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[PMID]:29324830
[Au] Autor:Skeate JG; Da Silva DM; Chavez-Juan E; Anand S; Nuccitelli R; Kast WM
[Ad] Endereço:Department of Molecular Microbiology & Immunology, University of Southern California, Los Angeles, CA, United States of America.
[Ti] Título:Nano-Pulse Stimulation induces immunogenic cell death in human papillomavirus-transformed tumors and initiates an adaptive immune response.
[So] Source:PLoS One;13(1):e0191311, 2018.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Nano-Pulse Stimulation (NPS) is a non-thermal pulsed electric field modality that has been shown to have cancer therapeutic effects. Here we applied NPS treatment to the human papillomavirus type 16 (HPV 16)-transformed C3.43 mouse tumor cell model and showed that it is effective at eliminating primary tumors through the induction of immunogenic cell death while subsequently increasing the number of tumor-infiltrating lymphocytes within the tumor microenvironment. In vitro NPS treatment of C3.43 cells resulted in a doubling of activated caspase 3/7 along with the translocation of phosphatidylserine (PS) to the outer leaflet of the plasma membrane, indicating programmed cell death activity. Tumor-bearing mice receiving standard NPS treatment showed an initial decrease in tumor volume followed by clearing of tumors in most mice, and a significant increase in overall survival. Intra-tumor analysis of mice that were unable to clear tumors showed an inverse correlation between the number of tumor infiltrating lymphocytes and the size of the tumor. Approximately half of the mice that cleared established tumors were protected against tumor re-challenge on the opposite flank. Selective depletion of CD8+ T cells eliminated this protection, suggesting that NPS treatment induces an adaptive immune response generating CD8+ T cells that recognize tumor antigen(s) associated with the C3.43 tumor model. This method may be utilized in the future to not only ablate primary tumors, but also to induce an anti-tumor response driven by effector CD8+ T cells capable of protecting individuals from disease recurrence.
[Mh] Termos MeSH primário: Imunidade Adaptativa
Morte Celular/imunologia
Transformação Celular Viral
Estimulação Elétrica
Papillomavirus Humano 16/fisiologia
[Mh] Termos MeSH secundário: Animais
Antígenos CD8/metabolismo
Caspase 3/metabolismo
Caspase 7/metabolismo
Linhagem Celular Tumoral
Ativação Enzimática
Seres Humanos
Camundongos
Nanotecnologia
Carga Tumoral
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (CD8 Antigens); EC 3.4.22.- (Caspase 3); EC 3.4.22.- (Caspase 7)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180226
[Lr] Data última revisão:
180226
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180112
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0191311


  2 / 1800 MEDLINE  
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[PMID]:29225137
[Au] Autor:Aztopal N; Erkisa M; Erturk E; Ulukaya E; Tokullugil AH; Ari F
[Ad] Endereço:Istinye University, Faculty of Medicine, Department of Clinical Biochemistry, Istanbul, Turkey; Uludag University, Science and Art Faculty, Department of Biology, Bursa, Turkey.
[Ti] Título:Valproic acid, a histone deacetylase inhibitor, induces apoptosis in breast cancer stem cells.
[So] Source:Chem Biol Interact;280:51-58, 2018 Jan 25.
[Is] ISSN:1872-7786
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:Cancer stem-like cells (CSCs) are a cell subpopulation that can reinitiate tumors, resist chemotherapy, give rise to metastases and lead to disease relapse because of an acquired resistance to apoptosis. Especially, epigenetic alterations play a crucial role in the regulation of stemness and also have been implicated in the development of drug resistance. Hence, in the present study, we examined the cytotoxic and apoptotic activity of valproic acid (VPA) as an inhibitor of histone deacetylases (HDACs) against breast CSCs (BCSCs). Increased expression of stemness markers were determined by western blotting in mammospheres (MCF-7s, a cancer stem cell-enriched population) propagated from parental MCF-7 cells. Anti-growth activity of VPA was determined via ATP viability assay. The sphere formation assay (SFA) was performed to assess the inhibitory effect of VPA on the self-renewal capacity of MCF-7s cells. Acetylation of histon H3 was detected with ELISA assay. Cell death mode was performed by Hoechst dye 33342 and propidium iodide-based flouresent stainings (for pyknosis and membrane integrity), by M30 and M65 ELISA assays (for apoptosis and primary or secondary necrosis) as well as cytofluorimetric analysis (caspase 3/7 activity and annexin-V-FITC staining for early and late stage apoptosis). VPA exhibited anti-growth effect against both MCF-7 and MCF-7s cells in a dose (0.6-20 mM) and time (24, 48, 72 h) dependent manner. As expected, MCF-7s cells were found more resistant to VPA than MCF-7 cells. It was observed that VPA prevented mammosphere formation at relatively lower doses (2.5 and 5 mM) while the acetylation of histon H3 was increased. At the same doses, VPA increased the M30 levels, annexin-V-FITC positivity and caspase 3/7 activation, implying the induction of apoptosis. The secondary necrosis (late stage of apoptosis) was also evidenced by nuclear pyknosis with propidium iodide staining positivity. Taken together, inhibition of HDACs is cytotoxic to BCSCs by apoptosis. Our results suggested that targeting the epigenetic regulation of histones may be a novel approach and hold significant promise for successful treatment of breast cancer.
[Mh] Termos MeSH primário: Apoptose/efeitos dos fármacos
Células-Tronco Neoplásicas/efeitos dos fármacos
Ácido Valproico/farmacologia
[Mh] Termos MeSH secundário: Acetilação/efeitos dos fármacos
Neoplasias da Mama/metabolismo
Neoplasias da Mama/patologia
Caspase 3/metabolismo
Caspase 7/metabolismo
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Feminino
Inibidores de Histona Desacetilases/farmacologia
Histonas/metabolismo
Seres Humanos
Queratina-18/metabolismo
Células MCF-7
Células-Tronco Neoplásicas/citologia
Células-Tronco Neoplásicas/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Histone Deacetylase Inhibitors); 0 (Histones); 0 (Keratin-18); 614OI1Z5WI (Valproic Acid); EC 3.4.22.- (Caspase 3); EC 3.4.22.- (Caspase 7)
[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


  3 / 1800 MEDLINE  
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[PMID]:28892560
[Au] Autor:Moawia A; Shaheen R; Rasool S; Waseem SS; Ewida N; Budde B; Kawalia A; Motameny S; Khan K; Fatima A; Jameel M; Ullah F; Akram T; Ali Z; Abdullah U; Irshad S; Höhne W; Noegel AA; Al-Owain M; Hörtnagel K; Stöbe P; Baig SM; Nürnberg P; Alkuraya FS; Hahn A; Hussain MS
[Ad] Endereço:Cologne Center for Genomics, University of Cologne, Cologne, Germany.
[Ti] Título:Mutations of KIF14 cause primary microcephaly by impairing cytokinesis.
[So] Source:Ann Neurol;82(4):562-577, 2017 Oct.
[Is] ISSN:1531-8249
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: Autosomal recessive primary microcephaly (MCPH) is a rare condition characterized by a reduced cerebral cortex accompanied with intellectual disability. Mutations in 17 genes have been shown to cause this phenotype. Recently, mutations in CIT, encoding CRIK (citron rho-interacting kinase)-a component of the central spindle matrix-were added. We aimed at identifying novel MCPH-associated genes and exploring their functional role in pathogenesis. METHODS: Linkage analysis and whole exome sequencing were performed in consanguineous and nonconsanguineous MCPH families to identify disease-causing variants. Functional consequences were investigated by RNA studies and on the cellular level using immunofluorescence and microscopy. RESULTS: We identified homozygous mutations in KIF14 (NM_014875.2;c.263T>A;pLeu88*, c.2480_2482delTTG; p.Val827del, and c.4071G>A;p.Gln1357=) as the likely cause in 3 MCPH families. Furthermore, in a patient presenting with a severe form of primary microcephaly and short stature, we identified compound heterozygous missense mutations in KIF14 (NM_014875.2;c.2545C>G;p.His849Asp and c.3662G>T;p.Gly1221Val). Three of the 5 identified mutations impaired splicing, and 2 resulted in a truncated protein. Intriguingly, Kif14 knockout mice also showed primary microcephaly. Human kinesin-like protein KIF14, a microtubule motor protein, localizes at the midbody to finalize cytokinesis by interacting with CRIK. We found impaired localization of both KIF14 and CRIK at the midbody in patient-derived fibroblasts. Furthermore, we observed a large number of binucleated and apoptotic cells-signs of failed cytokinesis that we also observed in experimentally KIF14-depleted cells. INTERPRETATION: Our data corroborate the role of an impaired cytokinesis in the etiology of primary and syndromic microcephaly, as has been proposed by recent findings on CIT mutations. Ann Neurol 2017;82:562-577.
[Mh] Termos MeSH primário: Citocinese/genética
Regulação da Expressão Gênica/genética
Cinesina/genética
Microcefalia/genética
Mutação/genética
Proteínas Oncogênicas/genética
[Mh] Termos MeSH secundário: Caspase 7/metabolismo
Movimento Celular/genética
Células Cultivadas
Criança
Pré-Escolar
Saúde da Família
Feminino
Fibroblastos/fisiologia
Estudo de Associação Genômica Ampla
Seres Humanos
Peptídeos e Proteínas de Sinalização Intracelular/genética
Peptídeos e Proteínas de Sinalização Intracelular/metabolismo
Masculino
Microcefalia/diagnóstico por imagem
Microcefalia/patologia
Proteínas Serina-Treonina Quinases/genética
Proteínas Serina-Treonina Quinases/metabolismo
Tubulina (Proteína)/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Intracellular Signaling Peptides and Proteins); 0 (Oncogene Proteins); 0 (Tubulin); EC 2.7.1.- (citron-kinase); EC 2.7.11.1 (Protein-Serine-Threonine Kinases); EC 3.4.22.- (CASP7 protein, human); EC 3.4.22.- (Caspase 7); EC 3.6.1.- (KIF14 protein, human); EC 3.6.4.4 (Kinesin)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171030
[Lr] Data última revisão:
171030
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170912
[St] Status:MEDLINE
[do] DOI:10.1002/ana.25044


  4 / 1800 MEDLINE  
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[PMID]:28870958
[Au] Autor:Bouhenna MM; Orlikova B; Talhi O; Schram B; Pinto DCGA; Taibi N; Bachari K; Diederich M; Silva AMS; Mameri N
[Ad] Endereço:Unité de Recherche URIE, Ecole Nationale Polytechnique, Alger, Algeria.
[Ti] Título:Anti-proliferative, Cytotoxic and NF-ĸB Inhibitory Properties of Spiro(Lactone-Cyclohexanone) Compounds in Human Leukemia.
[So] Source:Anticancer Res;37(9):5225-5233, 2017 09.
[Is] ISSN:1791-7530
[Cp] País de publicação:Greece
[La] Idioma:eng
[Ab] Resumo:BACKGROUND/AIM: NF-ĸB affects most aspects of cellular physiology. Deregulation of NF-ĸB signaling is associated with inflammatory diseases and cancer. In this study, we evaluated the cytotoxic and NF-ĸB inhibition potential of new spiro(lactone-cyclohexanone) compounds in two different human leukemia cell lines (U937 and K562). MATERIALS AND METHODS: The anti-proliferative effects of the spiro(lactone-cyclohexanone) compounds on human K562 and U937 cell lines was evaluated by trypan blue staining, as well as their involvement in NF-kB regulation were analyzed by luciferase reporter gene assay, Caspase-3/7 activities were evaluated to analyze apoptosis induction. RESULTS: Both spiro(coumarin-cyclohexanone) and spiro(6- methyllactone-cyclohexanone) down-regulated cancer cell viability and proliferation. Compound inhibited TNF-α-induced NF-ĸB activation in a dose-dependent manner and induced caspase-dependent apoptosis in both leukemia cell lines. CONCLUSION: Results show that compound and compound have potential as anti-cancer agents. In addition, compound exerted NF-kB inhibition activity in leukemia cancer cells.
[Mh] Termos MeSH primário: Cicloexanonas/farmacologia
Leucemia/patologia
NF-kappa B/metabolismo
Espironolactona/farmacologia
[Mh] Termos MeSH secundário: Bioensaio
Caspase 3/metabolismo
Caspase 7/metabolismo
Morte Celular/efeitos dos fármacos
Proliferação Celular/efeitos dos fármacos
Sobrevivência Celular/efeitos dos fármacos
Cromatografia Líquida de Alta Pressão
Cicloexanonas/síntese química
Cicloexanonas/química
Seres Humanos
Células K562
Espironolactona/síntese química
Espironolactona/química
Estereoisomerismo
Fator de Necrose Tumoral alfa/farmacologia
Células U937
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cyclohexanones); 0 (NF-kappa B); 0 (Tumor Necrosis Factor-alpha); 27O7W4T232 (Spironolactone); 5QOR3YM052 (cyclohexanone); EC 3.4.22.- (Caspase 3); EC 3.4.22.- (Caspase 7)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170918
[Lr] Data última revisão:
170918
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170906
[St] Status:MEDLINE


  5 / 1800 MEDLINE  
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[PMID]:28863261
[Au] Autor:Martini C; Bédard M; Lavigne P; Denault JB
[Ad] Endereço:Department of Pharmacology-Physiology and ‡Department of Biochemistry, Institut de Pharmacologie de Sherbrooke, Université de Sherbrooke, Faculty of Medicine and Health Sciences , 3001, 12th Avenue North, Sherbrooke, QC J1H 5N4, Canada.
[Ti] Título:Characterization of Hsp90 Co-Chaperone p23 Cleavage by Caspase-7 Uncovers a Peptidase-Substrate Interaction Involving Intrinsically Disordered Regions.
[So] Source:Biochemistry;56(38):5099-5111, 2017 Sep 26.
[Is] ISSN:1520-4995
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Caspases are cysteinyl peptidases involved in inflammation and apoptosis during which hundreds of proteins are cleaved by executioner caspase-3 and -7. Despite the fact that caspase-3 has a higher catalytic activity, caspase-7 is more proficient at cleaving poly(ADP ribose) polymerase 1 (PARP1) because it uses an exosite within its N-terminal domain (NTD). Here, we demonstrate that molecular determinants also located in the NTD enhance the recognition and proteolysis of the Hsp90 co-chaperone p23. Structure-activity relationship analyses using mutagenesis of the caspase-7 NTD and kinetics show that residues 36-45 of caspase-7, which overlap with residues necessary for efficacious PARP1 cleavage, participate in p23 recognition. We also demonstrate using chimeric and truncated proteins that the caspase-7 NTD binds close to the cleavage site in the C-terminal tail of p23. Moreover, because p23 is cleaved at a site bearing a P4 Pro residue (PEVD ↓G), which is far from the optimal sequence, we tested all residues at that position and found notable differences in the preference of caspase-7 and magnitude of differences between residues compared to the results of studies that have used small peptidic substrate libraries. Finally, bioinformatics shows that the regions we identified in caspase-7 and p23 are intrinsically disordered regions that contain molecular recognition features that permit a transient interaction between these two proteins. In summary, we characterized the binding mode for a caspase that is tailored to the specific recognition and cleavage of a substrate, highlighting the importance of studying the peptidase-substrate pair to understand the modalities of substrate recognition by caspases.
[Mh] Termos MeSH primário: Caspase 7/metabolismo
Chaperonas Moleculares/química
Chaperonas Moleculares/metabolismo
Fosfoproteínas/química
Fosfoproteínas/metabolismo
[Mh] Termos MeSH secundário: Caspase 7/genética
Dicroísmo Circular
Proteínas de Choque Térmico HSP90/metabolismo
Seres Humanos
Cinética
Chaperonas Moleculares/genética
Mutação
Fosfoproteínas/genética
Domínios Proteicos
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (HSP90 Heat-Shock Proteins); 0 (Molecular Chaperones); 0 (Phosphoproteins); 0 (TEBP protein, human); EC 3.4.22.- (Caspase 7)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171010
[Lr] Data última revisão:
171010
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170902
[St] Status:MEDLINE
[do] DOI:10.1021/acs.biochem.7b00298


  6 / 1800 MEDLINE  
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[PMID]:28821011
[Au] Autor:Miranda N; Volpato H; da Silva Rodrigues JH; Caetano W; Ueda-Nakamura T; de Oliveira Silva S; Nakamura CV
[Ad] Endereço:Post-Graduate Program in Pharmaceutical Sciences, State University of Maringá, Maringá, Paraná, Brazil. Electronic address: nathielle.miranda@gmail.com.
[Ti] Título:The photodynamic action of pheophorbide a induces cell death through oxidative stress in Leishmania amazonensis.
[So] Source:J Photochem Photobiol B;174:342-354, 2017 Sep.
[Is] ISSN:1873-2682
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:Leishmaniasis is a disease caused by hemoflagellate protozoa, affecting millions of people worldwide. The difficulties of treating patients with this parasitosis include the limited efficacy and many side effects of the currently available drugs. Therefore, the search for new compounds with leishmanicidal action is necessary. Photodynamic therapy has been studied in the medical field because of its selectivity, utilizing a combination of visible light, a photosensitizer compound, and singlet oxygen to reach the area of treatment. The continued search for selective alternative treatments and effective targets that impact the parasite and not the host are fundamentally important for the development of new drugs. Pheophorbide a is a photosensitizer that may be promising for the treatment of leishmaniasis. The present study evaluated the in vitro biological effects of pheophorbide a and its possible mechanisms of action in causing cell death in L. amazonensis. Pheophorbide a was active against promastigote and amastigote forms of the parasite. After treatment, we observed ultrastructural alterations in this protozoan. We also observed changes in promastigote macromolecules and organelles, such as loss of mitochondrial membrane potential [∆Ψ ], lipid peroxidation, an increase in lipid droplets, DNA fragmentation, phosphatidylserine exposure, an increase in caspase-like activity, oxidative imbalance, and a decrease in antioxidant defense systems. These findings suggest that cell death occurred through apoptosis. The mechanism of cell death in intracellular amastigotes appeared to involve autophagy, in which we clearly observed an increase in reactive oxygen species, a compromised ∆Ψ , and an increase in the number of autophagic vacuoles. The present study contributes to the development of new photosensitizers against L. amazonensis. We also elucidated the mechanism of action of pheophorbide a, mainly in intracellular amastigotes, which is the most clinically relevant form of this parasite.
[Mh] Termos MeSH primário: Clorofila/análogos & derivados
Leishmania/citologia
Leishmania/metabolismo
Luz
Estresse Oxidativo/efeitos dos fármacos
Fármacos Fotossensibilizantes/farmacologia
[Mh] Termos MeSH secundário: Apoptose/efeitos dos fármacos
Caspase 3/metabolismo
Caspase 7/metabolismo
Membrana Celular/efeitos dos fármacos
Membrana Celular/metabolismo
Membrana Celular/efeitos da radiação
Clorofila/farmacologia
Fragmentação do DNA/efeitos dos fármacos
Fragmentação do DNA/efeitos da radiação
Peróxido de Hidrogênio/metabolismo
Espaço Intracelular/efeitos dos fármacos
Espaço Intracelular/metabolismo
Espaço Intracelular/efeitos da radiação
Leishmania/efeitos dos fármacos
Leishmania/efeitos da radiação
Peroxidação de Lipídeos/efeitos dos fármacos
Peroxidação de Lipídeos/efeitos da radiação
Potencial da Membrana Mitocondrial/efeitos dos fármacos
Óxido Nítrico/metabolismo
Vacúolos/efeitos dos fármacos
Vacúolos/efeitos da radiação
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Photosensitizing Agents); 1406-65-1 (Chlorophyll); 31C4KY9ESH (Nitric Oxide); BBX060AN9V (Hydrogen Peroxide); EC 3.4.22.- (Caspase 3); EC 3.4.22.- (Caspase 7); IA2WNI2HO2 (pheophorbide a)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171012
[Lr] Data última revisão:
171012
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170819
[St] Status:MEDLINE


  7 / 1800 MEDLINE  
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[PMID]:28807721
[Au] Autor:Domracheva I; Kanepe-Lapsa I; Jackevica L; Vasiljeva J; Arsenyan P
[Ad] Endereço:Latvian Institute of Organic Synthesis, Aizkraukles 21, LV-1006 Riga, Latvia.
[Ti] Título:Selenopheno quinolinones and coumarins promote cancer cell apoptosis by ROS depletion and caspase-7 activation.
[So] Source:Life Sci;186:92-101, 2017 Oct 01.
[Is] ISSN:1879-0631
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:AIM: This study was designed to investigate the mechanism underlying cancer cell apoptosis caused by selenophenoquinolinones and coumarins. MATERIALS AND METHODS: Twelve derivatives were studied according to their ability to suppress the proliferation of cancer cells in vitro (i.e., HepG2, MH-22A, MCF-7), induce cell apoptosis, modulate cellular antioxidant enzyme system activities (i.e., SOD, GPx, TrxR), influence the level of ROS, and modulate caspase activity. RESULTS: A plausible mechanism of apoptosis is presented. The lack of change in the activity of caspase-8 demonstrates that these compounds affect the intrinsic rather than the extrinsic pathway; moreover, the absence of caspase-9 activation suggests that the studied compounds are involved in the intrinsic pathway of apoptosis in a non-canonical manner. Provisionally, the increase in Smac/Diablo released from the mitochondria removes the inhibitory effect and activates caspase-7, leading to apoptosis. Additionally, the activation of caspase-1 activates effector caspase-7, thereby increasing the amount of cytochrome c and Smac/Diablo released from the mitochondria and ultimately leading to apoptosis. CONCLUSION: This present study provides scientific evidence that selenopheno quinolinones and coumarins promote cancer cell apoptosis by ROS depletion and caspase-7 activation in malignant cells.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Apoptose/efeitos dos fármacos
Caspase 7/metabolismo
Cumarínicos/farmacologia
Compostos Organosselênicos/farmacologia
Quinolonas/farmacologia
Espécies Reativas de Oxigênio/metabolismo
[Mh] Termos MeSH secundário: Animais
Antineoplásicos/síntese química
Antineoplásicos/química
Antioxidantes/metabolismo
Técnicas de Cultura de Células
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Cumarínicos/síntese química
Cumarínicos/química
Células Hep G2
Seres Humanos
Células MCF-7
Camundongos
Estrutura Molecular
Compostos Organosselênicos/síntese química
Compostos Organosselênicos/química
Quinolonas/síntese química
Quinolonas/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Antioxidants); 0 (Coumarins); 0 (Organoselenium Compounds); 0 (Quinolones); 0 (Reactive Oxygen Species); EC 3.4.22.- (Caspase 7)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170919
[Lr] Data última revisão:
170919
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170816
[St] Status:MEDLINE


  8 / 1800 MEDLINE  
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[PMID]:28806777
[Au] Autor:Cairney CJ; Godwin LS; Bilsland AE; Burns S; Stevenson KH; McGarry L; Revie J; Moore JD; Wiggins CM; Collinson RS; Mudd C; Tsonou E; Sadaie M; Bennett DC; Narita M; Torrance CJ; Keith WN
[Ad] Endereço:Institute of Cancer Sciences, Wolfson Wohl Cancer Research Centre, University of Glasgow, Glasgow, United Kingdom.
[Ti] Título:A 'synthetic-sickness' screen for senescence re-engagement targets in mutant cancer backgrounds.
[So] Source:PLoS Genet;13(8):e1006942, 2017 Aug.
[Is] ISSN:1553-7404
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Senescence is a universal barrier to immortalisation and tumorigenesis. As such, interest in the use of senescence-induction in a therapeutic context has been gaining momentum in the past few years; however, senescence and immortalisation remain underserved areas for drug discovery owing to a lack of robust senescence inducing agents and an incomplete understanding of the signalling events underlying this complex process. In order to address this issue we undertook a large-scale morphological siRNA screen for inducers of senescence phenotypes in the human melanoma cell line A375P. Following rescreen and validation in a second cancer cell line, HCT116 colorectal carcinoma, a panel of 16 of the most robust hits were selected for further validation based on significance and the potential to be targeted by drug-like molecules. Using secondary assays for detection of senescence biomarkers p21, 53BP1 and senescence associated beta-galactosidase (SAßGal) in a panel of HCT116 cell lines carrying cancer-relevant mutations, we show that partial senescence phenotypes can be induced to varying degrees in a context dependent manner, even in the absence of p21 or p53 expression. However, proliferation arrest varied among genetic backgrounds with predominantly toxic effects in p21 null cells, while cells lacking PI3K mutation failed to arrest. Furthermore, we show that the oncogene ECT2 induces partial senescence phenotypes in all mutant backgrounds tested, demonstrating a dependence on activating KRASG13D for growth suppression and a complete senescence response. These results suggest a potential mechanism to target mutant KRAS signalling through ECT2 in cancers that are reliant on activating KRAS mutations and remain refractory to current treatments.
[Mh] Termos MeSH primário: Senescência Celular/genética
Regulação Neoplásica da Expressão Gênica
Melanoma/genética
[Mh] Termos MeSH secundário: Caspase 3/genética
Caspase 3/metabolismo
Caspase 7/genética
Caspase 7/metabolismo
Proliferação Celular
Inibidor de Quinase Dependente de Ciclina p21/genética
Inibidor de Quinase Dependente de Ciclina p21/metabolismo
Marcadores Genéticos
Células HCT116
Seres Humanos
Mutação
Fosfatidilinositol 3-Quinases/genética
Fosfatidilinositol 3-Quinases/metabolismo
RNA Interferente Pequeno/genética
RNA Interferente Pequeno/metabolismo
Reprodutibilidade dos Testes
Proteína Supressora de Tumor p53/genética
Proteína Supressora de Tumor p53/metabolismo
Proteína 1 de Ligação à Proteína Supressora de Tumor p53/genética
Proteína 1 de Ligação à Proteína Supressora de Tumor p53/metabolismo
beta-Galactosidase/genética
beta-Galactosidase/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (CDKN1A protein, human); 0 (Cyclin-Dependent Kinase Inhibitor p21); 0 (Genetic Markers); 0 (RNA, Small Interfering); 0 (TP53 protein, human); 0 (TP53BP1 protein, human); 0 (Tumor Suppressor Protein p53); 0 (Tumor Suppressor p53-Binding Protein 1); EC 2.7.1.- (Phosphatidylinositol 3-Kinases); EC 3.2.1.23 (beta-Galactosidase); EC 3.4.22.- (CASP3 protein, human); EC 3.4.22.- (CASP7 protein, human); EC 3.4.22.- (Caspase 3); EC 3.4.22.- (Caspase 7)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170815
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pgen.1006942


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[PMID]:28803117
[Au] Autor:George BP; Abrahamse H; Hemmaragala NM
[Ad] Endereço:Laser Research Centre, Faculty of Health Sciences, University of Johannesburg, Doornfontein, 2028, Johannesburg, South Africa. Electronic address: blassang@uj.ac.za.
[Ti] Título:Phenolics from Rubus fairholmianus induces cytotoxicity and apoptosis in human breast adenocarcinoma cells.
[So] Source:Chem Biol Interact;275:178-188, 2017 Sep 25.
[Is] ISSN:1872-7786
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:Herbal medicine is an important part of health care system in most of the countries. Rubus fairholmianus is an unexplored berry in folkloric medicine. In this study, we aimed to understand the importance of R. fairholmianus in pharmaceutical industry for the development of cost-effective cancer therapeutic drugs using in vivo and in vitro analysis. Chemical characterization, antioxidant, antiproliferative and apoptosis inducing properties of R. fairholmianus root methanolic column subfraction (RFM) were investigated. The RFM displayed the presence of alpha-tocopherol, flavonol glycoside and apigenin in the chemical characterization. DPPH (2, 2-diphenyl-1-picrylhydrazyl) and ABTS (2, 2'-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid)) radical scavenging assays exhibited an activity of 7.56 µg/mL (IC ) and 20514.7 µM trolox equivalents/g respectively. The solid and ascites tumors in mice were reduced significantly upon 100 mg/kg RFM treatment by reducing the tumor volume (1.86 cm ), tumor weight (69%) and increasing life span (31.74 days). The morphological features of RFM treated MCF-7 cells showed the cell damage and decreased cell numbers. The viability of treated cells decreased with 67.73% at 20 µg/mL against 96.50% in untreated cells. The treated cells (20 µg/mL) resulted in a substantial decrease (p < 0.001) in cellular ATP proliferation, increased the LDH cytotoxicity, increased apoptotic cells population (33.92%) and reduced the population of viable cells (Annexin V-/PI-) (45.56%). Increased caspase 3/7 activity and cytochrome c release were also observed in treated cells. This is the first evidence about in vitro and in vivo anticancer activity of R. fairholmianus phenolics. The major phenolics such as alpha-tocopherol, flavonol glycoside, and apigenin might be the reason behind the caspase-mediated apoptosis. Further work is warranted to study the individual effects of these bioactive compounds in the induction of cell death. Due to the apoptosis inducing properties, it can be considered as an effective adjuvant therapeutic agent in clinical trials.
[Mh] Termos MeSH primário: Antioxidantes/química
Apoptose/efeitos dos fármacos
Fenóis/química
Fenóis/farmacologia
Extratos Vegetais/química
Rubus/química
[Mh] Termos MeSH secundário: Adenocarcinoma/tratamento farmacológico
Adenocarcinoma/metabolismo
Adenocarcinoma/patologia
Animais
Antineoplásicos Fitogênicos/química
Antineoplásicos Fitogênicos/farmacologia
Antineoplásicos Fitogênicos/uso terapêutico
Neoplasias da Mama/tratamento farmacológico
Neoplasias da Mama/metabolismo
Neoplasias da Mama/patologia
Caspase 3/metabolismo
Caspase 7/metabolismo
Proliferação Celular/efeitos dos fármacos
Citocromos c/metabolismo
Feminino
Seres Humanos
Células MCF-7
Masculino
Camundongos
Fenóis/uso terapêutico
Raízes de Plantas/química
Raízes de Plantas/metabolismo
Rubus/metabolismo
Transplante Heterólogo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents, Phytogenic); 0 (Antioxidants); 0 (Phenols); 0 (Plant Extracts); 9007-43-6 (Cytochromes c); EC 3.4.22.- (Caspase 3); EC 3.4.22.- (Caspase 7)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170926
[Lr] Data última revisão:
170926
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170814
[St] Status:MEDLINE


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[PMID]:28800359
[Au] Autor:Nölting S; Rentsch J; Freitag H; Detjen K; Briest F; Möbs M; Weissmann V; Siegmund B; Auernhammer CJ; Aristizabal Prada ET; Lauseker M; Grossman A; Exner S; Fischer C; Grötzinger C; Schrader J; Grabowski P; GERMAN NET-Z study group
[Ad] Endereço:Department of Internal Medicine II, Klinikum der Universität München (KUM), Ludwig-Maximilians-Universität München, München, Bavaria, Germany.
[Ti] Título:The selective PI3Kα inhibitor BYL719 as a novel therapeutic option for neuroendocrine tumors: Results from multiple cell line models.
[So] Source:PLoS One;12(8):e0182852, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND/AIMS: The therapeutic options for metastatic neuroendocrine tumors (NETs) are limited. As PI3K signaling is often activated in NETs, we have assessed the effects of selective PI3Kp110α inhibition by the novel agent BYL719 on cell viability, colony formation, apoptosis, cell cycle, signaling pathways, differentiation and secretion in pancreatic (BON-1, QGP-1) and pulmonary (H727) NET cell lines. METHODS: Cell viability was investigated by WST-1 assay, colony formation by clonogenic assay, apoptosis by caspase3/7 assay, the cell cycle by FACS, cell signaling by Western blot analysis, expression of chromogranin A and somatostatin receptors 1/2/5 by RT-qPCR, and chromogranin A secretion by ELISA. RESULTS: BYL719 dose-dependently decreased cell viability and colony formation with the highest sensitivity in BON-1, followed by H727, and lowest sensitivity in QGP-1 cells. BYL719 induced apoptosis and G0/G1 cell cycle arrest associated with increased p27 expression. Western blots showed inhibition of PI3K downstream targets to a varying degree in the different cell lines, but IGF1R activation. The most sensitive BON-1 cells displayed a significant, and H727 cells a non-significant, GSK3 inhibition after BYL719 treatment, but these effects do not appear to be mediated through the IGF1R. In contrast, the most resistant QGP-1 cells showed no GSK3 inhibition, but a modest activation, which would partially counteract the other anti-proliferative effects. Accordingly, BYL719 enhanced neuroendocrine differentiation with the strongest effect in BON-1, followed by H727 cells indicated by induction of chromogranin A and somatostatin receptor 1/2 mRNA-synthesis, but not in QGP-1 cells. In BON-1 and QGP-1 cells, the BYL719/everolimus combination was synergistic through simultaneous AKT/mTORC1 inhibition, and significantly increased somatostatin receptor 2 transcription compared to each drug separately. CONCLUSION: Our results suggest that the agent BYL719 could be a novel therapeutic approach to the treatment of NETs that may sensitize NET cells to somatostatin analogs, and that if there is resistance to its action this may be overcome by combination with everolimus.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores
Everolimo/farmacologia
Regulação Neoplásica da Expressão Gênica
Pâncreas/efeitos dos fármacos
Inibidores de Proteínas Quinases/farmacologia
Tiazóis/farmacologia
[Mh] Termos MeSH secundário: Apoptose/efeitos dos fármacos
Caspase 3/genética
Caspase 3/metabolismo
Caspase 7/genética
Caspase 7/metabolismo
Ciclo Celular/efeitos dos fármacos
Linhagem Celular Tumoral
Cromogranina A/genética
Cromogranina A/metabolismo
Classe I de Fosfatidilinositol 3-Quinases/genética
Classe I de Fosfatidilinositol 3-Quinases/metabolismo
Relação Dose-Resposta a Droga
Sinergismo Farmacológico
Quinase 3 da Glicogênio Sintase/genética
Quinase 3 da Glicogênio Sintase/metabolismo
Seres Humanos
Pâncreas/metabolismo
Pâncreas/patologia
Proteínas Proto-Oncogênicas c-akt/genética
Proteínas Proto-Oncogênicas c-akt/metabolismo
Receptores de Somatostatina/genética
Receptores de Somatostatina/metabolismo
Transdução de Sinais
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Chromogranin A); 0 (NVP-BYL719); 0 (Protein Kinase Inhibitors); 0 (Receptors, Somatostatin); 0 (Thiazoles); 0 (somatostatin receptor 5); 0 (somatostatin receptor subtype 2, human); 0 (somatostatin receptor type 1); 9HW64Q8G6G (Everolimus); EC 2.7.1.137 (Class I Phosphatidylinositol 3-Kinases); EC 2.7.1.137 (PIK3CA protein, human); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt); EC 2.7.11.26 (Glycogen Synthase Kinase 3); EC 3.4.22.- (CASP3 protein, human); EC 3.4.22.- (CASP7 protein, human); EC 3.4.22.- (Caspase 3); EC 3.4.22.- (Caspase 7)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171004
[Lr] Data última revisão:
171004
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170812
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0182852



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