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[PMID]:28460467
[Au] Autor:Chen P; Zhang JY; Sha BB; Ma YE; Hu T; Ma YC; Sun H; Shi JX; Dong ZM; Li P
[Ad] Endereço:Cancer Chemoprevention Collaborative Innovation Center in Henan Province, Zhengzhou University, Zhengzhou, Henan, 450001, China.
[Ti] Título:Luteolin inhibits cell proliferation and induces cell apoptosis via down-regulation of mitochondrial membrane potential in esophageal carcinoma cells EC1 and KYSE450.
[So] Source:Oncotarget;8(16):27471-27480, 2017 Apr 18.
[Is] ISSN:1949-2553
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:In current study, we investigated the anti-tumor effect of luteolin in human ESCC cell lines in vitro and in vivo and tried to explore the potential mechanisms. Results from flow cytometry showed that luteolin could induce apoptosis and caspase-3 activation and induce cell cycle arrest at G2/M phase in a dose- and time-dependent manner in EC1 and KYSE450 cells. JC-1 test results showed that membrane potential of mitochondria after luteolin treatment was down-regulated and this was an indicator for intrinsic apoptosis. Western Blot results showed the expression of cell cycle regulatory protein p21 and p53 increased and three apoptosis related proteins that participate in mitochondrial apoptotic pathway, namely, Bim, CYT-c and cPARP, also increased in luteolin treated cells compared with control groups. We further confirmed that luteolin could significantly inhibit the growth of ESCC tumors in xenograft mouse models and no evidence of systemic toxicity was observed. Our results suggest that luteolin can induce cell apoptosis and cell cycle arrest in G2/M phase through mitochondrial pathway in EC1 and KYSE450 cell lines and proper utilization of luteolin might be a practical approach in ESCC chemotherapy.
[Mh] Termos MeSH primário: Apoptose/efeitos dos fármacos
Luteolina/farmacologia
Potencial da Membrana Mitocondrial/efeitos dos fármacos
[Mh] Termos MeSH secundário: Animais
Proteína 11 Semelhante a Bcl-2/genética
Proteína 11 Semelhante a Bcl-2/metabolismo
Caspase 3/metabolismo
Ciclo Celular/efeitos dos fármacos
Pontos de Checagem do Ciclo Celular/efeitos dos fármacos
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Inibidor de Quinase Dependente de Ciclina p21/genética
Inibidor de Quinase Dependente de Ciclina p21/metabolismo
Modelos Animais de Doenças
Neoplasias Esofágicas
Feminino
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos
Seres Humanos
Camundongos
Mitocôndrias/efeitos dos fármacos
Mitocôndrias/metabolismo
Poli(ADP-Ribose) Polimerases/genética
Poli(ADP-Ribose) Polimerases/metabolismo
Proteína Supressora de Tumor p53/genética
Proteína Supressora de Tumor p53/metabolismo
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Bcl-2-Like Protein 11); 0 (Cyclin-Dependent Kinase Inhibitor p21); 0 (Tumor Suppressor Protein p53); EC 2.4.2.30 (Poly(ADP-ribose) Polymerases); EC 3.4.22.- (Caspase 3); KUX1ZNC9J2 (Luteolin)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180305
[Lr] Data última revisão:
180305
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170503
[St] Status:MEDLINE
[do] DOI:10.18632/oncotarget.15832


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[PMID]:29335205
[Au] Autor:Chen X; Huan X; Liu Q; Wang Y; He Q; Tan C; Chen Y; Ding J; Xu Y; Miao Z; Yang C
[Ad] Endereço:Synthetic Organic & Medicinal Chemistry Laboratory, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China.
[Ti] Título:Design and synthesis of 2-(4,5,6,7-tetrahydrothienopyridin-2-yl)-benzoimidazole carboxamides as novel orally efficacious Poly(ADP-ribose)polymerase (PARP) inhibitors.
[So] Source:Eur J Med Chem;145:389-403, 2018 Feb 10.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:The nuclear protein poly(ADP-ribose) polymerases-1/2 (PARP-1/2) are involved in DNA repair damaged by endogenous or exogenous process. And PARP-1/2 inhibitors have been proved to be clinically efficacious for DNA repair deficient tumors in the past decade. We have developed a series of 4,5,6,7-tetrahydrothienopyridin-2-yl benzimidazole carboxamides as novel and potent PARP-1/2 inhibitors. The best compound resulted from this series is compound 27 which displays excellent PARP-1 and PARP-2 inhibitory activity with IC of 18 nM and 42 nM, respectively. Furthermore, it can selectively kill BRCA2 deficient V-C8 cells with a CC of 920 nM. In the MDA-MB-436 (BRCA-1 mutant) xenograft model, this compound was well tolerated and showed single-agent activity. Based on the results above, compound 27 has been selected as a lead candidate targeting PARP-1/2 and its preclinical characterization is also underway.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Benzimidazóis/farmacologia
Desenho de Drogas
Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia
Poli(ADP-Ribose) Polimerases/metabolismo
[Mh] Termos MeSH secundário: Administração Oral
Animais
Antineoplásicos/administração & dosagem
Antineoplásicos/química
Benzimidazóis/administração & dosagem
Benzimidazóis/química
Peso Corporal/efeitos dos fármacos
Linhagem Celular
Proliferação Celular/efeitos dos fármacos
Cricetulus
Relação Dose-Resposta a Droga
Ensaios de Seleção de Medicamentos Antitumorais
Seres Humanos
Camundongos
Modelos Moleculares
Estrutura Molecular
Neoplasias Experimentais/tratamento farmacológico
Neoplasias Experimentais/patologia
Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem
Inibidores de Poli(ADP-Ribose) Polimerases/química
Relação Estrutura-Atividade
Termodinâmica
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Benzimidazoles); 0 (Poly(ADP-ribose) Polymerase Inhibitors); EC 2.4.2.30 (Poly(ADP-ribose) Polymerases)
[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]:28468627
[Au] Autor:Yin Y; Sui C; Meng F; Ma P; Jiang Y
[Ad] Endereço:Cancer Institute, First Affiliated Hospital, China Medical University, Shenyang, Liaoning, 110001, China. doustar88@126.com.
[Ti] Título:The omega-3 polyunsaturated fatty acid docosahexaenoic acid inhibits proliferation and progression of non-small cell lung cancer cells through the reactive oxygen species-mediated inactivation of the PI3K /Akt pathway.
[So] Source:Lipids Health Dis;16(1):87, 2017 May 03.
[Is] ISSN:1476-511X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Docosahexaenoic acid(DHA) inhibits tumor growth and progression in various cancers, including lung cancer. However, the mechanisms involved remain unclear. The aim of this study was to identify the mechanism of DHA in inhibiting progression of non-small cell lung cancer (NSCLC) in vitro. METHODS: The proliferation of A549 was tested by MTT, and cell apoptosis was analysed using flow cytometer. The migration and invasion were examined respectively by wound healing assay and Transwell invasion assay. The level of ROS (reactive oxygen species, ROS) was checked by DCF (dichlorodihydrofluorescein, DCF) production in cells. The apoptosis associated protein (caspase-3, PARP,Bax,Bcl-2 and survivin) and metastases associated proteins including HEF1, MMP9 and VEGF were detected by Western blot, and the same method was used in the expression of PI3K and Akt. RESULTS: DHA inhibited proliferation and induced apoptosis of A549 cells. Moreover, it suppressed the invasion and metastasis of A549 cells, while downregulating the levels of metastasis-associated proteins, including HEF1, matrix metallopeptidase (MMP9), and vascular endothelial growth factor (VEGF), in a dose -dependent manner. In addition, DHA inactivated Akt phosphorylation. All of these responses were associated with the accumulation of intracellular ROS. DHA downregulated the level of antioxidant enzymes such as catalase, while the antioxidant N-acetyl-cysteine (NAC) reversed the effect of DHA, which further validated our findings. CONCLUSIONS: The present study demonstrates that DHA inhibits the development of non-small lung tumors through an ROS-mediated inactivation of the PI3K/Akt signaling pathway.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Ácidos Docosa-Hexaenoicos/farmacologia
Regulação Neoplásica da Expressão Gênica
Fosfatidilinositol 3-Quinases/genética
Proteínas Proto-Oncogênicas c-akt/genética
Espécies Reativas de Oxigênio/agonistas
[Mh] Termos MeSH secundário: Células A549
Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores
Proteínas Adaptadoras de Transdução de Sinal/genética
Proteínas Adaptadoras de Transdução de Sinal/metabolismo
Apoptose/efeitos dos fármacos
Caspase 3/genética
Caspase 3/metabolismo
Catalase/antagonistas & inibidores
Catalase/genética
Catalase/metabolismo
Movimento Celular/efeitos dos fármacos
Proliferação Celular/efeitos dos fármacos
Sobrevivência Celular/efeitos dos fármacos
Seres Humanos
Proteínas Inibidoras de Apoptose/genética
Proteínas Inibidoras de Apoptose/metabolismo
Metaloproteinase 9 da Matriz/genética
Metaloproteinase 9 da Matriz/metabolismo
Fosfatidilinositol 3-Quinases/antagonistas & inibidores
Fosfatidilinositol 3-Quinases/metabolismo
Fosfoproteínas/antagonistas & inibidores
Fosfoproteínas/genética
Fosfoproteínas/metabolismo
Fosforilação/efeitos dos fármacos
Poli(ADP-Ribose) Polimerases/genética
Poli(ADP-Ribose) Polimerases/metabolismo
Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores
Proteínas Proto-Oncogênicas c-akt/metabolismo
Proteínas Proto-Oncogênicas c-bcl-2/genética
Proteínas Proto-Oncogênicas c-bcl-2/metabolismo
Espécies Reativas de Oxigênio/metabolismo
Transdução de Sinais
Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores
Fator A de Crescimento do Endotélio Vascular/genética
Fator A de Crescimento do Endotélio Vascular/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adaptor Proteins, Signal Transducing); 0 (Antineoplastic Agents); 0 (BCL2 protein, human); 0 (BIRC5 protein, human); 0 (Inhibitor of Apoptosis Proteins); 0 (NEDD9 protein, human); 0 (Phosphoproteins); 0 (Proto-Oncogene Proteins c-bcl-2); 0 (Reactive Oxygen Species); 0 (VEGFA protein, human); 0 (Vascular Endothelial Growth Factor A); 25167-62-8 (Docosahexaenoic Acids); EC 1.11.1.6 (Catalase); EC 2.4.2.30 (Poly(ADP-ribose) Polymerases); EC 2.7.1.- (Phosphatidylinositol 3-Kinases); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt); EC 3.4.22.- (CASP3 protein, human); EC 3.4.22.- (Caspase 3); EC 3.4.24.35 (MMP9 protein, human); EC 3.4.24.35 (Matrix Metalloproteinase 9)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180219
[Lr] Data última revisão:
180219
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170505
[St] Status:MEDLINE
[do] DOI:10.1186/s12944-017-0474-x


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[PMID]:29293500
[Au] Autor:Márton J; Fodor T; Nagy L; Vida A; Kis G; Brunyánszki A; Antal M; Lüscher B; Bai P
[Ad] Endereço:Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
[Ti] Título:PARP10 (ARTD10) modulates mitochondrial function.
[So] Source:PLoS One;13(1):e0187789, 2018.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Poly(ADP-ribose) polymerase (PARP)10 is a PARP family member that performs mono-ADP-ribosylation of target proteins. Recent studies have linked PARP10 to metabolic processes and metabolic regulators that prompted us to assess whether PARP10 influences mitochondrial oxidative metabolism. The depletion of PARP10 by specific shRNAs increased mitochondrial oxidative capacity in cellular models of breast, cervical, colorectal and exocrine pancreas cancer. Upon silencing of PARP10, mitochondrial superoxide production decreased in line with increased expression of antioxidant genes pointing out lower oxidative stress upon PARP10 silencing. Improved mitochondrial oxidative capacity coincided with increased AMPK activation. The silencing of PARP10 in MCF7 and CaCo2 cells decreased the proliferation rate that correlated with increased expression of anti-Warburg enzymes (Foxo1, PGC-1α, IDH2 and fumarase). By analyzing an online database we showed that lower PARP10 expression increases survival in gastric cancer. Furthermore, PARP10 expression decreased upon fasting, a condition that is characterized by increases in mitochondrial biogenesis. Finally, lower PARP10 expression is associated with increased fatty acid oxidation.
[Mh] Termos MeSH primário: Mitocôndrias/fisiologia
Poli(ADP-Ribose) Polimerases/metabolismo
Proteínas Proto-Oncogênicas/metabolismo
[Mh] Termos MeSH secundário: Adenilato Quinase/metabolismo
Animais
Western Blotting
Linhagem Celular
Proliferação Celular/fisiologia
Eletroforese em Gel de Poliacrilamida
Inativação Gênica
Seres Humanos
Masculino
Camundongos Endogâmicos C57BL
Oxirredução
Estresse Oxidativo
Consumo de Oxigênio
Poli(ADP-Ribose) Polimerases/genética
Proteínas Proto-Oncogênicas/genética
Reação em Cadeia da Polimerase em Tempo Real
Reação em Cadeia da Polimerase Via Transcriptase Reversa
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Proto-Oncogene Proteins); EC 2.4.2.30 (PARP10 protein, human); EC 2.4.2.30 (Poly(ADP-ribose) Polymerases); EC 2.7.4.3 (Adenylate Kinase)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180215
[Lr] Data última revisão:
180215
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180103
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0187789


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[PMID]:29274782
[Au] Autor:Grimaldi G; Rajendra S; Matthews J
[Ad] Endereço:Department of Pharmacology and Toxicology, University of Toronto, Toronto, Canada.
[Ti] Título:The aryl hydrocarbon receptor regulates the expression of TIPARP and its cis long non-coding RNA, TIPARP-AS1.
[So] Source:Biochem Biophys Res Commun;495(3):2356-2362, 2018 01 15.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor and member of the basic helix-loop-helix-PAS family. AHR is activated by numerous dietary and endogenous compounds that contribute to its regulation of genes in diverse signaling pathways including xenobiotic metabolism, vascular development, immune responses and cell cycle control. However, it is most widely studied for its role in mediating 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) toxicity. The AHR target gene and mono-ADP-ribosyltransferase, TCDD-inducible poly-ADP-ribose polymerase (TIPARP), was recently shown to be part of a novel negative feedback loop regulating AHR activity through mono-ADP-ribosylation. However, the molecular characterization of how AHR regulates TIPARP remains elusive. Here we show that activated AHR is recruited to the TIPARP promoter, through its binding to two genomic regions that each contain multiple AHR response elements (AHREs), AHR regulates the expression of both TIPARP but also TIPARP-AS1, a long non-coding RNA (lncRNA) which lies upstream of TIPARP exon 1 and is expressed in the opposite orientation. Reporter gene and deletion studies showed that the distal AHRE cluster predominantly regulated TIPARP expression while the proximal cluster regulated TIPARP-AS1. Moreover, time course and promoter activity assays suggest that TIPARP and TIPARP-AS1 work in concert to regulate AHR signaling. Collectively, these data show an added level of complexity in the AHR signaling cascade which involves lncRNAs, whose functions remain poorly understood.
[Mh] Termos MeSH primário: Neoplasias Experimentais/genética
Neoplasias Experimentais/metabolismo
Poli(ADP-Ribose) Polimerases/genética
Poli(ADP-Ribose) Polimerases/metabolismo
RNA Longo não Codificante/genética
RNA Longo não Codificante/metabolismo
Receptores de Hidrocarboneto Arílico/metabolismo
[Mh] Termos MeSH secundário: Regulação Neoplásica da Expressão Gênica/genética
Seres Humanos
Células MCF-7
Neoplasias Experimentais/patologia
Transdução de Sinais/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (RNA, Long Noncoding); 0 (Receptors, Aryl Hydrocarbon); EC 2.4.2.30 (2,3,7,8-tetrachlorodibenzo-p-dioxin poly(ADP-ribose) polymerase, human); EC 2.4.2.30 (Poly(ADP-ribose) Polymerases)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180214
[Lr] Data última revisão:
180214
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171225
[St] Status:MEDLINE


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[PMID]:29309885
[Au] Autor:Fei HR; Li ZJ; Ying-Zhang; Yue-Liu; Wang FZ
[Ad] Endereço:School of Pharmacology, Taishan Medical University, Chang Cheng Road, Taian 271016, PR China.
[Ti] Título:HBXIP regulates etoposide-induced cell cycle checkpoints and apoptosis in MCF-7 human breast carcinoma cells.
[So] Source:Gene;647:39-47, 2018 Mar 20.
[Is] ISSN:1879-0038
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Etoposide, an anticancer DNA topoisomerase II poison, plays an important role in the therapy for human cancers. Unfortunately, many cancers develop etoposide resistance and do not respond to chemotherapy, leading to difficulty in treatment and poor prognosis. In this study, we investigate the effects of HBXIP gene silencing on etoposide chemosensitivity in MCF-7 human breast cancer cells. We find that etoposide increases HBXIP expression and promotes mobilization of HBXIP to the nucleus in MCF-7 cells. Knockdown of HBXIP alleviates etoposide-induced G2/M or S phase arrest. Upregulation of p53 and p21 upon etoposide treatment is attenuated in HBXIP knock-down cells. Moreover, HBXIP gene silencing sensitizes etoposide-induced cell apoptosis and cleavage of caspase-9 and PARP in MCF-7 cells. Knockdown of HBXIP expression by RNAi abrogates the etoposide-activated ERK and Akt. These results indicate that HBXIP can modulate the etoposide sensitivity of MCF-7 cell lines and further implicate HBXIP as a target for human breast cancer.
[Mh] Termos MeSH primário: Proteínas Adaptadoras de Transdução de Sinal/metabolismo
Apoptose/efeitos dos fármacos
Neoplasias da Mama/tratamento farmacológico
Neoplasias da Mama/metabolismo
Pontos de Checagem do Ciclo Celular/efeitos dos fármacos
Etoposídeo/farmacologia
[Mh] Termos MeSH secundário: Caspase 9/metabolismo
Linhagem Celular Tumoral
Inibidor de Quinase Dependente de Ciclina p21/metabolismo
Feminino
Seres Humanos
Sistema de Sinalização das MAP Quinases/efeitos dos fármacos
Células MCF-7
Poli(ADP-Ribose) Polimerases/metabolismo
Proteínas Proto-Oncogênicas c-akt/metabolismo
Proteína Supressora de Tumor p53/metabolismo
Regulação para Cima/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adaptor Proteins, Signal Transducing); 0 (Cyclin-Dependent Kinase Inhibitor p21); 0 (HBXIP protein, human); 0 (Tumor Suppressor Protein p53); 6PLQ3CP4P3 (Etoposide); EC 2.4.2.30 (Poly(ADP-ribose) Polymerases); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt); EC 3.4.22.- (Caspase 9)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180209
[Lr] Data última revisão:
180209
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180109
[St] Status:MEDLINE


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[PMID]:29225136
[Au] Autor:Vakamullu S; Arepalli SK; Velatooru LR; J VR; P KK; B N
[Ad] Endereço:Toxicology Unit, Biology Division, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500 607, India; MNR Foundation for Research and Innovation, MNR Medical College, Sangareddy, Telangana, 502294, India.
[Ti] Título:In vitro apoptotic mechanism of a novel synthetic Quinazolinyl derivative: Induces caspase-dependent intrinsic pathway on THP-1, leukemia cell line.
[So] Source:Chem Biol Interact;280:117-127, 2018 Jan 25.
[Is] ISSN:1872-7786
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:Several quinazoline derivatives have been found to possess a broad spectrum of biological activities. Previously our research group has synthesized and studied the anti-proliferative effects of N-Decyl-N-(2-Methyl-4-Quinazolinyl) Amine (DMQA). The current study evaluated the cytotoxic and apoptotic properties of DMQA in THP-1 cells. The cytotoxic potential of DMQA was assessed using MTT assay on a panel of cancer cell lines which include HeLa, Mia PaCa-2, A 375, B16-F10, A 549,A 431, U937, THP-1, HL-60 and peripheral blood mononuclear cells (PBMC's). Preliminary data revealed that the highest cytotoxic activity was against THP-1 leukemia cell line (IC 0.66 µg/ml). The apoptotic properties of DMQA on THP-1 cells were characterized by change in nuclear morphology, DNA fragmentation, reduction of pro-caspases-3, 9, Bax/Bcl-2 levels, cleavage of poly (ADP-ribose) polymerase and cytosolic release of cytochrome c. Further investigation revealed a sub-G1 peak, phosphatidyl serine exposure and loss of mitochondrial membrane potential (MMP) in THP-1 cells. The role of caspases was crucial and was demonstrated by the inhibitors Z-VAD-FMK and Z-DEVD-FMK. Moreover DMQA was markedly less effective in inhibiting the growth of normal cells (PBMC's, IC 62.17 µg/ml). Based on the results we suggest that DMQA induced apoptosis via intrinsic pathway and could be a promising anticancer agent.
[Mh] Termos MeSH primário: Apoptose/efeitos dos fármacos
Caspases/metabolismo
Quinazolinas/farmacologia
[Mh] Termos MeSH secundário: Clorometilcetonas de Aminoácidos/farmacologia
Animais
Antineoplásicos/química
Antineoplásicos/farmacologia
Caspases/química
Proliferação Celular/efeitos dos fármacos
Células Cultivadas
Fragmentação do DNA/efeitos dos fármacos
Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos
Células HL-60
Células HeLa
Seres Humanos
Leucemia/metabolismo
Leucemia/patologia
Leucócitos Mononucleares/citologia
Leucócitos Mononucleares/efeitos dos fármacos
Leucócitos Mononucleares/metabolismo
Potencial da Membrana Mitocondrial/efeitos dos fármacos
Camundongos
Poli(ADP-Ribose) Polimerases/metabolismo
Proteínas Proto-Oncogênicas c-bcl-2/metabolismo
Quinazolinas/química
Proteína X Associada a bcl-2/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amino Acid Chloromethyl Ketones); 0 (Antineoplastic Agents); 0 (Proto-Oncogene Proteins c-bcl-2); 0 (Quinazolines); 0 (bcl-2-Associated X Protein); 0 (benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone); EC 2.4.2.30 (Poly(ADP-ribose) Polymerases); EC 3.4.22.- (Caspases)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180129
[Lr] Data última revisão:
180129
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171212
[St] Status:MEDLINE


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[PMID]:28471449
[Au] Autor:Özata DM; Li X; Lee L; Liu J; Warsito D; Hajeri P; Hultman I; Fotouhi O; Marklund S; Ährlund-Richter L; Juhlin CC; Larsson C; Lui WO
[Ad] Endereço:Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
[Ti] Título:Loss of miR-514a-3p regulation of PEG3 activates the NF-kappa B pathway in human testicular germ cell tumors.
[So] Source:Cell Death Dis;8(5):e2759, 2017 May 04.
[Is] ISSN:2041-4889
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Deregulation of microRNAs (miRNAs) contributes to the development and progression of many cancer types; however, their functions in the pathogenesis of testicular germ cell tumor (TGCT) remain unclear. Here, we determined miRNA expression profiles of TGCTs and normal testes using small RNA sequencing, and identified several deregulated miRNAs in TGCTs, including the miR-506~514 cluster. In functional studies in vitro we demonstrated that miR-514a-3p induced apoptosis through direct regulation of the paternally expressed gene 3 (PEG3), and ectopically expressed PEG3 could rescue the apoptotic effect of miR-514a-3p overexpression. Silencing of PEG3 or miR-514a-3p overexpression reduced nuclear accumulation of p50 and NF-κB reporter activity. Furthermore, PEG3 was co-immunoprecipitated with tumor necrosis factor receptor-associated factor 2 (TRAF2) in TGCT cell lysates. We propose a model of PEG3-mediated activation of NF-κB in TGCT. Loss of miR-514a-3p expression in TGCT increases PEG3 expression that recruits TRAF2 and activates the NF-kappa B pathway, which protects germ cells from apoptosis. Importantly, we observed strong expression of PEG3 and nuclear p50 in the majority of TGCTs (83% and 78%, respectively). In conclusion, our study describes a novel function for miR-514a-3p in TGCT and highlights an unrecognized mechanism of PEG3 regulation and NF-κB activation in TGCT.
[Mh] Termos MeSH primário: Fatores de Transcrição Kruppel-Like/metabolismo
MicroRNAs/metabolismo
NF-kappa B/metabolismo
Neoplasias Embrionárias de Células Germinativas/patologia
Neoplasias Testiculares/patologia
[Mh] Termos MeSH secundário: Antagomirs/metabolismo
Apoptose
Sequência de Bases
Linhagem Celular Tumoral
Metilação de DNA
Seres Humanos
Imunoprecipitação
Fatores de Transcrição Kruppel-Like/antagonistas & inibidores
Fatores de Transcrição Kruppel-Like/genética
Masculino
MicroRNAs/antagonistas & inibidores
MicroRNAs/genética
Subunidade p50 de NF-kappa B/metabolismo
Neoplasias Embrionárias de Células Germinativas/metabolismo
Poli(ADP-Ribose) Polimerases/metabolismo
Regiões Promotoras Genéticas
Interferência de RNA
Alinhamento de Sequência
Transdução de Sinais
Fator 2 Associado a Receptor de TNF/metabolismo
Neoplasias Testiculares/metabolismo
Transcriptoma
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antagomirs); 0 (Kruppel-Like Transcription Factors); 0 (MicroRNAs); 0 (NF-kappa B); 0 (NF-kappa B p50 Subunit); 0 (PEG3 protein, human); 0 (TNF Receptor-Associated Factor 2); EC 2.4.2.30 (Poly(ADP-ribose) Polymerases)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180129
[Lr] Data última revisão:
180129
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170505
[St] Status:MEDLINE
[do] DOI:10.1038/cddis.2016.464


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[PMID]:28745489
[Au] Autor:Wani TH; Chakrabarty A; Shibata N; Yamazaki H; Guengerich FP; Chowdhury G
[Ad] Endereço:Departments of Chemistry and Life Sciences, SONS, Shiv Nadar University , Greater Noida, Uttar Pradesh 201314, India.
[Ti] Título:The Dihydroxy Metabolite of the Teratogen Thalidomide Causes Oxidative DNA Damage.
[So] Source:Chem Res Toxicol;30(8):1622-1628, 2017 08 21.
[Is] ISSN:1520-5010
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Thalidomide [α-(N-phthalimido)glutarimide] (1) is a sedative and antiemetic drug originally introduced into the clinic in the 1950s for the treatment of morning sickness. Although marketed as entirely safe, more than 10 000 babies were born with severe birth defects. Thalidomide was banned and subsequently approved for the treatment of multiple myeloma and complications associated with leprosy. Although known for more than 5 decades, the mechanism of teratogenicity remains to be conclusively understood. Various theories have been proposed in the literature including DNA damage and ROS and inhibition of angiogenesis and cereblon. All of the theories have their merits and limitations. Although the recently proposed cereblon theory has gained wide acceptance, it fails to explain the metabolism and low-dose requirement reported by a number of groups. Recently, we have provided convincing structural evidence in support of the presence of arene oxide and the quinone-reactive intermediates. However, the ability of these reactive intermediates to impart toxicity/teratogenicity needs investigation. Herein we report that the oxidative metabolite of thalidomide, dihydroxythalidomide, is responsible for generating ROS and causing DNA damage. We show, using cell lines, the formation of comet (DNA damage) and ROS. Using DNA-cleavage assays, we also show that catalase, radical scavengers, and desferal are capable of inhibiting DNA damage. A mechanism of teratogenicity is proposed that not only explains the DNA-damaging property but also the metabolism, low concentration, and species-specificity requirements of thalidomide.
[Mh] Termos MeSH primário: Dano ao DNA/efeitos dos fármacos
Talidomida/toxicidade
[Mh] Termos MeSH secundário: Catalase/metabolismo
Clivagem do DNA
Depuradores de Radicais Livres/química
Células HEK293
Células Hep G2
Células Endoteliais da Veia Umbilical Humana
Seres Humanos
Microscopia de Fluorescência
Plasmídeos/metabolismo
Poli(ADP-Ribose) Polimerases/metabolismo
Espécies Reativas de Oxigênio/análise
Espécies Reativas de Oxigênio/metabolismo
Teratogênios/química
Teratogênios/metabolismo
Teratogênios/toxicidade
Talidomida/química
Talidomida/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Free Radical Scavengers); 0 (Reactive Oxygen Species); 0 (Teratogens); 4Z8R6ORS6L (Thalidomide); EC 1.11.1.6 (Catalase); EC 2.4.2.30 (Poly(ADP-ribose) Polymerases)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:180127
[Lr] Data última revisão:
180127
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170727
[St] Status:MEDLINE
[do] DOI:10.1021/acs.chemrestox.7b00127


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[PMID]:29223166
[Au] Autor:Shilovsky GA; Shram SI; Morgunova GV; Khokhlov AN
[Ad] Endereço:Faculty of Biology, Lomonosov Moscow State University, Moscow, 119234, Russia. khokhlov@mail.bio.msu.ru.
[Ti] Título:Protein Poly(ADP-ribosyl)ation System: Changes in Development and Aging as well as due to Restriction of Cell Proliferation.
[So] Source:Biochemistry (Mosc);82(11):1391, 2017 Nov.
[Is] ISSN:1608-3040
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:It is well known that the number of dividing cells in an organism decreases with age. The average rate of cell division in tissues and organs of a mature organism sharply decreases, which is probably a trigger for accumulation of damage leading to disturbance of genome integrity. This can be a cause for the development of many age-related diseases and appearance of phenotypic and physiological signs of aging. In this connection, the protein poly(ADP-ribosyl)ation system, which is activated in response to appearance of various DNA damage, attracts great interest. This review summarizes and analyzes data on changes in the poly(ADP-ribosyl)ation system during development and aging in vivo and in vitro, and due to restriction of cell proliferation. Special attention is given to methodological aspects of determination of activity of poly(ADP-ribose) polymerases (PARPs). Analysis of relevant publications and our own data has led us to the conclusion that PARP activity upon the addition of free DNA ends (in this review referred to as stimulated PARP activity) is steadily decreasing with age. However, the dynamics of PARP activity measured without additional activation of the enzyme (in this review referred to as unstimulated activity) does not have such a clear trend: in many studies, the presented differences are statistically non-significant, although it is well known that the number of unrepaired DNA lesions steadily increases with aging. Apparently, the cell has additional regulatory systems that limit its own capability of reacting to DNA damage. Special attention is given to the influence of the cell proliferative status on PARP activity. We have systematized and analyzed data on changes in PARP activity during development and aging of an organism, as well as data on differences in the dynamics of this activity in the presence/absence of additional stimulation and on cellular processes that are associated with activation of these enzymes. Moreover, data obtained in different models of cellular aging are compared.
[Mh] Termos MeSH primário: Poli ADP Ribosilação/fisiologia
Poli(ADP-Ribose) Polimerases/metabolismo
[Mh] Termos MeSH secundário: Envelhecimento
Animais
Diferenciação Celular
Senescência Celular
Dano ao DNA
Reparo do DNA
Seres Humanos
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
EC 2.4.2.30 (Poly(ADP-ribose) Polymerases)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180103
[Lr] Data última revisão:
180103
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171211
[St] Status:MEDLINE
[do] DOI:10.1134/S0006297917110177



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