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[PMID]:29179736
[Au] Autor:Erives AJ
[Ad] Endereço:Department of Biology, University of Iowa, Iowa City, IA, 52242-1324, USA. albert-erives@uiowa.edu.
[Ti] Título:Phylogenetic analysis of the core histone doublet and DNA topo II genes of Marseilleviridae: evidence of proto-eukaryotic provenance.
[So] Source:Epigenetics Chromatin;10(1):55, 2017 11 28.
[Is] ISSN:1756-8935
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: While the genomes of eukaryotes and Archaea both encode the histone-fold domain, only eukaryotes encode the core histone paralogs H2A, H2B, H3, and H4. With DNA, these core histones assemble into the nucleosomal octamer underlying eukaryotic chromatin. Importantly, core histones for H2A and H3 are maintained as neofunctionalized paralogs adapted for general bulk chromatin (canonical H2 and H3) or specialized chromatin (H2A.Z enriched at gene promoters and cenH3s enriched at centromeres). In this context, the identification of core histone-like "doublets" in the cytoplasmic replication factories of the Marseilleviridae (MV) is a novel finding with possible relevance to understanding the origin of eukaryotic chromatin. Here, we analyze and compare the core histone doublet genes from all known MV genomes as well as other MV genes relevant to the origin of the eukaryotic replisome. RESULTS: Using different phylogenetic approaches, we show that MV histone domains encode obligate H2B-H2A and H4-H3 dimers of possible proto-eukaryotic origin. MV core histone moieties form sister clades to each of the four eukaryotic clades of canonical and variant core histones. This suggests that MV core histone moieties diverged prior to eukaryotic neofunctionalizations associated with paired linear chromosomes and variant histone octamer assembly. We also show that MV genomes encode a proto-eukaryotic DNA topoisomerase II enzyme that forms a sister clade to eukaryotes. This is a relevant finding given that DNA topo II influences histone deposition and chromatin compaction and is the second most abundant nuclear protein after histones. CONCLUSIONS: The combined domain architecture and phylogenomic analyses presented here suggest that a primitive origin for MV histone genes is a more parsimonious explanation than horizontal gene transfers + gene fusions + sufficient divergence to eliminate relatedness to eukaryotic neofunctionalizations within the H2A and H3 clades without loss of relatedness to each of the four core histone clades. We thus suggest MV histone doublet genes and their DNA topo II gene possibly were acquired from an organism with a chromatinized replisome that diverged prior to the origin of eukaryotic core histone variants for H2/H2A.Z and H3/cenH3. These results also imply that core histones were utilized ancestrally in viral DNA compaction and/or protection from host endonucleases.
[Mh] Termos MeSH primário: DNA Topoisomerases Tipo II/genética
Vírus de DNA/genética
Histonas/genética
Filogenia
[Mh] Termos MeSH secundário: Vírus de DNA/classificação
Genes Virais
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Histones); EC 5.99.1.3 (DNA Topoisomerases, Type II)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180310
[Lr] Data última revisão:
180310
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171129
[St] Status:MEDLINE
[do] DOI:10.1186/s13072-017-0162-0


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[PMID]:29335211
[Au] Autor:Li PH; Jiang H; Zhang WJ; Li YL; Zhao MC; Zhou W; Zhang LY; Tang YD; Dong CZ; Huang ZS; Chen HX; Du ZY
[Ad] Endereço:Institute of Natural Medicine & Green Chemistry, School of Chemical Engineering and Light Industry, Guandong University of Technology, Guangzhou, 510006, China.
[Ti] Título:Synthesis of carbazole derivatives containing chalcone analogs as non-intercalative topoisomerase II catalytic inhibitors and apoptosis inducers.
[So] Source:Eur J Med Chem;145:498-510, 2018 Feb 10.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:Novel topoisomerase II (Topo II) inhibitors have gained considerable interest for the development of anticancer agents. In this study, a series of carbazole derivatives containing chalcone analogs (CDCAs) were synthesized and investigated for their Topo II inhibition and cytotoxic activities. The results from Topo II mediated DNA relaxation assay showed that CDCAs could significantly inhibit the activity of Topo II, and the structure-activity relationship indicated the halogen substituent in phenyl ring play an important role in the activity. Further mechanism studies revealed that CDCAs function as non-intercalative Topo II catalytic inhibitors. Moreover, some CDCAs showed micromolar cytotoxic activities. The most potent compound 3h exhibited notable growth inhibition against four human cancer cell lines. Flow cytometric analysis revealed that compounds 3d and 3h arrested the HL-60 cells in sub G1 phase by induction of apoptosis. It was further confirmed by Annexin-V-FITC binding assay. Western blot analysis revealed that compound 3h induces apoptosis likely through the activation of caspase proteins.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Apoptose/efeitos dos fármacos
Carbazóis/farmacologia
Chalcona/farmacologia
DNA Topoisomerases Tipo II/metabolismo
Inibidores da Topoisomerase II/farmacologia
[Mh] Termos MeSH secundário: Antineoplásicos/síntese química
Antineoplásicos/química
Biocatálise
Carbazóis/síntese química
Carbazóis/química
Pontos de Checagem do Ciclo Celular/efeitos dos fármacos
Proliferação Celular/efeitos dos fármacos
Chalcona/química
Clivagem do DNA/efeitos dos fármacos
Relação Dose-Resposta a Droga
Ensaios de Seleção de Medicamentos Antitumorais
Células HL-60
Seres Humanos
Estrutura Molecular
Plasmídeos
Relação Estrutura-Atividade
Inibidores da Topoisomerase II/síntese química
Inibidores da Topoisomerase II/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Carbazoles); 0 (Topoisomerase II Inhibitors); 0P2197HHHN (carbazole); 5S5A2Q39HX (Chalcone); EC 5.99.1.3 (DNA Topoisomerases, Type II)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180302
[Lr] Data última revisão:
180302
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180117
[St] Status:MEDLINE


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[PMID]:29289884
[Au] Autor:Reddy VG; Bonam SR; Reddy TS; Akunuri R; Naidu VGM; Nayak VL; Bhargava SK; Kumar HMS; Srihari P; Kamal A
[Ad] Endereço:Academy of Scientific and Innovative Research (AcSIR), CSIR-Indian Institute of Chemical Technology (IICT), Hyderabad, 500007, India; Medicinal Chemistry and Biotechnology, CSIR-Indian Institute of Chemical Technology (IICT), Hyderabad, 500007, India; Division of Natural Products Chemistry, CSIR-Ind
[Ti] Título:4ß-amidotriazole linked podophyllotoxin congeners: DNA topoisomerase-IIα inhibition and potential anticancer agents for prostate cancer.
[So] Source:Eur J Med Chem;144:595-611, 2018 Jan 20.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:Topoisomerases (topo-I and topo-II) have occupied a significant role in DNA replication, transcription, and are a promising set of antitumor targets. In the present approach, a series of new 4ß-amidotriazole linked podophyllotoxin derivatives (10a-i and 11a-k) were designed, synthesized by employing the click chemistry and their biological activities were evaluated. The majority of derivatives showed promising antiproliferative activity with IC values ranging from 1 to 10 µM on the six human cancer cell lines; cervical (HeLa), breast (MCF-7), prostate (DU-145), lung (A549), liver (HepG2) and colon (HT-29). Among them, some of the congeners 10b, 10g and 10i have shown remarkable cytotoxicity with IC values of, < 1 µM against the tested cancer cell lines and found to be more active than etoposide. Topoisomerase-mediated DNA relaxation assay results showed that the derivatives could efficiently inhibit the activity of topoisomerase-II. In addition, flow cytometry analysis on DU-145 cells revealed that these compounds arrest G2/M phase of cell cycle. Further apoptotic studies were also performed on these DU-145 cells, which showed that this class of compounds could induce apoptosis effectively.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
DNA Topoisomerases Tipo II/metabolismo
Podofilotoxina/farmacologia
Neoplasias da Próstata/tratamento farmacológico
Inibidores da Topoisomerase II/farmacologia
Triazóis/farmacologia
[Mh] Termos MeSH secundário: Antineoplásicos/síntese química
Antineoplásicos/química
Apoptose/efeitos dos fármacos
Ciclo Celular/efeitos dos fármacos
Proliferação Celular/efeitos dos fármacos
Relação Dose-Resposta a Droga
Seres Humanos
Masculino
Potencial da Membrana Mitocondrial/efeitos dos fármacos
Simulação de Acoplamento Molecular
Estrutura Molecular
Podofilotoxina/química
Neoplasias da Próstata/metabolismo
Neoplasias da Próstata/patologia
Espécies Reativas de Oxigênio/análise
Espécies Reativas de Oxigênio/metabolismo
Relação Estrutura-Atividade
Inibidores da Topoisomerase II/síntese química
Inibidores da Topoisomerase II/química
Triazóis/síntese química
Triazóis/química
Células Tumorais Cultivadas
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Reactive Oxygen Species); 0 (Topoisomerase II Inhibitors); 0 (Triazoles); EC 5.99.1.3 (DNA Topoisomerases, Type II); L36H50F353 (Podophyllotoxin)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180302
[Lr] Data última revisão:
180302
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180101
[St] Status:MEDLINE


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[PMID]:29289881
[Au] Autor:Sathish M; Kavitha B; Nayak VL; Tangella Y; Ajitha A; Nekkanti S; Alarifi A; Shankaraiah N; Nagesh N; Kamal A
[Ad] Endereço:Medicinal Chemistry and Pharmacology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India.
[Ti] Título:Synthesis of podophyllotoxin linked ß-carboline congeners as potential anticancer agents and DNA topoisomerase II inhibitors.
[So] Source:Eur J Med Chem;144:557-571, 2018 Jan 20.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:A series of new podophyllotoxin linked ß-carboline congeners have been synthesized by coupling various substituted ß-carboline acids with 4ß-aminopodophyllotoxin. Evaluation of their anticancer activity against a panel of human cancer cell lines such as lung cancer (A549), prostate cancer (DU-145), MDA MB-231 (breast cancer), HT-29 (colon cancer) and HeLa (cervical cancer) suggested that 7i and 7j are the most cytotoxic compounds with IC values of 1.07 ±â€¯0.07 µM and 1.14 ±â€¯0.16 respectively against DU-145 cell line. Further, detailed biological studies such as cell cycle analysis, topoisomerase II inhibition, Comet assay, DNA binding studies and docking studies have revealed that these congeners are DNA interacting topoisomerase II inhibitors.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Carbolinas/farmacologia
DNA Topoisomerases Tipo II/metabolismo
Podofilotoxina/farmacologia
Inibidores da Topoisomerase II/farmacologia
[Mh] Termos MeSH secundário: Antineoplásicos/síntese química
Antineoplásicos/química
Carbolinas/química
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Relação Dose-Resposta a Droga
Ensaios de Seleção de Medicamentos Antitumorais
Seres Humanos
Simulação de Acoplamento Molecular
Estrutura Molecular
Podofilotoxina/química
Relação Estrutura-Atividade
Inibidores da Topoisomerase II/síntese química
Inibidores da Topoisomerase II/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Carbolines); 0 (Topoisomerase II Inhibitors); 94HMA1I78O (norharman); EC 5.99.1.3 (DNA Topoisomerases, Type II); L36H50F353 (Podophyllotoxin)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180302
[Lr] Data última revisão:
180302
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180101
[St] Status:MEDLINE


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[PMID]:29248296
[Au] Autor:Sang CY; Tian HZ; Chen Y; Liu JF; Chen SW; Hui L
[Ad] Endereço:School of Pharmacy, Lanzhou University, Lanzhou 730000, China.
[Ti] Título:Synthesis and biological evaluation of 4ß-(thiazol-2-yl)amino-4'-O-demethyl-4-deoxypodophyllotoxins as topoisomerase-II inhibitors.
[So] Source:Bioorg Med Chem Lett;28(2):71-76, 2018 01 15.
[Is] ISSN:1464-3405
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:A series of 4ß-(thiazol-2-yl)amino-4'-O-demethyl-4-deoxypodophyllotoxins were synthesized, and their cytotoxicities were evaluated against four human cancer cell lines (A549, HepG2, HeLa, and LOVO cells) and normal human diploid fibroblast line WI-38. Some of the compounds exhibited promising antitumor activity and less toxicity than the anticancer drug etoposide. Among them, compounds 15 and 17 were found to be the most potent synthetic derivatives as topo-II inhibitors, and induced DNA double-strand breaks via the p73/ATM pathway as well as the H2AX phosphorylation in A549 cells. These compounds also arrested A549 cells cycle in G2/M phase by regulating cyclinB1/cdc2(p34). Taken together, these results show that a series of compounds are potential anticancer agents.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
DNA Topoisomerases Tipo II/metabolismo
Peptídeos/farmacologia
Inibidores da Topoisomerase II/farmacologia
[Mh] Termos MeSH secundário: Antineoplásicos/síntese química
Antineoplásicos/química
Linhagem Celular
Proliferação Celular/efeitos dos fármacos
Relação Dose-Resposta a Droga
Ensaios de Seleção de Medicamentos Antitumorais
Fibroblastos/efeitos dos fármacos
Seres Humanos
Estrutura Molecular
Peptídeos/síntese química
Peptídeos/química
Relação Estrutura-Atividade
Inibidores da Topoisomerase II/síntese química
Inibidores da Topoisomerase II/química
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Peptides); 0 (Topoisomerase II Inhibitors); EC 5.99.1.3 (DNA Topoisomerases, Type II)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180216
[Lr] Data última revisão:
180216
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171218
[St] Status:MEDLINE


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[PMID]:29383954
[Au] Autor:Sinicropi MS; Iacopetta D; Rosano C; Randino R; Caruso A; Saturnino C; Muià N; Ceramella J; Puoci F; Rodriquez M; Longo P; Plutino MR
[Ad] Endereço:a Department of Pharmacy, Health and Nutritional Sciences , University of Calabria , Arcavacata di Rende , Italy.
[Ti] Título:N-thioalkylcarbazoles derivatives as new anti-proliferative agents: synthesis, characterisation and molecular mechanism evaluation.
[So] Source:J Enzyme Inhib Med Chem;33(1):434-444, 2018 Dec.
[Is] ISSN:1475-6374
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Synthetic or natural carbazole derivatives constitute an interesting class of heterocycles, which showed several pharmaceutical properties and occupied a promising place as antitumour tools in preclinical studies. They target several cellular key-points, e.g. DNA and Topoisomerases I and II. The most studied representative, i.e. Ellipticine, was introduced in the treatment of metastatic breast cancer. However, because of the onset of dramatic side effects, its use was almost dismissed. Many efforts were made in order to design and synthesise new carbazole derivatives with good activity and reduced side effects. The major goal of the present study was to synthesise a series of new N-thioalkylcarbazole derivatives with anti-proliferative effects. Two compounds, 5a and 5c, possess an interesting anti-proliferative activity against breast and uterine cancer cell lines without affecting non-tumoural cell lines viability. The most active compound (5c) induces cancer cells death triggering the intrinsic apoptotic pathway by inhibition of Topoisomerase II.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Carbazóis/farmacologia
DNA Topoisomerases Tipo II/metabolismo
Compostos de Sulfidrila/farmacologia
Inibidores da Topoisomerase II/farmacologia
[Mh] Termos MeSH secundário: Antineoplásicos/síntese química
Antineoplásicos/química
Carbazóis/síntese química
Carbazóis/química
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Sobrevivência Celular/efeitos dos fármacos
Relação Dose-Resposta a Droga
Ensaios de Seleção de Medicamentos Antitumorais
Seres Humanos
Modelos Moleculares
Estrutura Molecular
Relação Estrutura-Atividade
Compostos de Sulfidrila/síntese química
Compostos de Sulfidrila/química
Inibidores da Topoisomerase II/síntese química
Inibidores da Topoisomerase II/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Carbazoles); 0 (Sulfhydryl Compounds); 0 (Topoisomerase II Inhibitors); 0P2197HHHN (carbazole); EC 5.99.1.3 (DNA Topoisomerases, Type II)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180212
[Lr] Data última revisão:
180212
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180201
[St] Status:MEDLINE
[do] DOI:10.1080/14756366.2017.1419216


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[PMID]:29275239
[Au] Autor:Singh J; Srivastva AK; Mandal P; Chandra S; Dubey D; Dwivedi A; Chopra D; Tripathi A; Ray RS
[Ad] Endereço:Photobiology Laboratory, Systems Toxicology and Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhavan, 31, Mahatma Gandhi Marg, Lucknow 226001, Uttar Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), CSIR-IITR Campus, Lucknow,
[Ti] Título:Under ambient UVA exposure, pefloxacin exhibits both immunomodulatory and genotoxic effects via multiple mechanisms.
[So] Source:J Photochem Photobiol B;178:593-605, 2018 Jan.
[Is] ISSN:1873-2682
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:Pefloxacin (PFLX) is an antibiotic, which shows broad spectrum antimicrobial activities. It is an important derivative of fluoroquinolones (FLQs) group. Ultraviolet radiation (200-400nm) causes major problem for living being which comes at the earth surface naturally through sunlight and increasing regularly due to ozone depletion. PFLX was photodegraded in 5h and forms photoproduct under UVA exposure. At the non photocytotoxic dose PFLX, shows reduced phagocytosis activity, NO (nitric oxide) production, large vacuole formation and down regulated IL-6, TNF-α and IL-1 in BALB/c macrophages at both genes and proteins levels. At higher doses (photocytotoxic doses), PFLX induced a concentration dependent decrease in cell viability of human keratinocyte cell line (HaCaT) and peritoneal macrophages of BALB/c mice. Our molecular docking suggests that PFLX binds only to the cleaved DNA in the DNA-human TOP2A complex. Topoisomerase assay confirmed that PFLX inhibits human topoisomerase by forming an adduct with DNA. Photosensitized PFLX also caused intracellular ROS mediated DNA damage and formation of micronuclei and cyclobutane pyrimidine dimers (CPDs). Increase intracellular ROS leads to apoptosis which was proved through lysosomal destabilization and reduced mitochondrial membrane potential (MMP). Our present study shows that ambient UVA exposure in the presence of PFLX caused immunomodulatory as well as photogenotoxic effects. Therefore, patients under PFLX drug treatment should avoid sunlight exposure, especially during peak hours for their photosafety.
[Mh] Termos MeSH primário: Dano ao DNA/efeitos dos fármacos
Pefloxacina/química
Fármacos Fotossensibilizantes/química
Raios Ultravioleta
[Mh] Termos MeSH secundário: Animais
Apoptose/efeitos dos fármacos
Apoptose/efeitos da radiação
Sítios de Ligação
Pontos de Checagem do Ciclo Celular/efeitos dos fármacos
Pontos de Checagem do Ciclo Celular/efeitos da radiação
Células Cultivadas
DNA/química
DNA/metabolismo
Dano ao DNA/efeitos da radiação
DNA Topoisomerases Tipo II/química
DNA Topoisomerases Tipo II/metabolismo
Feminino
Seres Humanos
Interleucina-6/genética
Interleucina-6/metabolismo
Macrófagos/citologia
Macrófagos/efeitos dos fármacos
Macrófagos/metabolismo
Macrófagos/efeitos da radiação
Potencial da Membrana Mitocondrial/efeitos dos fármacos
Potencial da Membrana Mitocondrial/efeitos da radiação
Camundongos
Simulação de Acoplamento Molecular
Pefloxacina/toxicidade
Fármacos Fotossensibilizantes/toxicidade
Proteínas de Ligação a Poli-ADP-Ribose/química
Proteínas de Ligação a Poli-ADP-Ribose/metabolismo
Dímeros de Pirimidina/análise
Espécies Reativas de Oxigênio/metabolismo
Fator de Necrose Tumoral alfa/genética
Fator de Necrose Tumoral alfa/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Interleukin-6); 0 (Photosensitizing Agents); 0 (Poly-ADP-Ribose Binding Proteins); 0 (Pyrimidine Dimers); 0 (Reactive Oxygen Species); 0 (Tumor Necrosis Factor-alpha); 2H52Z9F2Q5 (Pefloxacin); 9007-49-2 (DNA); EC 5.99.1.3 (DNA Topoisomerases, Type II); EC 5.99.1.3 (TOP2A protein, human)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180212
[Lr] Data última revisão:
180212
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171225
[St] Status:MEDLINE


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[PMID]:27770267
[Au] Autor:Nayak VL; Nagesh N; Ravikumar A; Bagul C; Vishnuvardhan MVPS; Srinivasulu V; Kamal A
[Ad] Endereço:Medicinal Chemistry and Pharmacology, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500007, India.
[Ti] Título:2-aryl benzimidazole conjugate induced apoptosis in human breast cancer MCF-7 cells through caspase independent pathway.
[So] Source:Apoptosis;22(1):118-134, 2017 Jan.
[Is] ISSN:1573-675X
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Apoptosis is a representative form of programmed cell death, which has been assumed to be critical for cancer prevention. Thus, any agent that can induce apoptosis may be useful for cancer treatment and apoptosis induction is arguably the most potent defense against cancer promotion. In our previous studies, 2-aryl benzimidazole conjugates were synthesized and evaluated for their antiproliferative activity and one of the new molecule (2f) was considered as a potential lead. This lead molecule showed significant antiproliferative activity against human breast cancer cell line, MCF-7. The results of the present study revealed that this compound arrested the cell cycle at G2/M phase. Topoisomerase II inhibition assay and Western blot analysis suggested that this compound effectively inhibits topoisomerase II activity which leads to apoptotic cell death. Apoptosis induction in MCF-7 cells was further confirmed by loss of mitochondrial membrane potential (∆Ψm), release of cytochrome c from mitochondria, an increase in the level of apoptosis inducing factor (AIF), generation of reactive oxygen species (ROS), up regulation of proapoptotic protein Bax and down regulation of anti apoptotic protein Bcl-2. Apoptosis assay using Annexin V-FITC assay also suggested that this compound induced cell death by apoptosis. However, compound 2f induced apoptosis could not be reversed by Z-VAD-FMK (a pan-caspase inhibitor) demonstrated that the 2f induced apoptosis was caspase independent. Further, 2f treatment did not activate caspase-7 and caspase-9 activity, suggesting that this compound induced apoptosis in breast cancer cells via a caspase independent pathway. Most importantly, this compound was less toxic towards non-tumorigenic breast epithelial cells, MCF-10A. Furthermore, docking studies also support the potentiality of this molecule to bind to the DNA topoisomerase II.
[Mh] Termos MeSH primário: Apoptose/efeitos dos fármacos
Benzimidazóis/administração & dosagem
Neoplasias da Mama/tratamento farmacológico
DNA Topoisomerases Tipo II/química
[Mh] Termos MeSH secundário: Fator de Indução de Apoptose/genética
Benzimidazóis/química
Neoplasias da Mama/genética
Neoplasias da Mama/patologia
Inibidores de Caspase/administração & dosagem
Inibidores de Caspase/química
Caspases/genética
Proliferação Celular/efeitos dos fármacos
DNA Topoisomerases Tipo II/genética
Feminino
Seres Humanos
Células MCF-7
Potencial da Membrana Mitocondrial/efeitos dos fármacos
Mitocôndrias/efeitos dos fármacos
Mitocôndrias/genética
Simulação de Acoplamento Molecular
Espécies Reativas de Oxigênio/metabolismo
Transdução de Sinais
Proteína X Associada a bcl-2/genética
Proteína X Associada a bcl-2/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (AIFM1 protein, human); 0 (Apoptosis Inducing Factor); 0 (BAX protein, human); 0 (Benzimidazoles); 0 (Caspase Inhibitors); 0 (Reactive Oxygen Species); 0 (bcl-2-Associated X Protein); E24GX49LD8 (benzimidazole); EC 3.4.22.- (Caspases); EC 5.99.1.3 (DNA Topoisomerases, Type II)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180212
[Lr] Data última revisão:
180212
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161023
[St] Status:MEDLINE
[do] DOI:10.1007/s10495-016-1290-x


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[PMID]:29283334
[Au] Autor:Zheng F; Zhao J; Du F; Zhao J; Shen G; Ma F; Ma X; Dong L; Ma W; Shen C; Wang S; Ma J; Luo Y; Wang Z; Xu B
[Ad] Endereço:Affiliated Hospital of Qinghai University, Qinghai University, Xining, China.
[Ti] Título:Relationship between Topoisomerase II Alpha Overexpression and Prognosis in Chinese Gastric Cancer Patients.
[So] Source:J Environ Pathol Toxicol Oncol;36(3):207-216, 2017.
[Is] ISSN:2162-6537
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The aim of this study was to investigate topoisomerase II alpha (TOP2α) overexpression and its association with clinicopathological features and prognosis in gastric cancer (GC) patients. All selected GC patients at Affiliated Hospital of Qinghai University and Cancer Hospital, Chinese Academy of Medical Sciences, between December 2009 and December 2011, had formalin-fixed and paraffin-embedded tumor tissues. The patients received a telephone follow-up or in-/outpatient review, and their clinicopathological features and prognoses were analyzed. Also, the relationship between TOP2α expression and postoperative chemotherapy in GC patients was estimated. The results of the study showed that TOP2α overexpression correlated with location of tumor, depth of invasion, and pTNM stage. Moreover, it was associated with lower 5-year overall survival (OS) in noncardia GC patients younger than 60 years, with multivariate analysis demonstrating that it was an independent prognostic factor for these patients. Univariate analysis and multivariate analysis showed that TOP2α overexpression was associated with worse 5-year OS in noncardia GC patients ≤ 60 years receiving postoperative chemotherapy. TOP2α overexpression exhibited associations with location of tumor, depth of invasion, pTNM stage, and postoperative chemotherapy, making it a potential target for early diagnosis of GC patients. In addition, TOP2α overexpression was shown to be a predictor of 5-year OS in both noncardia GC patients ≤ 60 years and noncardia GC patients ≤ 60 years and receiving postoperative chemotherapy.
[Mh] Termos MeSH primário: DNA Topoisomerases Tipo II/fisiologia
Neoplasias Gástricas/mortalidade
[Mh] Termos MeSH secundário: Adulto
Idoso
Terapia Combinada
Feminino
Seres Humanos
Masculino
Meia-Idade
Prognóstico
Modelos de Riscos Proporcionais
Neoplasias Gástricas/enzimologia
Neoplasias Gástricas/patologia
Neoplasias Gástricas/terapia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
EC 5.99.1.3 (DNA Topoisomerases, Type II)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180104
[Lr] Data última revisão:
180104
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171229
[St] Status:MEDLINE
[do] DOI:10.1615/JEnvironPatholToxicolOncol.2017018602


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[PMID]:28462840
[Au] Autor:Han X; Zhong Y; Zhou G; Qi H; Li S; Ding Q; Liu Z; Song Y; Qiao X
[Ad] Endereço:Key Laboratory of Pharmaceutical Quality Control of Hebei Province, College of Pharmaceutical Sciences, Hebei University, Baoding 071002, China.
[Ti] Título:Synthesis and biological evaluation of N-(carbobenzyloxy)-l-phenylalanine and N-(carbobenzyloxy)-l-aspartic acid-ß-benzyl ester derivatives as potent topoisomerase IIα inhibitors.
[So] Source:Bioorg Med Chem;25(12):3116-3126, 2017 06 15.
[Is] ISSN:1464-3391
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:A new series of thirteen N-(carbobenzyloxy)-l-phenylalanine and N-(carbobenzyloxy)-l-aspartic acid-ß-benzyl ester compounds were synthesized and evaluated for antiproliferative activity against four different human cancer cell lines: cervical cancer (HeLa), lung cancer (A549), gastric cancer (MGC-803) and breast cancer (MCF-7) as well as topoisomerase I and IIα inhibitory activity. Compounds (5a, 5b, 5e, 8a, 8b) showed significant antiproliferative activity with low IC values against the four cancer cell lines. Equally, compounds 5a, 5b, 5e, 5f, 8a, 8d, 8e and 8f showed topoisomerase IIα inhibitory activity at 100µM with 5b, 5e, 8f exhibiting potential topoisomerase IIα inhibitory activity compared to positive control at 100µM and 20µM, respectively. Conversely compounds 5e, 5f, 5g and 8a showed weaker topoisomerase I inhibitory activity compared to positive control at 100µM. Compound 5b exhibited the most potent topoisomerase IIα inhibitory activity at low concentration and better antiproliferative activity against the four human cancer cell lines. The molecular interactions between compounds 5a-5g, 8a-8f and the topoisomerase IIα (PDB ID: 1ZXM) were further investigated through molecular docking. The results indicated that these compounds could serve as promising leads for further optimization as novel antitumor agents.
[Mh] Termos MeSH primário: Ácido Aspártico/análogos & derivados
Ácido Aspártico/farmacologia
Proteínas de Ligação a DNA/antagonistas & inibidores
Fenilalanina/análogos & derivados
Fenilalanina/farmacologia
Inibidores da Topoisomerase II/química
Inibidores da Topoisomerase II/farmacologia
[Mh] Termos MeSH secundário: Antígenos de Neoplasias/metabolismo
Antineoplásicos/síntese química
Antineoplásicos/química
Antineoplásicos/farmacologia
Ácido Aspártico/síntese química
Linhagem Celular Tumoral
DNA Topoisomerases Tipo II/metabolismo
Proteínas de Ligação a DNA/metabolismo
Células HeLa
Seres Humanos
Simulação de Acoplamento Molecular
Neoplasias/tratamento farmacológico
Neoplasias/enzimologia
Fenilalanina/síntese química
Relação Estrutura-Atividade
Inibidores da Topoisomerase II/síntese química
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antigens, Neoplasm); 0 (Antineoplastic Agents); 0 (DNA-Binding Proteins); 0 (Topoisomerase II Inhibitors); 30KYC7MIAI (Aspartic Acid); 47E5O17Y3R (Phenylalanine); EC 5.99.1.3 (DNA Topoisomerases, Type II)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171208
[Lr] Data última revisão:
171208
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170503
[St] Status:MEDLINE



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