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[PMID]:28668853
[Au] Autor:Athyala PK; Kanwar JR; Chitipothu S; Kanwar RK; Krishnakumar S; Watson JP; Narayanan J
[Ad] Endereço:Department of Nanobiotechnology, Kamalnayan Bajaj Institute for Research in Vision and Ophthalmology, Vision Research Foundation, Chennai, India.
[Ti] Título:Neocarzinostatin, Aptamer Conjugates for Targeting EpCAM-positive Tumor Cells.
[So] Source:Anticancer Res;37(7):3615-3629, 2017 07.
[Is] ISSN:1791-7530
[Cp] País de publicação:Greece
[La] Idioma:eng
[Ab] Resumo:BACKGROUND/AIM: The aim of this study was to investigate the role of Neocarzinostatin (NCS) conjugated with epithelial cell adhesion molecule (EpCAM) aptamer in EpCAM-positive cancer cells. NCS is an antitumor antibiotic protein chromophore that has the ability to cleave double stranded DNA and can be used as a potential drug for the treatment of EpCAM-positive cancers. EpCAM aptamer is an oligonucleotide ligand that binds specifically to EpCAM, a protein overexpressed in tumor cells. MATERIALS AND METHODS: NCS was conjugated with EpCAM aptamer using Sulfo-Succinimidyl 6-(3-(2-pyridyldithio) - propionamide hexanoate) LC-(SPDP) cross-linker to deliver it to EpCAM-positive tumor cells. The conjugates were characterized using polyacrylamide gel electrophoresis (PAGE) and high-performance liquid chromatography (HPLC). Flow cytometry was used to study the binding efficiency of the aptamer and the conjugates in cancer cells. The effect of the conjugate on cancer cells was studied using propidium iodide (PI) to analyze the cell cycle phase changes. The apoptosis assay was performed using the IC concentration of NCS. Microarrays were performed to study the gene level changes in cancer cells upon treatment with NCS and the conjugate. RESULTS: Flow cytometry revealed significant binding of aptamer and conjugate in the MCF-7 and WERI-Rb1 cell lines. Briefly, 62% in MCF and 30% in WERI-Rb1 cells with conjugate treated cells (p<0.005). The cell-cycle analysis indicated G phase arrest in MCF-7 cells and S phase arrest in WERI-Rb1 cells (p<0.005). Microarray analysis showed differentially expressed genes involved in cell cycle, DNA damage, and apoptosis. The BrDU assay and the apoptosis assay showed that the expression of BrDU was reduced in conjugate-treated cells and the PARP levels were increased confirming the double stranded DNA breaks (p<0.005). In MCF-7 and WERI-Rb1 cells, most of the cells underwent necrosis (p<0.005). CONCLUSION: The EpCAM aptamer conjugated NCS showed specificity to EpCAM-positive cells. The effect of the conjugates on cancer cells were impressive as the conjugate arrested the cell cycle and promoted apoptosis and necrosis. The high levels of PARP expression confirmed the DNA breaks upon conjugate treatment. Our study demonstrates that the NCS conjugated with EpCAM can be targeted to cancer cells sparing normal cells.
[Mh] Termos MeSH primário: Molécula de Adesão da Célula Epitelial/metabolismo
Neoplasias/tratamento farmacológico
Zinostatina/farmacologia
[Mh] Termos MeSH secundário: Antibióticos Antineoplásicos/farmacologia
Apoptose/efeitos dos fármacos
Ciclo Celular/efeitos dos fármacos
Linhagem Celular Tumoral
Quebras de DNA de Cadeia Dupla/efeitos dos fármacos
Dano ao DNA/efeitos dos fármacos
Seres Humanos
Células MCF-7
Neoplasias/metabolismo
Oligonucleotídeos/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antibiotics, Antineoplastic); 0 (EPCAM protein, human); 0 (Epithelial Cell Adhesion Molecule); 0 (Oligonucleotides); 9014-02-2 (Zinostatin)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170906
[Lr] Data última revisão:
170906
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170703
[St] Status:MEDLINE


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[PMID]:27573809
[Au] Autor:Croco E; Marchionni S; Bocchini M; Angeloni C; Stamato T; Stefanelli C; Hrelia S; Sell C; Lorenzini A
[Ad] Endereço:Department for Life Quality Studies and.
[Ti] Título:DNA Damage Detection by 53BP1: Relationship to Species Longevity.
[So] Source:J Gerontol A Biol Sci Med Sci;72(6):763-770, 2017 Jun 01.
[Is] ISSN:1758-535X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:In order to examine potential differences in genomic stability, we have challenged fibroblasts derived from five different mammalian species of variable longevity with the genotoxic agents, etoposide and neocarzinostatin. We report that cells from longer-lived species exhibit more tumor protein p53 binding protein 1 (53BP1) foci for a given degree of DNA damage relative to shorter-lived species. The presence of a greater number of 53BP1 foci was associated with decreased DNA fragmentation and a lower percentage of cells exhibiting micronuclei. These data suggest that cells from longer-lived species have an enhanced DNA damage response. We propose that the number of 53BP1 foci that form in response to damage reflects the intrinsic capacity of cells to detect and respond to DNA harms.
[Mh] Termos MeSH primário: Dano ao DNA
Fibroblastos/metabolismo
Longevidade
Proteína 1 de Ligação à Proteína Supressora de Tumor p53/metabolismo
[Mh] Termos MeSH secundário: Animais
Bovinos
Pontos de Checagem do Ciclo Celular
Linhagem Celular
Quirópteros
Ciclina A/metabolismo
Citotoxinas/toxicidade
Fragmentação do DNA
Cães
Etoposídeo/toxicidade
Fibroblastos/efeitos dos fármacos
Instabilidade Genômica
Histonas/metabolismo
Seres Humanos
Expectativa de Vida
Camundongos
Micronúcleos com Defeito Cromossômico
Testes para Micronúcleos
Quinases Relacionadas a NIMA/metabolismo
Inibidores da Topoisomerase II/toxicidade
Zinostatina/toxicidade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cyclin A); 0 (Cytotoxins); 0 (H2AFX protein, human); 0 (Histones); 0 (Topoisomerase II Inhibitors); 0 (Tumor Suppressor p53-Binding Protein 1); 6PLQ3CP4P3 (Etoposide); 9014-02-2 (Zinostatin); EC 2.7.11.1 (NIMA-Related Kinases); EC 2.7.11.1 (Nek4 protein, human)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170817
[Lr] Data última revisão:
170817
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:160831
[St] Status:MEDLINE
[do] DOI:10.1093/gerona/glw170


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[PMID]:27431785
[Au] Autor:Tianqin G; Chunlei C; Jingjing W
[Ad] Endereço:Binzhou Medical University Hospital.
[Ti] Título:Synergistic Anti-glioma Effects in Vitro and in Vivo of Enediyne Antibiotic Neocarzinostatin and Paclitaxel via Enhanced Growth Delay and Apoptosis-Induction.
[So] Source:Biol Pharm Bull;39(10):1623-1630, 2016 Oct 01.
[Is] ISSN:1347-5215
[Cp] País de publicação:Japan
[La] Idioma:eng
[Ab] Resumo:Neocarzinostatin (NCS) is a member of enediyne antibiotics with high anticancer potential. Our study was performed to explore the synergistic anti-glioma effects of NCS and paclitaxel (PTX) in vitro and in vivo. By 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, the cytotoxicities of the drugs to human glioma cells U87MG and rat glioma cells C6 were evaluated. The results showed that the combinations of NCS and PTX can synergistically inhibit glioma cells survival. Cell apoptosis was detected by flow cytometry, and the results showed that the combinations of NCS and PTX synergistically enhanced apoptosis ratio of glioma cells. Western blot revealed that the cell signaling pathways of proliferation and apoptosis were synergistically regulated, in which Akt was synergistically inactivated, p53 was up-regulated with down-regulation of bcl-2. Meanwhile, with the subcutaneous model of U87MG cells and intracerebral implantation model of C6 cells, the combination strategy could synergistically delay the glioma growth and significantly prolong the survival of rats bearing orthotopic glioma. This study demonstrates that the combination of NCS and PTX can potentiate the effect on survival and apoptosis of glioma cells via suppression of Akt, bcl-2, and activations of p53; Meanwhile, the in vivo studies also confirmed that the combination of NCS and PTX synergistically inhibit the gliom growth. Our data about the combinational effects of NCS with PTX may provide an alternative strategy for glioma therapy.
[Mh] Termos MeSH primário: Antibióticos Antineoplásicos/uso terapêutico
Antineoplásicos Fitogênicos/uso terapêutico
Neoplasias Encefálicas/tratamento farmacológico
Glioma/tratamento farmacológico
Paclitaxel/uso terapêutico
Zinostatina/uso terapêutico
[Mh] Termos MeSH secundário: Animais
Antibióticos Antineoplásicos/farmacologia
Antineoplásicos Fitogênicos/farmacologia
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico
Apoptose/efeitos dos fármacos
Neoplasias Encefálicas/patologia
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Sinergismo Farmacológico
Glioma/patologia
Seres Humanos
Masculino
Camundongos Nus
Paclitaxel/farmacologia
Proteínas Proto-Oncogênicas c-akt/metabolismo
Proteínas Proto-Oncogênicas c-bcl-2/metabolismo
Ratos Wistar
Carga Tumoral/efeitos dos fármacos
Proteína Supressora de Tumor p53/metabolismo
Zinostatina/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antibiotics, Antineoplastic); 0 (Antineoplastic Agents, Phytogenic); 0 (Proto-Oncogene Proteins c-bcl-2); 0 (Tumor Suppressor Protein p53); 9014-02-2 (Zinostatin); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt); P88XT4IS4D (Paclitaxel)
[Em] Mês de entrada:1702
[Cu] Atualização por classe:170202
[Lr] Data última revisão:
170202
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160720
[St] Status:MEDLINE


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[PMID]:26982737
[Au] Autor:Tidball AM; Neely MD; Chamberlin R; Aboud AA; Kumar KK; Han B; Bryan MR; Aschner M; Ess KC; Bowman AB
[Ad] Endereço:Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, 37240, United States of America.
[Ti] Título:Genomic Instability Associated with p53 Knockdown in the Generation of Huntington's Disease Human Induced Pluripotent Stem Cells.
[So] Source:PLoS One;11(3):e0150372, 2016.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Alterations in DNA damage response and repair have been observed in Huntington's disease (HD). We generated induced pluripotent stem cells (iPSC) from primary dermal fibroblasts of 5 patients with HD and 5 control subjects. A significant fraction of the HD iPSC lines had genomic abnormalities as assessed by karyotype analysis, while none of our control lines had detectable genomic abnormalities. We demonstrate a statistically significant increase in genomic instability in HD cells during reprogramming. We also report a significant association with repeat length and severity of this instability. Our karyotypically normal HD iPSCs also have elevated ATM-p53 signaling as shown by elevated levels of phosphorylated p53 and H2AX, indicating either elevated DNA damage or hypersensitive DNA damage signaling in HD iPSCs. Thus, increased DNA damage responses in the HD genotype is coincidental with the observed chromosomal aberrations. We conclude that the disease causing mutation in HD increases the propensity of chromosomal instability relative to control fibroblasts specifically during reprogramming to a pluripotent state by a commonly used episomal-based method that includes p53 knockdown.
[Mh] Termos MeSH primário: Técnicas de Silenciamento de Genes
Instabilidade Genômica
Doença de Huntington/patologia
Células-Tronco Pluripotentes Induzidas/patologia
Proteína Supressora de Tumor p53/genética
[Mh] Termos MeSH secundário: Adulto
Idoso
Células Cultivadas
Dano ao DNA
Seres Humanos
Doença de Huntington/genética
Cariotipagem
Meia-Idade
Inibidores da Síntese de Ácido Nucleico/farmacologia
Transdução de Sinais/efeitos dos fármacos
Adulto Jovem
Zinostatina/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Nucleic Acid Synthesis Inhibitors); 0 (Tumor Suppressor Protein p53); 9014-02-2 (Zinostatin)
[Em] Mês de entrada:1607
[Cu] Atualização por classe:170324
[Lr] Data última revisão:
170324
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160317
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0150372


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[PMID]:26745237
[Au] Autor:Mayer A; Baran V; Sakakibara Y; Brzakova A; Ferencova I; Motlik J; Kitajima TS; Schultz RM; Solc P
[Ad] Endereço:a Institute of Animal Physiology and Genetics AS CR , Libechov , Czech Republic.
[Ti] Título:DNA damage response during mouse oocyte maturation.
[So] Source:Cell Cycle;15(4):546-58, 2016.
[Is] ISSN:1551-4005
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Because low levels of DNA double strand breaks (DSBs) appear not to activate the ATM-mediated prophase I checkpoint in full-grown oocytes, there may exist mechanisms to protect chromosome integrity during meiotic maturation. Using live imaging we demonstrate that low levels of DSBs induced by the radiomimetic drug Neocarzinostatin (NCS) increase the incidence of chromosome fragments and lagging chromosomes but do not lead to APC/C activation and anaphase onset delay. The number of DSBs, represented by γH2AX foci, significantly decreases between prophase I and metaphase II in both control and NCS-treated oocytes. Transient treatment with NCS increases >2-fold the number of DSBs in prophase I oocytes, but less than 30% of these oocytes enter anaphase with segregation errors. MRE11, but not ATM, is essential to detect DSBs in prophase I and is involved in H2AX phosphorylation during metaphase I. Inhibiting MRE11 by mirin during meiotic maturation results in anaphase bridges and also increases the number of γH2AX foci in metaphase II.  Compromised DNA integrity in mirin-treated oocytes indicates a role for MRE11 in chromosome integrity during meiotic maturation.
[Mh] Termos MeSH primário: Dano ao DNA/genética
Enzimas Reparadoras do DNA/genética
Proteínas de Ligação a DNA/genética
Meiose/genética
Oócitos/metabolismo
[Mh] Termos MeSH secundário: Animais
Proteínas Mutadas de Ataxia Telangiectasia/genética
Quebras de DNA de Cadeia Dupla/efeitos dos fármacos
Dano ao DNA/efeitos dos fármacos
Histonas/genética
Proteína Homóloga a MRE11
Metáfase/genética
Camundongos
Oócitos/crescimento & desenvolvimento
Zinostatina/administração & dosagem
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (DNA-Binding Proteins); 0 (H2AX protein, mouse); 0 (Histones); 0 (Mre11a protein, mouse); 9014-02-2 (Zinostatin); EC 2.7.11.1 (Ataxia Telangiectasia Mutated Proteins); EC 2.7.11.1 (Atm protein, mouse); EC 3.1.- (MRE11 Homologue Protein); EC 6.5.1.- (DNA Repair Enzymes)
[Em] Mês de entrada:1612
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160109
[St] Status:MEDLINE
[do] DOI:10.1080/15384101.2015.1128592


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[PMID]:26677011
[Au] Autor:Ghattas W; Cotchico-Alonso L; Maréchal JD; Urvoas A; Rousseau M; Mahy JP; Ricoux R
[Ad] Endereço:Institute de Chimie Moléculaire et des Matériaux d'Orsay (ICMMO), UMR 8182, CNRS, Université Paris-Sud, Bât. 420, rue du Doyen Georges Poitou, 91405, Orsay Cedex, France.
[Ti] Título:Artificial Metalloenzymes with the Neocarzinostatin Scaffold: Toward a Biocatalyst for the Diels-Alder Reaction.
[So] Source:Chembiochem;17(5):433-40, 2016 Mar 02.
[Is] ISSN:1439-7633
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:A copper(II) cofactor coupled to a testosterone anchor, copper(II)-(5-(Piperazin-1-yl)-1,10-phenanthroline)testosterone-17-hemisuccinamide (10) was synthesized and associated with a neocarzinostatin variant, NCS-3.24 (KD =3 µm), thus generating a new artificial metalloenzyme by following a "Trojan horse" strategy. Interestingly, the artificial enzyme was able to efficiently catalyze the Diels-Alder cyclization reaction of cyclopentadiene (1) with 2-azachalcone (2). In comparison with what was observed with cofactor 10 alone, the artificial enzymes favored formation of the exo products (endo/exo ratios of 84:16 and 62:38, respectively, after 12 h). Molecular modeling studies assigned the synergy between the copper complex and the testosterone (KD =13 µm) moieties in the binding of 10 to good van der Waals complementarity. Moreover, by pushing the modeling exercise to its limits, we hypothesize on the molecular grounds that are responsible for the observed selectivity.
[Mh] Termos MeSH primário: Enzimas/metabolismo
Metaloproteínas/metabolismo
Zinostatina/metabolismo
[Mh] Termos MeSH secundário: Biocatálise
Espectroscopia de Ressonância Magnética Nuclear de Carbono-13
Reação de Cicloadição
Simulação de Acoplamento Molecular
Espectroscopia de Prótons por Ressonância Magnética
Espectrometria de Massas por Ionização por Electrospray
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Enzymes); 0 (Metalloproteins); 9014-02-2 (Zinostatin)
[Em] Mês de entrada:1610
[Cu] Atualização por classe:161230
[Lr] Data última revisão:
161230
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151218
[St] Status:MEDLINE
[do] DOI:10.1002/cbic.201500445


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[PMID]:26642954
[Au] Autor:Athyala PK; Kanwar JR; Alameen M; Kanwar RK; Krishnakumar S; Watson J; Vetrivel U; Narayanan J
[Ad] Endereço:Department of Nanobiotechnology, Vision Research Foundation, Chennai, India; Nanomedicine-Laboratory of Immunology and Molecular Biomedical Research (NLIMBR), School of Medicine (SoM), Centre for Molecular and Medical Research (C-MMR), Faculty of Health, Deakin University, Geelong, Pigdons Road, Wau
[Ti] Título:Probing the biophysical interaction between Neocarzinostatin toxin and EpCAM RNA aptamer.
[So] Source:Biochem Biophys Res Commun;469(2):257-62, 2016 Jan 08.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Neocarzinostatin (NCS) a potent DNA-damaging, anti-tumor toxin extracted from Streptomyces carzinostaticus that recognizes double-stranded DNA bulge and induces DNA damage. 2 Fluoro (2F) Modified EpCAM RNA aptamer is a 23-mer that targets EpCAM protein, expressed on the surface of epithelial tumor cells. Understanding the interaction between NCS and the ligand is important for carrying out the targeted tumor therapy. In this study, we have investigated the biophysical interactions between NCS and 2-fluro Modified EpCAM RNA aptamer using Circular Dichroism (CD) and Infra-Red (IR) spectroscopy. The aromatic amino acid residues spanning the ß sheets of NCS are found to participate in intermolecular interactions with 2 F Modified EpCAM RNA aptamer. In-silico modeling and simulation studies corroborate with CD spectra data. Furthermore, it reinforces the involvement of C and D1 strand of NCS in intermolecular interactions with EpCAM RNA aptamer. This the first report on interactions involved in the stabilization of NCS-EpCAM aptamer complex and will aid in the development of therapeutic modalities towards targeted cancer therapy.
[Mh] Termos MeSH primário: Antígenos de Neoplasias/química
Antígenos de Neoplasias/ultraestrutura
Aptâmeros de Nucleotídeos/química
Moléculas de Adesão Celular/química
Moléculas de Adesão Celular/ultraestrutura
Modelos Químicos
Simulação de Acoplamento Molecular
Zinostatina/química
[Mh] Termos MeSH secundário: Sítios de Ligação
Citotoxinas
Molécula de Adesão da Célula Epitelial
Conformação Molecular
Ligação Proteica
Mapeamento de Interação de Proteínas/métodos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antigens, Neoplasm); 0 (Aptamers, Nucleotide); 0 (Cell Adhesion Molecules); 0 (Cytotoxins); 0 (Epithelial Cell Adhesion Molecule); 9014-02-2 (Zinostatin)
[Em] Mês de entrada:1605
[Cu] Atualização por classe:161126
[Lr] Data última revisão:
161126
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151209
[St] Status:MEDLINE


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[PMID]:26457548
[Au] Autor:Jiang W; Shang B; Li L; Zhang S; Zhen Y
[Ad] Endereço:aDepartment of Medicine and Pharmacy Center, Binzhou Medical University, Yantai bInstitute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
[Ti] Título:Construction of a genetically engineered chimeric apoprotein consisting of sequences derived from lidamycin and neocarzinostatin.
[So] Source:Anticancer Drugs;27(1):24-8, 2016 Jan.
[Is] ISSN:1473-5741
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Neocarzinostatin (NCS) consists of an enediyne chromophore and an apoprotein (NCP). Lidamycin (LDM) is composed of another active enediyne chromophore (AE) and an acidic protein (LDP). Although the structures of NCP and LDP are very similar, LDM has been shown to have an increased tumor-suppressive activity than that of NCS. The aim of this study was to construct a chimeric protein (CMP) that consists of both the terminus residue of NCP and an LDP pocket-forming residue that can bind AE. This CMP will have a structure similar to NCS and an antitumor activity similar to LDM. The assembling efficiency of LDP, CMP, and NCP was 73.9, 1.5, and 1.1%, respectively. The cytotoxicity was consistent with their assembling efficiency of AE in proteins. When CMP-AE and NCP-AE were administered at equivalent AE doses of LDM, the inhibition rate of CMP-AE was the same as LDM and significantly higher than that of NCP-AE. Our study implied that the binding activity between LDP and AE was very specific. The terminus residue of LDP could affect the specifically binding activity. The pocket-forming residue could confer a protective function to the chromophore. Further investigation of its bioactivity might serve as a new drug design strategy and drug-delivery carrier in targeted cancer therapy.
[Mh] Termos MeSH primário: Aminoglicosídeos/química
Antineoplásicos/química
Apoproteínas/química
Enedi-Inos/química
Proteínas Recombinantes de Fusão/química
Zinostatina/química
[Mh] Termos MeSH secundário: Aminoglicosídeos/genética
Animais
Antineoplásicos/farmacologia
Apoproteínas/genética
Apoproteínas/farmacologia
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Seres Humanos
Masculino
Camundongos
Transplante de Neoplasias
Proteínas Recombinantes de Fusão/genética
Proteínas Recombinantes de Fusão/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Aminoglycosides); 0 (Antineoplastic Agents); 0 (Apoproteins); 0 (Enediynes); 0 (Recombinant Fusion Proteins); 120177-69-7 (C 1027); 9014-02-2 (Zinostatin)
[Em] Mês de entrada:1605
[Cu] Atualização por classe:151121
[Lr] Data última revisão:
151121
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151013
[St] Status:MEDLINE
[do] DOI:10.1097/CAD.0000000000000300


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[PMID]:26208712
[Au] Autor:Wagner W; Ciszewski WM; Kania KD
[Ad] Endereço:Laboratory of Cellular Immunology, Institute of Medical Biology, Polish Academy of Science, Lodz, Poland. wwagner@cbm.pan.pl.
[Ti] Título:L- and D-lactate enhance DNA repair and modulate the resistance of cervical carcinoma cells to anticancer drugs via histone deacetylase inhibition and hydroxycarboxylic acid receptor 1 activation.
[So] Source:Cell Commun Signal;13:36, 2015 Jul 25.
[Is] ISSN:1478-811X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: The consideration of lactate as an active metabolite is a newly emerging and attractive concept. Recently, lactate has been reported to regulate gene transcription via the inhibition of histone deacetylases (HDACs) and survival of cancer cells via hydroxycarboxylic acid receptor 1 (HCAR1). This study examined the role of L- and D-lactate in the DNA damage response in cervical cancer cells. METHODS: Three cervical cancer cell lines were examined: HeLa, Ca Ski and C33A. The inhibitory activity of lactate on HDACs was analysed using Western blot and biochemical methods. The lactate-mediated stimulation of DNA repair and cellular resistance to neocarzinostatin, doxorubicin and cisplatin were studied using γ-H2AX, comet and clonogenic assays. HCAR1 and DNA repair gene expression was quantified by real-time PCR. DNA-PKcs activity and HCAR1 protein expression were evaluated via immunocytochemistry and Western blot, respectively. HCAR1 activation was investigated by measuring intracellular cAMP accumulation and Erk phosphorylation. HCAR1 expression was silenced using shRNA. RESULTS: L- and D-lactate inhibited HDACs, induced histone H3 and H4 hyperacetylation, and decreased chromatin compactness in HeLa cells. Treating cells with lactate increased LIG4, NBS1, and APTX expression by nearly 2-fold and enhanced DNA-PKcs activity. Based on γ-H2AX and comet assays, incubation of cells in lactate-containing medium increased the DNA repair rate. Furthermore, clonogenic assays demonstrated that lactate mediates cellular resistance to clinically used chemotherapeutics. Western blot and immunocytochemistry showed that all studied cell lines express HCAR1 on the cellular surface. Inhibiting HCAR1 function via pertussis toxin pretreatment partially abolished the effects of lactate on DNA repair. Down-regulating HCAR1 decreased the efficiency of DNA repair, abolished the cellular response to L-lactate and decreased the effect of D-lactate. Moreover, HCAR1 shRNA-expressing cells produced significantly lower mRNA levels of monocarboxylate transporter 4. Finally, the enhancement of DNA repair and cell survival by lactate was suppressed by pharmacologically inhibiting monocarboxylate transporters using the inhibitor α-cyano-4-hydroxycinnamic acid (α-CHCA). CONCLUSIONS: Our data indicate that L- and D-lactate present in the uterine cervix may participate in the modulation of cellular DNA damage repair processes and in the resistance of cervical carcinoma cells to anticancer therapy.
[Mh] Termos MeSH primário: Reparo do DNA
Resistência a Medicamentos Antineoplásicos
Histona Desacetilases/metabolismo
Ácido Láctico/metabolismo
Receptores Acoplados a Proteínas-G/metabolismo
Neoplasias do Colo do Útero/tratamento farmacológico
Neoplasias do Colo do Útero/metabolismo
[Mh] Termos MeSH secundário: Acetilação
Antineoplásicos/farmacologia
Linhagem Celular Tumoral
Sobrevivência Celular/efeitos dos fármacos
Colo do Útero/efeitos dos fármacos
Colo do Útero/metabolismo
Cisplatino/farmacologia
Quebras de DNA de Cadeia Dupla/efeitos dos fármacos
Doxorrubicina/farmacologia
Feminino
Regulação Neoplásica da Expressão Gênica
Células HeLa
Histonas/genética
Histonas/metabolismo
Seres Humanos
Transportadores de Ácidos Monocarboxílicos/metabolismo
Interferência de RNA
RNA Interferente Pequeno/genética
Receptores Acoplados a Proteínas-G/genética
Neoplasias do Colo do Útero/genética
Zinostatina/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (GPR81 protein, human); 0 (Histones); 0 (Monocarboxylic Acid Transporters); 0 (RNA, Small Interfering); 0 (Receptors, G-Protein-Coupled); 33X04XA5AT (Lactic Acid); 80168379AG (Doxorubicin); 9014-02-2 (Zinostatin); EC 3.5.1.98 (Histone Deacetylases); Q20Q21Q62J (Cisplatin)
[Em] Mês de entrada:1603
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150726
[St] Status:MEDLINE
[do] DOI:10.1186/s12964-015-0114-x


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[PMID]:24984934
[Au] Autor:Urvoas A; Ghattas W; Maréchal JD; Avenier F; Bellande F; Mao W; Ricoux R; Mahy JP
[Ad] Endereço:Institut de Biochimie et de Biophysique Moléculaire et Cellulaire, UMR 8619 CNRS, Laboratoire de Modélisation et d'Ingénierie des Protéines, Bât. 430, Université Paris XI, 91405 Orsay Cedex, France.
[Ti] Título:Neocarzinostatin-based hybrid biocatalysts with a RNase like activity.
[So] Source:Bioorg Med Chem;22(20):5678-86, 2014 Oct 15.
[Is] ISSN:1464-3391
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:A new zinc(II)-cofactor coupled to a testosterone anchor, zinc(II)-N,N-bis(2-pyridylmethyl)-1,3-diamino-propa-2-ol-N'(17'-succinimidyltestosterone) (Zn-Testo-BisPyPol) 1-Zn has been synthesized and fully characterized. It has been further associated with a neocarzinostatin variant, NCS-3.24, to generate a new artificial metalloenzyme following the so-called 'Trojan horse' strategy. This new 1-Zn-NCS-3.24 biocatalyst showed an interesting catalytic activity as it was found able to catalyze the hydrolysis of the RNA model HPNP with a good catalytic efficiency (kcat/KM=13.6M(-1)s(-1) at pH 7) that places it among the best artificial catalysts for this reaction. Molecular modeling studies showed that a synergy between the binding of the steroid moiety and that of the BisPyPol into the protein binding site can explain the experimental results, indicating a better affinity of 1-Zn for the NCS-3.24 variant than testosterone and testosterone-hemisuccinate themselves. They also show that the artificial cofactor entirely fills the cavity, the testosterone part of 1-Zn being bound to one the two subdomains of the protein providing with good complementarities whereas its metal ion remains widely exposed to the solvent which made it a valuable tool for the catalysis of hydrolysis reactions, such as that of HPNP. Some possible improvements in the 'Trojan horse' strategy for obtaining better catalysts of selective reactions will be further studied.
[Mh] Termos MeSH primário: Biocatálise
Compostos Organometálicos/metabolismo
Ribonucleases/metabolismo
Zinco/metabolismo
Zinostatina/metabolismo
[Mh] Termos MeSH secundário: Modelos Moleculares
Estrutura Molecular
Compostos Organometálicos/química
Zinco/química
Zinostatina/química
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Organometallic Compounds); 9014-02-2 (Zinostatin); EC 3.1.- (Ribonucleases); J41CSQ7QDS (Zinc)
[Em] Mês de entrada:1504
[Cu] Atualização por classe:141001
[Lr] Data última revisão:
141001
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:140703
[St] Status:MEDLINE



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