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[PMID]:28453705
[Au] Autor:Mato AR; Hill BT; Lamanna N; Barr PM; Ujjani CS; Brander DM; Howlett C; Skarbnik AP; Cheson BD; Zent CS; Pu JJ; Kiselev P; Foon K; Lenhart J; Henick Bachow S; Winter AM; Cruz AL; Claxton DF; Goy A; Daniel C; Isaac K; Kennard KH; Timlin C; Fanning M; Gashonia L; Yacur M; Svoboda J; Schuster SJ; Nabhan C
[Ad] Endereço:Center for CLL, Abramson Cancer Center, University of Pennsylvania, Philadelphia, USA.
[Ti] Título:Optimal sequencing of ibrutinib, idelalisib, and venetoclax in chronic lymphocytic leukemia: results from a multicenter study of 683 patients.
[So] Source:Ann Oncol;28(5):1050-1056, 2017 05 01.
[Is] ISSN:1569-8041
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Background: Ibrutinib, idelalisib, and venetoclax are approved for treating CLL patients in the United States. However, there is no guidance as to their optimal sequence. Patients and methods: We conducted a multicenter, retrospective analysis of CLL patients treated with kinase inhibitors (KIs) or venetoclax. We examined demographics, discontinuation reasons, overall response rates (ORR), survival, and post-KI salvage strategies. Primary endpoint was progression-free survival (PFS). Results: A total of 683 patients were identified. Baseline characteristics were similar in the ibrutinib and idelalisib groups. ORR to ibrutinib and idelalisib as first KI was 69% and 81%, respectively. With a median follow-up of 17 months (range 1-60), median PFS and OS for the entire cohort were 35 months and not reached. Patients treated with ibrutinib (versus idelalisib) as first KI had a significantly better PFS in all settings; front-line [hazard ratios (HR) 2.8, CI 1.3-6.3, P = 0.01], relapsed-refractory (HR 2.8, CI 1.9-4.1, P < 0.001), del17p (HR 2.0, CI 1.2-3.4, P = 0.008), and complex karyotype (HR 2.5, CI 1.2-5.2, P = 0.02). At the time of initial KI failure, use of an alternate KI or venetoclax had a superior PFS when compared with chemoimmunotherapy. Furthermore, patients who discontinued ibrutinib due to progression or toxicity had marginally improved outcomes if they received venetoclax (ORR 79%) versus idelalisib (ORR 46%) (PFS HR .6, CI.3-1.0, P = 0.06). Conclusions: In the largest real-world experience of novel agents in CLL, ibrutinib appears superior to idelalisib as first KI. Furthermore, in the setting of KI failure, alternate KI or venetoclax therapy appear superior to chemoimmunotherapy combinations. The use of venetoclax upon ibrutinib failure might be superior to idelalisib. These data support the need for trials testing sequencing strategies to optimize treatment algorithms.
[Mh] Termos MeSH primário: Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico
Leucemia Linfocítica Crônica de Células B/tratamento farmacológico
[Mh] Termos MeSH secundário: Adulto
Idoso
Idoso de 80 Anos ou mais
Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem
Intervalo Livre de Doença
Esquema de Medicação
Seres Humanos
Estimativa de Kaplan-Meier
Leucemia Linfocítica Crônica de Células B/mortalidade
Meia-Idade
Modelos de Riscos Proporcionais
Purinas/administração & dosagem
Pirazóis/administração & dosagem
Pirimidinas/administração & dosagem
Quinazolinonas/administração & dosagem
Estudos Retrospectivos
Sulfonamidas/administração & dosagem
Resultado do Tratamento
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE; MULTICENTER STUDY
[Nm] Nome de substância:
0 (Bridged Bicyclo Compounds, Heterocyclic); 0 (PCI 32765); 0 (Purines); 0 (Pyrazoles); 0 (Pyrimidines); 0 (Quinazolinones); 0 (Sulfonamides); N54AIC43PW (venetoclax); YG57I8T5M0 (idelalisib)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180308
[Lr] Data última revisão:
180308
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170429
[St] Status:MEDLINE
[do] DOI:10.1093/annonc/mdx031


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[PMID]:29289887
[Au] Autor:Moussa G; Alaaeddine R; Alaeddine LM; Nassra R; Belal ASF; Ismail A; El-Yazbi AF; Abdel-Ghany YS; Hazzaa A
[Ad] Endereço:Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt.
[Ti] Título:Novel click modifiable thioquinazolinones as anti-inflammatory agents: Design, synthesis, biological evaluation and docking study.
[So] Source:Eur J Med Chem;144:635-650, 2018 Jan 20.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:Click chemistry was used to synthesize a new series of thioquinazolinone molecules equipped with propargyl moiety,1,2,3-triazolyl and isoxazolyl rings. Our design was based on merging pharmacophores previously reported to exhibit COX-2 inhibitory activities to a thioquinazolinone-privileged scaffold. The synthesized compounds were subjected to in vitro cyclooxygenase COX-1/COX-2 and 15-LOX inhibition assays. Compounds 2c, 3b, 3h, 3j, and 3k showed COX-2 inhibition with IC (µM) 0.18, 0.19, 0.11, 0.16 and 0.17 respectively. These values were compared to celecoxib (IC 0.05 µM), diclofenac (IC 0.8 µM) and indomethacin (IC 0.49 µM) reference drugs. They also showed 15-LOX inhibition with IC (µM) 6.21, 4.33, 7.62, 5.21 and 3.98 respectively. These values were compared with Zileuton (IC 2.41 µM) and Meclofenamate sodium (IC 5.64 µM) as positive controls. These compounds were further challenged by PMA-induced THP-1 differentiation assay where compounds 2c and 3j inhibited monocyte to macrophage differentiation efficiently with IC values of 4.78 µM and 5.63 µM, respectively, compared to that of diclofenac sodium (4.86 µM). On the other hand, 3h demonstrated a significantly increased potency compared to diclofenac in this assay (IC = 0.13 µM). The same compounds exhibited significant in vivo anti-inflammatory effect as indicated by the formalin-induced rat-paw edema test. Docking experiments of compounds 2c, 3b, 3h, 3j, and 3k into COX-2 binding pocket have been conducted, where strong binding interactions have been identified and effective overall docking scores have been recorded. Their drug-likeness has been assessed using Molinspiration, Molsoft and Pre-ADMET software products.
[Mh] Termos MeSH primário: Anti-Inflamatórios não Esteroides/farmacologia
Inibidores de Ciclo-Oxigenase/farmacologia
Desenho de Drogas
Inibidores de Lipoxigenase/farmacologia
Quinazolinonas/farmacologia
Compostos de Sulfidrila/farmacologia
[Mh] Termos MeSH secundário: Animais
Anti-Inflamatórios não Esteroides/síntese química
Anti-Inflamatórios não Esteroides/química
Araquidonato 15-Lipoxigenase/metabolismo
Diferenciação Celular/efeitos dos fármacos
Química Click
Ciclo-Oxigenase 1/metabolismo
Ciclo-Oxigenase 2/metabolismo
Inibidores de Ciclo-Oxigenase/síntese química
Inibidores de Ciclo-Oxigenase/química
Relação Dose-Resposta a Droga
Feminino
Seres Humanos
Inibidores de Lipoxigenase/síntese química
Inibidores de Lipoxigenase/química
Macrófagos/efeitos dos fármacos
Simulação de Acoplamento Molecular
Estrutura Molecular
Quinazolinonas/síntese química
Quinazolinonas/química
Ratos
Ratos Wistar
Relação Estrutura-Atividade
Compostos de Sulfidrila/síntese química
Compostos de Sulfidrila/química
Células Tumorais Cultivadas
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anti-Inflammatory Agents, Non-Steroidal); 0 (Cyclooxygenase Inhibitors); 0 (Lipoxygenase Inhibitors); 0 (Quinazolinones); 0 (Sulfhydryl Compounds); EC 1.13.11.33 (Arachidonate 15-Lipoxygenase); EC 1.14.99.1 (Cyclooxygenase 1); EC 1.14.99.1 (Cyclooxygenase 2); EC 1.14.99.1 (PTGS1 protein, human); EC 1.14.99.1 (PTGS2 protein, human)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180302
[Lr] Data última revisão:
180302
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180101
[St] Status:MEDLINE


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[PMID]:29395086
[Au] Autor:Deng S; Ai Y; Gong H; Feng Q; Li X; Chen C; Liu Z; Wang Y; Peng Q; Zhang L
[Ad] Endereço:Department of Critical Care Medicine, Xiangya Hospital, Central South University, Changsha, 410008, PR China. Electronic address: dengsy2014@foxmail.com.
[Ti] Título:Mitochondrial dynamics and protective effects of a mitochondrial division inhibitor, Mdivi-1, in lipopolysaccharide-induced brain damage.
[So] Source:Biochem Biophys Res Commun;496(3):865-871, 2018 02 12.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Sepsis is one of the most common reasons for mortality in Intensive Care Units. As a common but severe neurological complication, sepsis associated encephalopathy (SAE) has always been ignored and there is no generally accepted treatment. In this study, we demonstrated that Mdivi-1 ameliorated brain damage assessed by Nissl staining. Furthermore, Mdivi-1 reduced TUNEL-positive cells in hippocampus, and inhibited S100 calcium binding protein B (S100B) and neuron-specific enolase (NSE) release into plasma. Biochemical analysis also showed that Mdivi-1 protected hippocampus from oxidative stresses. Western blot analysis revealed that Mdivi-1, as a Drp1 inhibitor, inhibited LPS induced dynamin-related GTPase (Drp1) increase. Interestingly, it can also attenuate LPS induced optic atrophy 1 (OPA1) and phosphorylated Drp1 (p-Drp1) decrease. Thus Mdivi-1 protected rats from SAE, and this protective effect could be associated with its inhibition of Drp1 and its activation of p-Drp1 and OPA1. Mitochondrial dynamics may be a potential pharmacological therapeutic target for treating SAE.
[Mh] Termos MeSH primário: Encéfalo/metabolismo
Encéfalo/patologia
Mitocôndrias/efeitos dos fármacos
Mitocôndrias/metabolismo
Quinazolinonas/administração & dosagem
Encefalopatia Associada a Sepse/tratamento farmacológico
Encefalopatia Associada a Sepse/patologia
[Mh] Termos MeSH secundário: Animais
Encéfalo/efeitos dos fármacos
Relação Dose-Resposta a Droga
Dinaminas/metabolismo
Lipopolissacarídeos
Masculino
Mitocôndrias/patologia
Fármacos Neuroprotetores/administração & dosagem
Ratos
Ratos Sprague-Dawley
Encefalopatia Associada a Sepse/metabolismo
Resultado do Tratamento
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (3-(2,4-dichloro-5-methoxyphenyl)-2-sulfanyl-4(3H)-quinazolinone); 0 (Lipopolysaccharides); 0 (Neuroprotective Agents); 0 (Quinazolinones); EC 3.6.5.5 (Drp1 protein, rat); EC 3.6.5.5 (Dynamins)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180222
[Lr] Data última revisão:
180222
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180204
[St] Status:MEDLINE


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[PMID]:29326040
[Au] Autor:Noh MR; Jang HS; Song DK; Lee SR; Lipschutz JH; Park KM; Kim JI
[Ad] Endereço:Department of Anatomy and BK21 Plus, Kyungpook National University School of Medicine, Daegu, Republic of Korea.
[Ti] Título:Downregulation of exocyst Sec10 accelerates kidney tubule cell recovery through enhanced cell migration.
[So] Source:Biochem Biophys Res Commun;496(2):309-315, 2018 02 05.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Migration of surviving kidney tubule cells after sub-lethal injury, for example ischemia/reperfusion (I/R), plays a critical role in recovery. Exocytosis is known to be involved in cell migration, and a key component in exocytosis is the highly-conserved eight-protein exocyst complex. We investigated the expression of a central exocyst complex member, Sec10, in kidneys following I/R injury, as well as the role of Sec10 in wound healing following scratch injury of cultured Madin-Darby canine kidney (MDCK) cells. Sec10 overexpression and knockdown (KD) in MDCK cells were used to investigate the speed of wound healing and the mechanisms underlying recovery. In mice, Sec10 decreased after I/R injury, and increased during the recovery period. In cell culture, Sec10 OE inhibited ruffle formation and wound healing, while Sec10 KD accelerated it. Sec10 OE cells had higher amounts of diacylglycerol kinase (DGK) gamma at the leading edge than did control cells. A DGK inhibitor reversed the inhibition of wound healing and ruffle formation in Sec10 OE cells. Conclusively, downregulation of Sec10 following I/R injury appears to accelerate recovery of kidney tubule cells through activated ruffle formation and enhanced cell migration.
[Mh] Termos MeSH primário: Diacilglicerol Quinase/antagonistas & inibidores
Túbulos Renais/metabolismo
Traumatismo por Reperfusão/prevenção & controle
Proteínas de Transporte Vesicular/genética
[Mh] Termos MeSH secundário: Animais
Bioensaio
Linhagem Celular
Movimento Celular/efeitos dos fármacos
Diacilglicerol Quinase/genética
Diacilglicerol Quinase/metabolismo
Cães
Inibidores Enzimáticos/farmacologia
Exocitose
Regulação da Expressão Gênica
Túbulos Renais/patologia
Células Madin Darby de Rim Canino
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Piperidinas/farmacologia
Quinazolinonas/farmacologia
RNA Interferente Pequeno/genética
RNA Interferente Pequeno/metabolismo
Traumatismo por Reperfusão/genética
Traumatismo por Reperfusão/metabolismo
Traumatismo por Reperfusão/patologia
Proteínas de Transporte Vesicular/agonistas
Proteínas de Transporte Vesicular/antagonistas & inibidores
Proteínas de Transporte Vesicular/metabolismo
Cicatrização/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (EXOC5 protein, mouse); 0 (Enzyme Inhibitors); 0 (Piperidines); 0 (Quinazolinones); 0 (RNA, Small Interfering); 0 (Vesicular Transport Proteins); 120166-69-0 (R 59949); EC 2.7.1.107 (Diacylglycerol Kinase)
[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:180113
[St] Status:MEDLINE


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[PMID]:28462807
[Au] Autor:Zhang Y; Zhang Z; Huang X; Kang S; Chen G; Wu M; Miao S; Huang Y; Zhao H; Zhang L
[Ad] Endereço:Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China; State Key Laboratory of Oncology in South China, Guangzhou, China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
[Ti] Título:Therapeutic Efficacy Comparison of 5 Major EGFR-TKIs in Advanced EGFR-positive Non-Small-cell Lung Cancer: A Network Meta-analysis Based on Head-to-Head Trials.
[So] Source:Clin Lung Cancer;18(5):e333-e340, 2017 Sep.
[Is] ISSN:1938-0690
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Five major first- and second-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), including erlotinib, gefitinib, icotinib, afatinib, and dacomitinib, are currently optional for patients with advanced non-small-cell lung cancer (NSCLC) who harbor EGFR mutations. However, there was no head-to-head-based network meta-analysis among all the TKIs in EGFR-mutated populations. METHODS: Eligible literature was searched from an electronic database. Data of objective response rate, disease control rate, progression-free survival, and overall survival were extracted from enrolled studies. Multiple treatment comparisons based on Bayesian network integrated the efficacy of all included treatments. RESULTS: Six phase III randomized trials involving 1055 EGFR-mutated patients with advanced NSCLC were enrolled. Multiple treatment comparisons showed that 5 different EGFR-TKIs shared equivalent therapeutic efficacy in terms of all outcome measures. Rank probabilities indicated that dacomitinib and afatinib had potentially better efficacy compared with erlotinib, gefitinib, and icotinib in the EGFR-mutated patients. When compared with other agents, potential survival benefits (progression-free and overall survival) were observed in dacomitinib, whereas afatinib showed a better rank probability in overall response rate and disease control rate. CONCLUSION: Our study indicated a preferable therapeutic efficacy in the second-generation TKIs (dacomitinib and afatinib) when compared with the first-generation TKIs (erlotinib, gefitinib, and icotinib).
[Mh] Termos MeSH primário: Antineoplásicos/uso terapêutico
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico
Neoplasias Pulmonares/tratamento farmacológico
Inibidores de Proteínas Quinases/uso terapêutico
Receptor do Fator de Crescimento Epidérmico/antagonistas & inibidores
[Mh] Termos MeSH secundário: Carcinoma Pulmonar de Células não Pequenas/metabolismo
Ensaios Clínicos Fase III como Assunto
Éteres de Coroa/uso terapêutico
Intervalo Livre de Doença
Cloridrato de Erlotinib/uso terapêutico
Seres Humanos
Neoplasias Pulmonares/metabolismo
Metanálise em Rede
Quinazolinas/uso terapêutico
Quinazolinonas/uso terapêutico
Ensaios Clínicos Controlados Aleatórios como Assunto
Taxa de Sobrevida
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE; META-ANALYSIS; REVIEW
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Crown Ethers); 0 (PF 00299804); 0 (Protein Kinase Inhibitors); 0 (Quinazolines); 0 (Quinazolinones); 41UD74L59M (afatinib); 9G6U5L461Q (icotinib); DA87705X9K (Erlotinib Hydrochloride); EC 2.7.10.1 (Receptor, Epidermal Growth Factor); S65743JHBS (gefitinib)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180213
[Lr] Data última revisão:
180213
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170503
[St] Status:MEDLINE


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[PMID]:28921512
[Au] Autor:Van Sebille YZA; Gibson RJ; Wardill HR; Ball IA; Keefe DMK; Bowen JM
[Ad] Endereço:Discipline of Physiology, Adelaide Medical School, University of Adelaide, Australia.
[Ti] Título:Dacomitinib-induced diarrhea: Targeting chloride secretion with crofelemer.
[So] Source:Int J Cancer;142(2):369-380, 2018 Jan 15.
[Is] ISSN:1097-0215
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Dacomitinib, an irreversible small-molecule pan-ErbB TKI, has a high incidence of diarrhea, which has been suggested to be due to chloride secretory mechanisms. Based on this hypothesis, crofelemer, an antisecretory agent may be an effective intervention. T84 monolayers were treated with 1 µM dacomitinib and 10 µM crofelemer, and mounted into Ussing chambers for electrogenic ion analysis. Crofelemer attenuated increases in chloride secretion in cells treated with dacomitinib. Albino Wistar rats (n = 48) were treated with 7.5 mg/kg dacomitinib and/or 25 mg/kg crofelemer via oral gavage for 21 days. Crofelemer significantly worsened dacomitinib-induced diarrhea (p = 0.0003), and did not attenuate weight loss (p < 0.0001). Sections of the ileum and colon were mounted into Ussing chambers, and secretory processes analyzed. This indicated that crofelemer lost its anti-secretory action in the presence of dacomitinib in this model. Mass spectrometry revealed that crofelemer did not change serum concentration of dacomitinib. Serum FITC dextran levels indicated that crofelemer was unable to attenuate dacomitinib-induced barrier dysfunction. Tight junction proteins were visualized with immunofluorescence. Qualitative analysis showed dacomitinib induced proteolysis of ZO-1 and occludin, and internalization of claudin-1, which was not attenuated by crofelemer. Detailed histopathological analysis showed that crofelemer was unable to attenuate dacomitinib-induced ileal damage. Crofelemer worsened dacomitinib-induced diarrhea, suggesting that antisecretory drug therapy may be ineffective in this setting.
[Mh] Termos MeSH primário: Cloretos/metabolismo
Diarreia/tratamento farmacológico
Proantocianidinas/farmacologia
Quinazolinonas/toxicidade
[Mh] Termos MeSH secundário: Animais
Permeabilidade da Membrana Celular/efeitos dos fármacos
Neoplasias Colorretais/tratamento farmacológico
Neoplasias Colorretais/metabolismo
Neoplasias Colorretais/patologia
Diarreia/induzido quimicamente
Diarreia/metabolismo
Eletrofisiologia
Trato Gastrointestinal/efeitos dos fármacos
Trato Gastrointestinal/metabolismo
Trato Gastrointestinal/patologia
Seres Humanos
Masculino
Ratos
Ratos Wistar
Células Tumorais Cultivadas
Perda de Peso/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Chlorides); 0 (PF 00299804); 0 (Proanthocyanidins); 0 (Quinazolinones); PY79D6C8RX (crofelemer)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171214
[Lr] Data última revisão:
171214
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170919
[St] Status:MEDLINE
[do] DOI:10.1002/ijc.31048


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[PMID]:29024815
[Au] Autor:Tang ZH; Cao WX; Guo X; Dai XY; Lu JH; Chen X; Zhu H; Lu JJ
[Ad] Endereço:State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China.
[Ti] Título:Identification of a novel autophagic inhibitor cepharanthine to enhance the anti-cancer property of dacomitinib in non-small cell lung cancer.
[So] Source:Cancer Lett;412:1-9, 2018 Jan 01.
[Is] ISSN:1872-7980
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:Inhibition of autophagy is a promising strategy for non-small cell lung cancer (NSCLC) treatment, which is in the clinical trials. However, only chloroquine is used in clinic as an autophagic inhibitor and the inhibitory effect of chloroquine on autophagy is finite. Therefore, the development of an alternative autophagic inhibitor for NSCLC therapy becomes necessary. In the present study, cepharanthine (CEP), an alkaloid extracted from Stephania cepharantha Hayata, was identified as a novel autophagic inhibitor in NSCLC cells. The potential mechanism of the CEP-inhibited autophagy was by blockage of autophagosome-lysosome fusion and inhibition of lysosomal cathepsin B and cathepsin D maturation. Furthermore, we found for the first time that dacomitinib (DAC), a second-generation epidermal growth factor receptor inhibitor that in the phase III clinical trials for NSCLC treatment, induced a protective autophagy to decrease its anti-cancer effect. Combined treatment with CEP increased the anti-proliferative and apoptotic effects of DAC in vitro and enhanced the anti-cancer effect of DAC in NCI-H1975 xenograft mice. Collectively, CEP might be further developed as an autophagic inhibitor, and combined treatment of CEP and DAC could offer an effective strategy for NSCLC treatment.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Autofagia/efeitos dos fármacos
Benzilisoquinolinas/farmacologia
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico
Neoplasias Pulmonares/tratamento farmacológico
Quinazolinonas/farmacologia
[Mh] Termos MeSH secundário: Animais
Carcinoma Pulmonar de Células não Pequenas/patologia
Catepsinas/metabolismo
Linhagem Celular Tumoral
Seres Humanos
Concentração de Íons de Hidrogênio
Neoplasias Pulmonares/patologia
Camundongos
Receptor do Fator de Crescimento Epidérmico/antagonistas & inibidores
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Benzylisoquinolines); 0 (PF 00299804); 0 (Quinazolinones); 7592YJ0J6T (cepharanthine); EC 2.7.10.1 (Receptor, Epidermal Growth Factor); EC 3.4.- (Cathepsins)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171205
[Lr] Data última revisão:
171205
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171013
[St] Status:MEDLINE


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[PMID]:28968439
[Au] Autor:Kim JH; Park SJ; Kim B; Choe YG; Lee DS
[Ad] Endereço:School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu, Republic of Korea.
[Ti] Título:Insulin-stimulated lipid accumulation is inhibited by ROS-scavenging chemicals, but not by the Drp1 inhibitor Mdivi-1.
[So] Source:PLoS One;12(10):e0185764, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Adipocyte differentiation is regulated by intracellular reactive oxygen species (ROS) generation and mitochondrial fission and fusion processes. However, the correlation between intracellular ROS generation and mitochondrial remodeling during adipocyte differentiation is still unknown. Here, we investigated the effect on adipocyte differentiation of 3T3-L1 cells of intracellular ROS inhibition using N-acetyl cysteine (Nac) and Mito-TEMPO and of mitochondrial fission inhibition using Mdivi-1. Differentiated 3T3-L1 adipocytes displayed an increase in mitochondrial fission, ROS generation, and the expression of adipogenic and mitochondrial dynamics-related proteins. ROS scavenger (Nac or Mito-TEMPO) treatment inhibited ROS production, lipid accumulation, the expression of adipogenic and mitochondrial dynamics-related proteins, and mitochondrial fission during adipogenesis of 3T3-L1 cells. On the other hand, treatment with the mitochondrial fission inhibitor Mdivi-1 inhibited mitochondrial fission but did not inhibit ROS production, lipid accumulation, or the expression of adipogenic and mitochondrial dynamics-related proteins, with the exception of phosphorylated Drp1 (Ser616), in differentiated 3T3-L1 adipocytes. The inhibition of mitochondrial fission did not affect adipocyte differentiation, while intracellular ROS production decreased in parallel with inhibition of adipocyte differentiation. Therefore, our results indicated that ROS are an essential regulator of adipocyte differentiation in 3T3-L1 cells.
[Mh] Termos MeSH primário: Dinaminas/antagonistas & inibidores
Radicais Livres/metabolismo
Insulina/farmacologia
Metabolismo dos Lipídeos
Quinazolinonas/farmacologia
Espécies Reativas de Oxigênio/metabolismo
[Mh] Termos MeSH secundário: Células 3T3-L1
Adipócitos/citologia
Adipócitos/metabolismo
Animais
Antioxidantes/metabolismo
Camundongos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (3-(2,4-dichloro-5-methoxyphenyl)-2-sulfanyl-4(3H)-quinazolinone); 0 (Antioxidants); 0 (Free Radicals); 0 (Insulin); 0 (Quinazolinones); 0 (Reactive Oxygen Species); EC 3.6.5.5 (Dnm1l protein, mouse); EC 3.6.5.5 (Dynamins)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171031
[Lr] Data última revisão:
171031
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171003
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0185764


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[PMID]:28948843
[Au] Autor:El-Azab AS; Abdel-Aziz AA; Ghabbour HA; Al-Gendy MA
[Ad] Endereço:a Department of Pharmaceutical Chemistry, College of Pharmacy , King Saud University , Riyadh , Saudi Arabia.
[Ti] Título:Synthesis, in vitro antitumour activity, and molecular docking study of novel 2-substituted mercapto-3-(3,4,5-trimethoxybenzyl)-4(3H)-quinazolinone analogues.
[So] Source:J Enzyme Inhib Med Chem;32(1):1229-1239, 2017 Dec.
[Is] ISSN:1475-6374
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:A novel series of 2-substituted mercapto-3-(3,4,5-trimethoxybenzyl)-4(3H)-quinazolinones 1-20 was synthesised and evaluated for in vitro antitumour activity. N-(4-Chlorophenyl)-2-[(3-(3,4,5-trimethoxybenzyl)-4(3H)-quinazolinon-2-yl)thio)acetamide (7) and N-(3,4,5 trimethoxybenzyl)-2-[(3-(3,4,5-trimethoxybenzyl)-4(3H)-quinazolinon-2-yl)thio]propanamide (19) exhibited excellent antitumour properties, with mean growth inhibitory concentration (GI ) of 17.90 and 6.33 µΜ, respectively, compared with those of 5-fluorouracil 5-FU, gefitinib, and erlotinib (mean GI : 18.60, 3.24, and 7.29 µΜ, respectively). Comparison of the GI (µM) values of compounds 7 and 19 versus those of 5-FU, gefitinib, and erlotinib against an in vitro subpanel of tumour cells lines showed that compounds 7 and 19 have activities almost equal to or higher than that of those standard drugs, especially against lung, CNS, and breast cancer cells. However, compounds 5, 10, 14, 15, 16, 17, and 20 exhibited effective antitumour activity against the different cell lines tested, with growth inhibition percentage (MGI%) of 19, 24, 19, 17, 16, 15, and 16, respectively. A modelling study was performed for compounds 7 and 19 by docking them into the EGFR kinase enzyme to study their mode of binding with the putative binding site.
[Mh] Termos MeSH primário: Acetamidas/síntese química
Amidas/síntese química
Simulação de Acoplamento Molecular
Quinazolinonas/síntese química
Quinazolinonas/farmacologia
Receptor do Fator de Crescimento Epidérmico/efeitos dos fármacos
[Mh] Termos MeSH secundário: Acetamidas/química
Acetamidas/farmacologia
Amidas/química
Amidas/farmacologia
Antineoplásicos/síntese química
Antineoplásicos/química
Antineoplásicos/farmacologia
Sítios de Ligação
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Ensaios de Seleção de Medicamentos Antitumorais
Seres Humanos
Modelos Moleculares
Estrutura Molecular
Ligação Proteica/efeitos dos fármacos
Quinazolinas/farmacologia
Quinazolinonas/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Acetamides); 0 (Amides); 0 (Antineoplastic Agents); 0 (N-(3,4,5 trimethoxybenzyl)-2-((3-(3,4,5-trimethoxybenzyl)-4(3H)-quinazolinon-2-yl)thio)propanamide); 0 (N-(4-chlorophenyl)-2-((3-(3,4,5-trimethoxybenzyl)-4(3H)-quinazolinon-2-yl)thio)acetamide); 0 (Quinazolines); 0 (Quinazolinones); 84JOT4EY5X (4-hydroxyquinazoline); EC 2.7.10.1 (EGFR protein, human); EC 2.7.10.1 (Receptor, Epidermal Growth Factor); S65743JHBS (gefitinib)
[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:170927
[St] Status:MEDLINE
[do] DOI:10.1080/14756366.2017.1368504


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[PMID]:28945111
[Au] Autor:Lampson BL; Brown JR
[Ad] Endereço:a Department of Medical Oncology , Dana-Farber Cancer Institute , Boston , MA , USA.
[Ti] Título:PI3Kδ-selective and PI3Kα/δ-combinatorial inhibitors in clinical development for B-cell non-Hodgkin lymphoma.
[So] Source:Expert Opin Investig Drugs;26(11):1267-1279, 2017 Nov.
[Is] ISSN:1744-7658
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:INTRODUCTION: The efficacy of the prototypical phosphatidylinositol-3-kinase (PI3K) inhibitor idelalisib for the treatment of chronic lymphocytic leukemia (CLL) and indolent non-Hodgkin lymphoma (iNHL) has led to development of multiple compounds targeting this pathway. Areas Covered: We review the hypothesized therapeutic mechanisms of PI3K inhibitors, including abrogation of B cell receptor signaling, blockade of microenvironmental pro-survival signals, and enhancement of anti-tumor immunity. We examine toxicities of idelalisib, including bacterial infections (possibly secondary to drug-induced neutropenia), opportunistic infections (possibly attributable to on-target inhibition of T cell function), and organ toxicities such as transaminitis and enterocolitis (possibly autoimmune, secondary to on-target inhibition of p110δ in regulatory T cells). We evaluate PI3K inhibitors that have entered trials for the treatment of lymphoma, focusing on agents with selectivity for PI3Kα and PI3Kδ. Expert Opinion: PI3K inhibitors, particularly those that target p110δ, have robust efficacy in the treatment of CLL and iNHL. However, idelalisib has infectious and autoimmune toxicities that limit its use. Outside of trials, idelalisib should be restricted to CLL patients with progression on ibrutinib or iNHL patients with progression on two prior therapies. Whether newer PI3K inhibitors will demonstrate differentiated toxicity profiles in comparable patient populations while retaining efficacy remains to be seen.
[Mh] Termos MeSH primário: Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores
Leucemia Linfocítica Crônica de Células B/tratamento farmacológico
Linfoma não Hodgkin/tratamento farmacológico
[Mh] Termos MeSH secundário: Animais
Antineoplásicos/administração & dosagem
Antineoplásicos/efeitos adversos
Antineoplásicos/farmacologia
Desenho de Drogas
Inibidores Enzimáticos/administração & dosagem
Inibidores Enzimáticos/efeitos adversos
Inibidores Enzimáticos/farmacologia
Seres Humanos
Leucemia Linfocítica Crônica de Células B/patologia
Linfoma não Hodgkin/patologia
Terapia de Alvo Molecular
Purinas/administração & dosagem
Purinas/efeitos adversos
Purinas/farmacologia
Quinazolinonas/administração & dosagem
Quinazolinonas/efeitos adversos
Quinazolinonas/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Enzyme Inhibitors); 0 (Purines); 0 (Quinazolinones); EC 2.7.1.137 (Class I Phosphatidylinositol 3-Kinases); EC 2.7.1.137 (PIK3CA protein, human); EC 2.7.1.137 (PIK3CD protein, human); YG57I8T5M0 (idelalisib)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171119
[Lr] Data última revisão:
171119
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170926
[St] Status:MEDLINE
[do] DOI:10.1080/13543784.2017.1384815



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