between cBid and Bcl-xL in giant unilamellar vesicles and compare it with solution and mitochondria. We show that the BH3 peptides derived from Hrk, Bim, Bid, and Bad are the most efficient in disrupting cBid/Bcl-xL complexes in the membrane, which correlates with their activity in mitochondria. Our findings support the targeting to the membrane of small molecules that bind Bcl-2 proteins as a strategy to improve their efficiency.
[Mh] Termos MeSH primário: Proteína Agonista de Morte Celular de Domínio Interatuante com BH3/metabolismo
Proteína bcl-X/metabolismo
[Mh] Termos MeSH secundário: Proteína Agonista de Morte Celular de Domínio Interatuante com BH3/química
Sítios de Ligação
Membrana Celular/metabolismo
Seres Humanos
Simulação de Acoplamento Molecular
Mimetismo Molecular
Peptídeos/metabolismo
Ligação Proteica
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (BH3 Interacting Domain Death Agonist Protein); 0 (Peptides); 0 (bcl-X Protein)
[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:170208
[St] Status:MEDLINE
[do] DOI:10.1021/acschembio.6b01084


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[PMID]:28073006
[Au] Autor:López-García C; Sansregret L; Domingo E; McGranahan N; Hobor S; Birkbak NJ; Horswell S; Grönroos E; Favero F; Rowan AJ; Matthews N; Begum S; Phillimore B; Burrell R; Oukrif D; Spencer-Dene B; Kovac M; Stamp G; Stewart A; Danielsen H; Novelli M; Tomlinson I; Swanton C
[Ad] Endereço:Translational Cancer Therapeutics Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
[Ti] Título:BCL9L Dysfunction Impairs Caspase-2 Expression Permitting Aneuploidy Tolerance in Colorectal Cancer.
[So] Source:Cancer Cell;31(1):79-93, 2017 Jan 09.
[Is] ISSN:1878-3686
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Chromosomal instability (CIN) contributes to cancer evolution, intratumor heterogeneity, and drug resistance. CIN is driven by chromosome segregation errors and a tolerance phenotype that permits the propagation of aneuploid genomes. Through genomic analysis of colorectal cancers and cell lines, we find frequent loss of heterozygosity and mutations in BCL9L in aneuploid tumors. BCL9L deficiency promoted tolerance of chromosome missegregation events, propagation of aneuploidy, and genetic heterogeneity in xenograft models likely through modulation of Wnt signaling. We find that BCL9L dysfunction contributes to aneuploidy tolerance in both TP53-WT and mutant cells by reducing basal caspase-2 levels and preventing cleavage of MDM2 and BID. Efforts to exploit aneuploidy tolerance mechanisms and the BCL9L/caspase-2/BID axis may limit cancer diversity and evolution.
[Mh] Termos MeSH primário: Aneuploidia
Caspase 2/fisiologia
Neoplasias Colorretais/genética
Cisteína Endopeptidases/fisiologia
Proteínas de Ligação a DNA/fisiologia
Fatores de Transcrição/fisiologia
[Mh] Termos MeSH secundário: Idoso
Idoso de 80 Anos ou mais
Animais
Proteína Agonista de Morte Celular de Domínio Interatuante com BH3/fisiologia
Caspase 2/análise
Segregação de Cromossomos
Cisteína Endopeptidases/análise
Proteínas de Ligação a DNA/genética
Células HCT116
Seres Humanos
Camundongos
Meia-Idade
Mutação
Proteínas Proto-Oncogênicas c-mdm2/fisiologia
Fatores de Transcrição/genética
Proteína Supressora de Tumor p53/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (BCL9L protein, human); 0 (BH3 Interacting Domain Death Agonist Protein); 0 (BID protein, human); 0 (DNA-Binding Proteins); 0 (TP53 protein, human); 0 (Transcription Factors); 0 (Tumor Suppressor Protein p53); EC 2.3.2.27 (MDM2 protein, human); EC 2.3.2.27 (Proto-Oncogene Proteins c-mdm2); EC 3.4.22.- (CASP2 protein, human); EC 3.4.22.- (Caspase 2); EC 3.4.22.- (Cysteine Endopeptidases)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170111
[St] Status:MEDLINE


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[PMID]:28004114
[Au] Autor:Huang G; Chen X; Cai Y; Wang X; Xing C
[Ad] Endereço:Department of General Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, P.R. China.
[Ti] Título:miR-20a-directed regulation of BID is associated with the TRAIL sensitivity in colorectal cancer.
[So] Source:Oncol Rep;37(1):571-578, 2017 Jan.
[Is] ISSN:1791-2431
[Cp] País de publicação:Greece
[La] Idioma:eng
[Ab] Resumo:MicroRNAs (miRNAs) are small, non-coding RNAs that play important roles in cancer processes. Although miR-20a has been reported to be altered in a range of cancers, the role of miR-20a in colorectal cancer is not fully characterized, and the relationship between miR-20a dysregulation and the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) sensitivity is not defined. In the present study, we demonstrated significant upregulation of miR-20a in the serum of colorectal cancer patients, tumor tissues and cell lines by quantitative RT-PCR analysis. Furthermore, we found that the TRAIL-induced apoptosis was associated with the expression level of miR-20a in colorectal cancer. The knockdown of miR-20a by inhibitors increased the antitumor effect of TRAIL via caspase-8 dependent pathway. BID, which is a pro-apoptotic member of the Bcl-2 family, was found to be directly regulated by miR-20a in SW480 cells. The knockdown of miR-20a inhibited the translocation of tBID to the mitochondria, which induced the mitochondrial pathway of apoptosis. Notably, we found that the knockdown of miR-20a also reversed the resistance of TRAIL in established TRAIL-resistant SW480 cells by tBID-mitochondria pathway. Therefore, our results suggest that miR-20a acts as a tumor promoter in colorectal cancer, and the understanding of the miR-20a might be a potential therapeutic target for colorectal cancer.
[Mh] Termos MeSH primário: Proteína Agonista de Morte Celular de Domínio Interatuante com BH3/genética
Neoplasias Colorretais/genética
MicroRNAs/metabolismo
Ligante Indutor de Apoptose Relacionado a TNF/farmacologia
[Mh] Termos MeSH secundário: Apoptose/efeitos dos fármacos
Apoptose/genética
Proteína Agonista de Morte Celular de Domínio Interatuante com BH3/metabolismo
Estudos de Casos e Controles
Linhagem Celular Tumoral
Neoplasias Colorretais/tratamento farmacológico
Neoplasias Colorretais/metabolismo
Citosol/metabolismo
Regulação Neoplásica da Expressão Gênica
Técnicas de Silenciamento de Genes
Seres Humanos
MicroRNAs/genética
Mitocôndrias/metabolismo
Regulação para Cima
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (BH3 Interacting Domain Death Agonist Protein); 0 (BID protein, human); 0 (MIRN20 microRNA, human); 0 (MicroRNAs); 0 (TNF-Related Apoptosis-Inducing Ligand)
[Em] Mês de entrada:1703
[Cu] Atualização por classe:170313
[Lr] Data última revisão:
170313
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161223
[St] Status:MEDLINE
[do] DOI:10.3892/or.2016.5278



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