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Pesquisa : D03.383.621.808 [Categoria DeCS]
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[PMID]:29351887
[Au] Autor:Jin R; Chen Q; Yao S; Bai E; Fu W; Wang L; Wang J; Du X; Wei T; Xu H; Jiang C; Qiu P; Wu J; Li W; Liang G
[Ad] Endereço:Department of Digestive Diseases, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China; Chemical Biology Research Center, College of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
[Ti] Título:Synthesis and anti-tumor activity of EF24 analogues as IKKß inhibitors.
[So] Source:Eur J Med Chem;144:218-228, 2018 Jan 20.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:EF24 is an IKKß inhibitor (IC : 72 µM) containing various anti-tumor activities. In this study, a series of EF24 analogs targeting IKKß were designed and synthesized. Several IKKß inhibitors with better activities than EF24 were screened out and B3 showed best IKKß inhibitory (IC : 6.6 µM). Molecular docking and dynamic simulation experiments further confirmed this inhibitory effect. B3 obviously suppressed the viability of Hela229, A549, SGC-7901 and MGC-803 cells. Then, in SGC-7901 and MGC-803 cells, B3 blocked the NF-κB signal pathway by inhibiting IKKß phosphorylation, and followed arrested the cell cycle at G2/M phase by suppressing the Cyclin B1 and Cdc2 p34 expression, induced the cell apoptosis by down-regulating Bcl-2 protein and up-regulating cleaved-caspase3. Moreover, B3 significantly reduced tumor growth and suppressed the IKKß-NF-κB signal pathway in SGC-7901 xenograft model. In total, this study present a potential IKKß inhibitor as anti-tumor precursor.
[Mh] Termos MeSH primário: Antineoplásicos/química
Antineoplásicos/farmacologia
Compostos de Benzilideno/química
Compostos de Benzilideno/farmacologia
Quinase I-kappa B/antagonistas & inibidores
Piperidonas/química
Piperidonas/farmacologia
[Mh] Termos MeSH secundário: Animais
Antineoplásicos/síntese química
Antineoplásicos/uso terapêutico
Apoptose/efeitos dos fármacos
Compostos de Benzilideno/síntese química
Compostos de Benzilideno/uso terapêutico
Linhagem Celular Tumoral
Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos
Seres Humanos
Quinase I-kappa B/metabolismo
Camundongos Nus
Simulação de Acoplamento Molecular
NF-kappa B/metabolismo
Neoplasias/tratamento farmacológico
Neoplasias/metabolismo
Neoplasias/patologia
Fosforilação/efeitos dos fármacos
Piperidonas/síntese química
Piperidonas/uso terapêutico
Transdução de Sinais/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (3,5-bis(2-fluorobenzylidene)piperidin-4-one); 0 (Antineoplastic Agents); 0 (Benzylidene Compounds); 0 (NF-kappa B); 0 (Piperidones); EC 2.7.11.10 (I-kappa B Kinase)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180121
[St] Status:MEDLINE


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[PMID]:29192703
[Au] Autor:Osorio-Nieto U; Vázquez-Amaya LY; Höpfl H; Quintero L; Sartillo-Piscil F
[Ad] Endereço:Centro de Investigación de la Facultad de Ciencias Químicas, Benemérita Universidad Autónoma de Puebla (BUAP), 14 Sur Esq. San Claudio, Col. San Manuel, 72570, Puebla, México. fernando.sartillo@correo.buap.mx.
[Ti] Título:The direct and highly diastereoselective synthesis of 3,4-epoxy-2-piperidones. Application to the total synthesis and absolute configurational assignment of 3α,4α-epoxy-5ß-pipermethystine.
[So] Source:Org Biomol Chem;16(1):77-88, 2017 Dec 19.
[Is] ISSN:1477-0539
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The substrate-controlled asymmetric total synthesis and absolute configurational assignment of biologically active 3α,4α-epoxy-5ß-pipermethystine, a minor component in the aerial parts of kava, has been achieved by featuring, as a key step, the environmentally friendly and direct synthesis of 2,3-epoxyamides from allyl amines. By using the chiron approach, first a carbohydrate-derived dehydropiperidine was prepared and subjected to a stereoselective tandem C-H/C[double bond, length as m-dash]C oxidation reaction. In this attempt, the required α,α-trans-epoxy-2-piperidone skeleton of the kava metabolite precursor was not achieved, although the tandem oxidation was highly stereoselective. However, starting from non-carbohydrate 3-hydroxy-4,5-dehydropiperidine, and using the same tandem oxidation, the target intermediate was obtained in high yield and complete unprecedented anti-stereoselectivity. Since the proposed mechanistic course of this tandem oxidation implies the transient formation of an α,ß-unsaturated amide followed by the subsequent epoxidation reaction, this second approach supports the previously established biotransformation proposal of (-)-pipermethystine to (-)-3α,4α-epoxy-5ß-pipermethystine.
[Mh] Termos MeSH primário: Piperidonas/síntese química
Piridonas/síntese química
[Mh] Termos MeSH secundário: Estrutura Molecular
Piperidonas/química
Piridonas/química
Estereoisomerismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Piperidones); 0 (Pyridones); 71627-22-0 (pipermethystine)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180223
[Lr] Data última revisão:
180223
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171202
[St] Status:MEDLINE
[do] DOI:10.1039/c7ob02700a


  3 / 917 MEDLINE  
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[PMID]:28982855
[Au] Autor:Bakalova R; Zhelev Z; Shibata S; Nikolova B; Aoki I; Higashi T
[Ad] Endereço:Department of Molecular Imaging and Theranostics, National Institute of Radiological Sciences (NIRS), National Institute for Quantum and Radiological Science and Technology (QST), Chiba, Japan bakalova.rumiana@qst.go.jp.
[Ti] Título:Impressive Suppression of Colon Cancer Growth by Triple Combination SN38/EF24/Melatonin: "Oncogenic" "Onco-Suppressive" Reactive Oxygen Species.
[So] Source:Anticancer Res;37(10):5449-5458, 2017 10.
[Is] ISSN:1791-7530
[Cp] País de publicação:Greece
[La] Idioma:eng
[Ab] Resumo:BACKGROUND/AIM: The study aimed to investigate the effect of multi-targeted combinations (SN38/EF24; SN38/EF24/melatonin) on the growth of colon cancer in experimental animals and their impact on the ratio "oncogenic"/"onco-suppressive" reactive oxygen species (ROS) - a crucial factor for triggering carcinogenesis, as well as for development of effective therapeutic strategies. MATERIALS AND METHODS: The experiments were conducted on colon cancer-grafted mice - non-treated, SN38/EF24-treated and SN38/EF24/melatonin-treated within 22 days. The balance between different types of ROS was measured in vivo by nitroxide-enhanced magnetic resonance imaging (MRI), as well as on isolated tissue specimens by conventional analytical tests. RESULTS: Both combinations significantly suppressed the tumor growth. Impressive anticancer effect was observed in SN38/EF24/melatonin-treated mice - almost complete destruction of the tumor. Both types of ROS (superoxide and hydroperoxides) were elevated in cancer, but the MRI data suggest that the ratio between them tends towards superoxide. SN38/EF24 decreased the level of superoxide, but did not affect the level of hydroperoxides in the cancerous tissue, while SN38/EF24/melatonin decreased the level of superoxide below the control and increased significantly the level of hydroperoxides. CONCLUSION: The most important observations are that: (i) colon cancer was characterized by a vicious cycle, that ensures a permanent domination of "oncogenic" ROS (as superoxide) over "onco-suppressive" ROS (as hydrogen peroxide); (ii) the anticancer effect of the triple combination EF24/SN38/melatonin was accompanied by decreasing "oncogenic" and increasing "onco-suppressive" ROS; (iii) the ratio between both types of ROS could be a new onco-target for combined therapy; and (iv) nitroxide-enhanced MRI is a valuable tool for analyzing of this ratio.
[Mh] Termos MeSH primário: Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia
Compostos de Benzilideno/farmacologia
Camptotecina/análogos & derivados
Proliferação Celular/efeitos dos fármacos
Neoplasias Colorretais/tratamento farmacológico
Melatonina/farmacologia
Oncogenes
Estresse Oxidativo/efeitos dos fármacos
Piperidonas/farmacologia
Espécies Reativas de Oxigênio/metabolismo
[Mh] Termos MeSH secundário: Animais
Camptotecina/farmacologia
Linhagem Celular Tumoral
Neoplasias Colorretais/genética
Neoplasias Colorretais/metabolismo
Neoplasias Colorretais/patologia
Peróxido de Hidrogênio/metabolismo
Imagem por Ressonância Magnética
Masculino
Camundongos Endogâmicos BALB C
Camundongos Nus
Transdução de Sinais/efeitos dos fármacos
Superóxidos/metabolismo
Fatores de Tempo
Carga Tumoral/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (3,5-bis(2-fluorobenzylidene)piperidin-4-one); 0 (Benzylidene Compounds); 0 (Piperidones); 0 (Reactive Oxygen Species); 11062-77-4 (Superoxides); 7673326042 (irinotecan); BBX060AN9V (Hydrogen Peroxide); JL5DK93RCL (Melatonin); XT3Z54Z28A (Camptothecin)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171007
[St] Status:MEDLINE


  4 / 917 MEDLINE  
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[PMID]:28982310
[Au] Autor:Kim SH; Kang JG; Kim CS; Ihm SH; Choi MG; Yoo HJ; Lee SJ
[Ad] Endereço:Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon, Republic of Korea.
[Ti] Título:The dipeptidyl peptidase-IV inhibitor gemigliptin alone or in combination with NVP-AUY922 has a cytotoxic activity in thyroid carcinoma cells.
[So] Source:Tumour Biol;39(10):1010428317722068, 2017 Oct.
[Is] ISSN:1423-0380
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The effect of the dipeptidyl peptidase-IV inhibitor gemigliptin alone or in combination with the heat shock protein 90 inhibitor NVP-AUY922 (AUY922) on survival of thyroid carcinoma cells was elucidated. The SW1736 and TPC-1 human thyroid carcinoma cells were used. Cell viability, the percentage of viable cells, cytotoxic activity, the percentage of apoptotic cells, and mitochondrial membrane potential were measured. To evaluate the combined effect of gemigliptin with AUY922, the interactions were estimated by calculating combination index. Gemigliptin led to cell death in conjunction with overexpression of the phosphorylated protein levels of Akt, extracellular signal-regulated kinase 1/2, and adenosine monophosphate-activated protein kinase. In gemigliptin-treated cells, wortmannin augmented cell death, whereas AZD6244 and compound C did not affect cell survival. Wortmannin decreased phosphorylated adenosine monophosphate-activated protein kinase protein levels, and AZD6244 increased phosphorylated Akt protein levels. Meanwhile, cotreatment of both gemigliptin and AUY922, compared with treatment of AUY922 alone, potentiated cell death. All the combination index values were lower than 1.0, suggesting synergistic cytotoxicity of gemigliptin with AUY922. In treatment of both gemigliptin and AUY922, compared with AUY922 alone, the protein levels of total and phosphorylated Akt, phosphorylated extracellular signal-regulated kinase 1/2, and phosphorylated adenosine monophosphate-activated protein kinase increased without alteration in those of total extracellular signal-regulated kinase 1/2 and total adenosine monophosphate-activated protein kinase. The percentage of apoptotic cells increased. The protein levels of Bax and cleaved poly (ADP-ribose) polymerase increased, whereas Bcl2 protein levels were unchanged, resulting in increment of Bax/Bcl2 ratio. Transfection of Bax small interfering RNA did not cause any variation in cell viability, the percentage of viable cells and cytotoxic activity. Our results demonstrate that gemigliptin exerts a cytotoxic activity with concomitant alterations in expression of Akt, extracellular signal-regulated kinase 1/2, and adenosine monophosphate-activated protein kinase in thyroid carcinoma cells. Furthermore, gemigliptin synergizes with AUY922 in induction of cytotoxicity via regulation of Akt, extracellular signal-regulated kinase 1/2, and adenosine monophosphate-activated protein kinase as well as involvement of Bcl2 family proteins in thyroid carcinoma cells.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Carcinoma/patologia
Isoxazóis/farmacologia
Piperidonas/farmacologia
Pirimidinas/farmacologia
Resorcinóis/farmacologia
Neoplasias da Glândula Tireoide/patologia
[Mh] Termos MeSH secundário: Apoptose/efeitos dos fármacos
Western Blotting
Linhagem Celular Tumoral
Sobrevivência Celular/efeitos dos fármacos
Inibidores da Dipeptidil Peptidase IV/farmacologia
Sinergismo Farmacológico
Citometria de Fluxo
Seres Humanos
Transdução de Sinais/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide); 0 (Antineoplastic Agents); 0 (Dipeptidyl-Peptidase IV Inhibitors); 0 (Isoxazoles); 0 (LC15-0444); 0 (Piperidones); 0 (Pyrimidines); 0 (Resorcinols)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171017
[Lr] Data última revisão:
171017
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171007
[St] Status:MEDLINE
[do] DOI:10.1177/1010428317722068


  5 / 917 MEDLINE  
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[PMID]:28716495
[Au] Autor:Addala E; Rafiei H; Das S; Bandy B; Das U; Karki SS; Dimmock JR
[Ad] Endereço:Drug Discovery and Development Research Group, College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon S7N 5E5, Canada.
[Ti] Título:3,5-Bis(3-dimethylaminomethyl-4-hydroxybenzylidene)-4-piperidone and related compounds induce glutathione oxidation and mitochondria-mediated cell death in HCT-116 colon cancer cells.
[So] Source:Bioorg Med Chem Lett;27(16):3669-3673, 2017 08 15.
[Is] ISSN:1464-3405
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:This study aims at investigating the cytotoxicity and some of the modes of action of 3,5-bis(3-dimethylamino-4-hydroxybenzylidene)-4-piperidone trihydrochloride 3 and two related compounds 2 (which lacks the dimethylaminomethyl groups) and 4 (which has an additional dimethylaminoethyl substituent in both aryl rings) in order to ascertain the contribution of dimethylaminoethyl substituent to bioactivity. The bioactivities of 2-4 were compared with curcumin 5. Both 2 and 3 displayed submicromolar GI values towards HCT-116 cells and were significantly more potent than 4, 5 and 5-fluorouracil (5-FU). All of the compounds displayed greater toxicity towards HCT-116 cells than human CRL-1790 non-malignant colon cells. In HCT-116 cells, the compounds 2, 3 and 5 increased the ratio of oxidised to reduced glutathione and destabilized the mitochondrial membrane potential. Both 2 and 5 produced an increase in mitochondrial superoxide and a burst in intracellular reactive oxygen species in HCT 116 cells. In addition, 2 and 4 stimulated respiration in rat liver mitochondria while 2 and 5 induced mitochondrial swelling. The results suggest that 2 and 5 cause oxidation or cross-linking of the thiols which control the mitochondrial permeability transition.
[Mh] Termos MeSH primário: Apoptose/efeitos dos fármacos
Glutationa/química
Mitocôndrias/metabolismo
Piperidonas/química
Piperidonas/farmacologia
[Mh] Termos MeSH secundário: Linhagem Celular
Neoplasias do Colo/metabolismo
Neoplasias do Colo/patologia
Curcumina/farmacologia
Glutationa/metabolismo
Células HCT116
Seres Humanos
Potencial da Membrana Mitocondrial/efeitos dos fármacos
Mitocôndrias/efeitos dos fármacos
Oxirredução/efeitos dos fármacos
Piperidonas/síntese química
Espécies Reativas de Oxigênio/metabolismo
Superóxidos/metabolismo
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Piperidones); 0 (Reactive Oxygen Species); 11062-77-4 (Superoxides); GAN16C9B8O (Glutathione); IT942ZTH98 (Curcumin)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171125
[Lr] Data última revisão:
171125
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170719
[St] Status:MEDLINE


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[PMID]:28686724
[Au] Autor:Choi SY; Ryu HM; Oh EJ; Choi JY; Cho JH; Kim CD; Kim YL; Park SH
[Ad] Endereço:Division of Nephrology and Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, Korea.
[Ti] Título:Dipeptidyl peptidase-4 inhibitor gemigliptin protects against vascular calcification in an experimental chronic kidney disease and vascular smooth muscle cells.
[So] Source:PLoS One;12(7):e0180393, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Although dipeptidyl peptidase-4 inhibitors, a class of antidiabetic drugs, have various pleiotropic effects, it remains undetermined whether gemigliptin has a beneficial effect on vascular calcification. Therefore, this study was performed to evaluate the effect of gemigliptin on vascular calcification in a rat model of adenine-induced chronic kidney disease and in cultured vascular smooth muscle cells. Gemigliptin attenuated calcification of abdominal aorta and expression of RUNX2 in adenine-induced chronic kidney disease rats. In cultured vascular smooth muscle cells, phosphate-induced increase in calcium content was reduced by gemigliptin. Gemigliptin reduced phosphate-induced PiT-1 mRNA expression, reactive oxygen species generation, and NADPH oxidase mRNA expression (p22phox and NOX4). The reduction of oxidative stress by gemigliptin was associated with the downregulation of phospho-PI3K/AKT expression. High phosphate increased the expression of frizzled-3 (FDZ3) and decreased the expression of dickkopf-related protein-1 (DKK-1) in the Wnt pathway. These changes were attenuated by gemigliptin treatment. Gemigliptin restored the decreased expression of vascular smooth muscle cells markers (α-SMA and SM22α) and increased expression of osteogenic makers (CBFA1, OSX, E11, and SOST) induced by phosphate. In conclusion, gemigliptin attenuated vascular calcification and osteogenic trans-differentiation in vascular smooth muscle cells via multiple steps including downregulation of PiT-1 expression and suppression of reactive oxygen species generation, phospho-PI3K/AKT, and the Wnt signaling pathway.
[Mh] Termos MeSH primário: Inibidores da Dipeptidil Peptidase IV/farmacologia
Miócitos de Músculo Liso/efeitos dos fármacos
Piperidonas/farmacologia
Pirimidinas/farmacologia
Insuficiência Renal Crônica/genética
Fator de Transcrição Pit-1/genética
Calcificação Vascular/prevenção & controle
[Mh] Termos MeSH secundário: Adenina
Animais
Aorta Abdominal/efeitos dos fármacos
Aorta Abdominal/metabolismo
Aorta Abdominal/patologia
Cálcio/metabolismo
Subunidade alfa 1 de Fator de Ligação ao Core/genética
Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo
Receptores Frizzled/genética
Receptores Frizzled/metabolismo
Regulação da Expressão Gênica
Peptídeos e Proteínas de Sinalização Intercelular/genética
Peptídeos e Proteínas de Sinalização Intercelular/metabolismo
Masculino
Músculo Liso Vascular/efeitos dos fármacos
Músculo Liso Vascular/metabolismo
Músculo Liso Vascular/patologia
Miócitos de Músculo Liso/metabolismo
Miócitos de Músculo Liso/patologia
NADPH Oxidase 4
NADPH Oxidases/genética
NADPH Oxidases/metabolismo
Fosfatos/antagonistas & inibidores
Fosfatos/farmacologia
Fosfatidilinositol 3-Quinases/genética
Fosfatidilinositol 3-Quinases/metabolismo
Cultura Primária de Células
Proteínas Proto-Oncogênicas c-akt/genética
Proteínas Proto-Oncogênicas c-akt/metabolismo
Ratos
Ratos Sprague-Dawley
Espécies Reativas de Oxigênio/antagonistas & inibidores
Espécies Reativas de Oxigênio/metabolismo
Insuficiência Renal Crônica/induzido quimicamente
Insuficiência Renal Crônica/metabolismo
Insuficiência Renal Crônica/patologia
Fator de Transcrição Pit-1/antagonistas & inibidores
Fator de Transcrição Pit-1/metabolismo
Calcificação Vascular/genética
Calcificação Vascular/metabolismo
Calcificação Vascular/patologia
Via de Sinalização Wnt
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Core Binding Factor Alpha 1 Subunit); 0 (Dipeptidyl-Peptidase IV Inhibitors); 0 (Frizzled Receptors); 0 (Intercellular Signaling Peptides and Proteins); 0 (LC15-0444); 0 (Phosphates); 0 (Piperidones); 0 (Pyrimidines); 0 (Reactive Oxygen Species); 0 (Runx2 protein, rat); 0 (Transcription Factor Pit-1); 0 (dickkopf-1 protein, rat); EC 1.6.3.- (NADPH Oxidase 4); EC 1.6.3.- (NADPH Oxidases); EC 1.6.3.- (Nox4 protein, rat); EC 1.6.3.1 (p22-phox protein, rat); EC 2.7.1.- (Phosphatidylinositol 3-Kinases); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt); JAC85A2161 (Adenine); SY7Q814VUP (Calcium)
[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:170708
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0180393


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[PMID]:28646535
[Au] Autor:Bixel K; Saini U; Kumar Bid H; Fowler J; Riley M; Wanner R; Deepa Priya Dorayappan K; Rajendran S; Konishi I; Matsumura N; Cohn DE; Selvendiran K
[Ad] Endereço:Division of Gynecologic Oncology, Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH.
[Ti] Título:Targeting STAT3 by HO3867 induces apoptosis in ovarian clear cell carcinoma.
[So] Source:Int J Cancer;141(9):1856-1866, 2017 Nov 01.
[Is] ISSN:1097-0215
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Advanced ovarian clear cell carcinoma (OCCC) carries a very poor prognosis in large part secondary to the extremely high rate of resistance to standard platinum and taxane chemotherapy. Signal transducer and activator of transcription 3(STAT3) expression and activation has been shown to regulate tumor progression in various human cancers, though has not been well studied in OCCC. Preliminary work in our lab has demonstrated constitutive activation of STAT3 (pSTAT3Tyr705 or pSTAT3727) in OCCC cell lines as well as human OCCC tumor tissue samples. Significantly, pSTAT3 is expressed in the absence of other forms of activated STAT (pSTAT1, 2, 6). Therefore, this work was planned to investigate the role of STAT3 and examine the efficacy of a novel anti-cancer compound -HO-3867, which is an inhibitor of STAT3, using known OCCC cell lines. Results demonstrate that treatment with HO-3867 decreased expression of pSTAT3 Tyr705 as well pSTAT3 Ser727, while total STAT3 remained constant. STAT3 overexpression increased the migration capability in OVTOKO cells in vitro and led to an increased tumor size when injected in vivo. The inhibitory effect of HO-3867 on cell proliferation and cell survival was accompanied by increased apoptosis, within 24 h post treatment. Treatment with HO-3867 resulted in a decrease in Bcl-2 and increase of cleavage of caspase 3, caspase 7, and PARP, confirming induction of apoptosis after treatment with HO-3867. In addition, HO-3867 significantly inhibited formation of human umbilical vein endothelial cells capillary-like structures and invasion at both 5 and 10 µM concentrations. STAT3 expression plays an important role in the spread of OCCC in vitro as well as in vivo. Thus, we can exploit the STAT3 pathway for targeted drug therapy. Inhibition of pSTAT3 using HO-3867in OCCC cell lines appears to be a promising therapy. This is of utmost importance given the poor response of OCCC to standard chemotherapy regimens.
[Mh] Termos MeSH primário: Adenocarcinoma de Células Claras/tratamento farmacológico
Neoplasias Ovarianas/tratamento farmacológico
Piperidonas/administração & dosagem
Fator de Transcrição STAT3/genética
[Mh] Termos MeSH secundário: Adenocarcinoma de Células Claras/genética
Adenocarcinoma de Células Claras/patologia
Animais
Apoptose/efeitos dos fármacos
Linhagem Celular Tumoral
Movimento Celular/efeitos dos fármacos
Proliferação Celular/efeitos dos fármacos
Resistência a Medicamentos Antineoplásicos/genética
Feminino
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos
Seres Humanos
Camundongos
Neoplasias Ovarianas/genética
Neoplasias Ovarianas/patologia
Transdução de Sinais/efeitos dos fármacos
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 ((3,5-bis((4-fluorophenyl)methylidene)-1-((1-hydroxy-2,2,5,5-tetramethyl-2,5-dihydro-1H-pyrrol-3-yl)methyl)piperidin-4-one)); 0 (Piperidones); 0 (STAT3 Transcription Factor); 0 (STAT3 protein, human)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171009
[Lr] Data última revisão:
171009
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170625
[St] Status:MEDLINE
[do] DOI:10.1002/ijc.30847


  8 / 917 MEDLINE  
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[PMID]:28637181
[Au] Autor:Zhang Z; Nikolai BC; Gates LA; Jung SY; Siwak EB; He B; Rice AP; O'Malley BW; Feng Q
[Ad] Endereço:Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
[Ti] Título:Crosstalk between histone modifications indicates that inhibition of arginine methyltransferase CARM1 activity reverses HIV latency.
[So] Source:Nucleic Acids Res;45(16):9348-9360, 2017 Sep 19.
[Is] ISSN:1362-4962
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:In eukaryotic cells, the gene expression status is strictly controlled by epigenetic modifications on chromatin. The repressive status of chromatin largely contributes to HIV latency. Studies have shown that modification of histone H3K27 acts as a key molecular switch for activation or suppression of many cellular genes. In this study, we found that K27-acetylated histone H3 specifically recruited Super Elongation Complex (SEC), the transcriptional elongation complex essential for HIV-1 long terminal repeat (LTR)-mediated and general cellular transcription. Interestingly, H3K27 acetylation further stimulates H3R26 methylation, which subsequently abrogates the recruitment of SEC, forming a negative feedback regulatory loop. Importantly, by inhibiting methyltransferase activity of CARM1, the enzyme responsible for H3R26 methylation, HIV-1 transcription is reactivated in several HIV latency cell models, including a primary resting CD4+ T cell model. When combined with other latency disrupting compounds such as JQ1 or vorinostat/SAHA, the CARM1 inhibitor achieved synergistic effects on HIV-1 activation. This study suggests that coordinated and dynamic modifications at histone H3K27 and H3R26 orchestrate HIV-1 LTR-mediated transcription, and potentially opens a new avenue to disrupt latent HIV-1 infection by targeting specific epigenetic enzymes.
[Mh] Termos MeSH primário: Regulação Viral da Expressão Gênica
HIV-1/genética
Código das Histonas
Histonas/metabolismo
Proteína-Arginina N-Metiltransferases/antagonistas & inibidores
Latência Viral/genética
[Mh] Termos MeSH secundário: Acetilação
Compostos de Benzilideno/química
Compostos de Benzilideno/farmacologia
Linhagem Celular
Inibidores Enzimáticos/química
Inibidores Enzimáticos/farmacologia
Repetição Terminal Longa de HIV
HIV-1/efeitos dos fármacos
HIV-1/metabolismo
HIV-1/fisiologia
Seres Humanos
Metilação
Piperidonas/química
Piperidonas/farmacologia
Elongação da Transcrição Genética
Fatores de Transcrição/metabolismo
Latência Viral/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (1-benzyl-3,5-bis-(3-bromo-4-hydroxybenzylidene)piperidin-4-one); 0 (Benzylidene Compounds); 0 (Enzyme Inhibitors); 0 (Histones); 0 (Piperidones); 0 (Transcription Factors); EC 2.1.1.319 (Protein-Arginine N-Methyltransferases); EC 2.1.1.319 (coactivator-associated arginine methyltransferase 1)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171024
[Lr] Data última revisão:
171024
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170623
[St] Status:MEDLINE
[do] DOI:10.1093/nar/gkx550


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[PMID]:28601309
[Au] Autor:Megna BW; Carney PR; Depke MG; Nukaya M; McNally J; Larsen L; Rosengren RJ; Kennedy GD
[Ad] Endereço:Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
[Ti] Título:The aryl hydrocarbon receptor as an antitumor target of synthetic curcuminoids in colorectal cancer.
[So] Source:J Surg Res;213:16-24, 2017 Jun 01.
[Is] ISSN:1095-8673
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Curcumin has proven to be a potent antitumor agent in both preclinical and clinical models of colorectal cancer (CRC). It has also been identified as a ligand of the transcription factor known as the aryl hydrocarbon receptor (AHR). Our laboratory has identified the AHR as a mechanism which contributes to both tumorigenesis in a mouse model of inflammatory CRC as well an apoptotic target in vitro. Curcumin's role as an AHR ligand may modulate its effects to induce colon cancer cell death, and this role may be enhanced via structural modification of the curcumin backbone. We sought to determine if the two piperidone analogs of curcumin, RL66 and RL118, exhibit more robust antitumor actions than their parent compound in the context of colorectal cancer in vitro. Moreover, to ascertain the ability of curcumin, RL66 and RL118 to activate the AHR and evaluate if this activation has any effect on CRC cell death. MATERIALS AND METHODS: DLD1, HCT116, LS513, and RKO colon cell lines were propagated in vitro. Natural curcumin was obtained commercially, whereas RL66 and RL118 were synthesized and characterized de novo. Multiwell fluorescent/luminescent signal detection was used to simultaneously ascertain cell viability, cell cytonecrosis, and relative amounts of apoptotic activity. AHR activity was measured with a dual luciferase reporter gene system. Stable expression of small interfering RNA interference was established in the HCT116 cell lines to create AHR "knock down" cell lines. RESULTS: Both RL66 and RL118 proved to be more potent antitumor agents than their parent compound curcumin in all cell lines tested. The majority of this cell death was due to induction of apoptosis, which occurred earlier and to a greater degree following RL66 and RL118 treatment as opposed to curcumin. Also, RL66 and RL118 were found to be activators of AHR, and a portion of their ability to cause cell death was dependent on this induction. Curcumin was found unable to activate the AHR, and levels of AHR messenger RNA did not change their effects on cell death. CONCLUSIONS: Piperidone analogs of curcumin exhibited enhanced antitumor effects in vitro as opposed to their parent compound. Even more, this enhanced cell death profile may be partially attributed to the ability of these compounds to activate the AHR. Further study of synthetic curcumin analogs as chemopreventives and chemoadjuncts in CRC is warranted. Also, more generally, the AHR may represent a potential putative target for novel anticancer agents for CRC.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo
Biomarcadores Tumorais/metabolismo
Neoplasias Colorretais/tratamento farmacológico
Curcumina/farmacologia
Piperidonas/farmacologia
Piridinas/farmacologia
Receptores de Hidrocarboneto Arílico/metabolismo
[Mh] Termos MeSH secundário: Antineoplásicos/metabolismo
Antineoplásicos/uso terapêutico
Apoptose/efeitos dos fármacos
Apoptose/fisiologia
Sobrevivência Celular/efeitos dos fármacos
Sobrevivência Celular/fisiologia
Neoplasias Colorretais/metabolismo
Curcumina/metabolismo
Curcumina/uso terapêutico
Células HCT116
Seres Humanos
Piperidonas/metabolismo
Piperidonas/uso terapêutico
Piridinas/metabolismo
Piridinas/uso terapêutico
[Pt] Tipo de publicação:EVALUATION STUDIES; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (1-isopropyl-3,5-bis((pyridine-3-yl)methylene)piperidine-4-one); 0 (1-methyl-3,5-bis((4-pyridyl)methylidene)-4-piperidone); 0 (AHR protein, human); 0 (Antineoplastic Agents); 0 (Basic Helix-Loop-Helix Transcription Factors); 0 (Biomarkers, Tumor); 0 (Piperidones); 0 (Pyridines); 0 (Receptors, Aryl Hydrocarbon); IT942ZTH98 (Curcumin)
[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:170612
[St] Status:MEDLINE


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[PMID]:28556437
[Au] Autor:Zhang HL; Wu XY; Mi J; Peng YJ; Wang ZG; Liu Y; Wu XL; Gao Y
[Ad] Endereço:School of Pharmacy, Xi'an Jiaotong University, Xi'an, 710061, P. R. China.
[Ti] Título:A New Anti-Inflammatory Alkaloid from Roots of Heracleum dissectum.
[So] Source:Chem Biodivers;14(9), 2017 Sep.
[Is] ISSN:1612-1880
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:Using various chromatographic methods, a new piperidinone alkaloid, (3S)-3-{4-[(1E)-3-hydroxyprop-1-en-1-yl]-2-methoxyphenoxy}piperidin-2-one (1), together with 10 known compounds, bergapten (2), xanthotoxol (3), isopimpinellin (4), isobergapten (5), heratomol-6-O-ß-d-glucopyranoside (6), scopoletin (7), apterin (8), 3-methoxy-4-ß-d-glucopyranosyloxypropiophenone, (praeroside; 9), tachioside (10) and coniferin (11), were isolated from roots of Heracleum dissectum Ledeb. Their structures were elucidated on the basis of physicochemical properties and the detailed interpretation of various spectroscopic data. All the isolated compounds were screened for anti-inflammatory activity in vitro. As the results, compound 1 and 8 showed significantly inhibitory activity on nitric oxide production in RAW264.7 cells.
[Mh] Termos MeSH primário: Alcaloides/química
Anti-Inflamatórios/química
Heracleum/química
Piperidonas/química
Raízes de Plantas/química
[Mh] Termos MeSH secundário: Alcaloides/isolamento & purificação
Alcaloides/farmacologia
Animais
Anti-Inflamatórios/isolamento & purificação
Anti-Inflamatórios/farmacologia
Macrófagos/efeitos dos fármacos
Macrófagos/imunologia
Camundongos
Modelos Moleculares
Óxido Nítrico/imunologia
Piperidonas/isolamento & purificação
Piperidonas/farmacologia
Extratos Vegetais/química
Células RAW 264.7
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Alkaloids); 0 (Anti-Inflammatory Agents); 0 (Piperidones); 0 (Plant Extracts); 31C4KY9ESH (Nitric Oxide); WLN0GQQ6EK (2-piperidone)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171006
[Lr] Data última revisão:
171006
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170531
[St] Status:MEDLINE
[do] DOI:10.1002/cbdv.201700184



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