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[PMID]:29505507
[Au] Autor:Wang CG; Zeng DX; Huang JA; Jiang JH
[Ad] Endereço:Department of Respiratory and Critical Care, First Affiliated Hospital of Soochow University, Suzhou, P.R. China.
[Ti] Título:Effective assessment of low times MET amplification in pleural effusion after epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) acquired resistance: Cases report.
[So] Source:Medicine (Baltimore);97(1):e9021, 2018 Jan.
[Is] ISSN:1536-5964
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:RATIONALE: The mechanism of the first-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) acquired resistance included T790M mutation, cellular-mesenchymal to epithelial transition factor (MET) or EGFR amplification, PIK3CA mutation, and transformation to small cell lung cancer. MET amplification accounted for only about 5% of the resistance cases. PATIENTS CONCERNS: Few report detected MET amplification in pleural effusion. Here, we reported 2 lung adenocarcinoma cases with MET amplification in pleural effusion rapidly responded to crizotinib after EGFR-TKIs acquired resistance. DIAGNOSES: Biopsy via bronchoscopy, next-generation sequencing (NGS) in pleural effusion. INTERVENTIONS: EGFR-TKIs (Icotinib), MET inhibitor crizotinib. OUTCOMES: After a progression-free survival of 9 months and 23months, respectively, both cases progressed accompanying with pleural effusion. Results of NGS in pleural effusion showed MET amplification (2-3 times) in both cases. The 2 patients were treated with a MET inhibitor crizotinib and rapidly responded. CONCLUSION: MET amplification in pleural effusion could predict a perfect response to crizotinib after EGFR-TKIs acquired resistance, even only a low times gene amplification.
[Mh] Termos MeSH primário: Adenocarcinoma/genética
Resistência a Medicamentos Antineoplásicos/genética
Neoplasias Pulmonares/genética
Derrame Pleural Maligno/metabolismo
Proteínas Proto-Oncogênicas c-met/genética
[Mh] Termos MeSH secundário: Adenocarcinoma/tratamento farmacológico
Idoso
Feminino
Amplificação de Genes
Seres Humanos
Neoplasias Pulmonares/tratamento farmacológico
Masculino
Meia-Idade
Inibidores de Proteínas Quinases/uso terapêutico
Proteínas Proto-Oncogênicas c-met/metabolismo
Pirazóis/uso terapêutico
Piridinas/uso terapêutico
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Protein Kinase Inhibitors); 0 (Pyrazoles); 0 (Pyridines); 53AH36668S (crizotinib); EC 2.7.10.1 (MET protein, human); EC 2.7.10.1 (Proto-Oncogene Proteins c-met)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:180306
[St] Status:MEDLINE
[do] DOI:10.1097/MD.0000000000009021


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[PMID]:28456787
[Au] Autor:Hichert V; Scholl C; Steffens M; Paul T; Schumann C; Rüdiger S; Boeck S; Heinemann V; Kächele V; Seufferlein T; Stingl J
[Ad] Endereço:Research Division, Federal Institute for Drugs and Medical Devices, Bonn, Germany.
[Ti] Título:Predictive blood plasma biomarkers for EGFR inhibitor-induced skin rash.
[So] Source:Oncotarget;8(21):35193-35204, 2017 May 23.
[Is] ISSN:1949-2553
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Epidermal growth factor receptor overexpression in human cancer can be effectively targeted by drugs acting as specific inhibitors of the receptor, like erlotinib, gefitinib, cetuximab and panitumumab. A common adverse effect is a typical papulopustular acneiform rash, whose occurrence and severity are positively correlated with overall survival in several cancer types. We studied molecules involved in epidermal growth factor receptor signaling which are quantifiable in plasma, with the aim of identifying biomarkers for the severity of rash. With a predictive value for the rash these biomarkers may also have a prognostic value for survival and disease outcome.The concentrations of amphiregulin, hepatocyte growth factor (HGF) and calcidiol were determined by specific enzyme-linked immunosorbent assays in plasma samples from 211 patients.We observed a significant inverse correlation between the plasma concentration of HGF and overall survival in patients with an inhibitor-induced rash (p-value = 0.0075; mean overall survival low HGF: 299 days, high HGF: 240 days) but not in patients without rash. The concentration of HGF was also significantly inversely correlated with severity of rash (p-value = 0.00124).High levels of HGF lead to increased signaling via its receptor MET, which can activate numerous pathways which are normally also activated by epidermal growth factor receptor. Increased HGF/MET signaling might compensate the inhibitory effect of epidermal growth factor receptor inhibitors in skin as well as tumor cells, leading to less severe skin rash and decreased efficacy of the anti-tumor therapy, rendering the plasma concentration of HGF a candidate for predictive biomarkers.
[Mh] Termos MeSH primário: Exantema/induzido quimicamente
Fator de Crescimento de Hepatócito/sangue
Neoplasias/sangue
Neoplasias/tratamento farmacológico
Inibidores de Proteínas Quinases/administração & dosagem
Proteínas Proto-Oncogênicas c-met/sangue
[Mh] Termos MeSH secundário: Adulto
Idoso
Idoso de 80 Anos ou mais
Anfirregulina/sangue
Biomarcadores Tumorais/sangue
Calcifediol/sangue
Cetuximab/administração & dosagem
Cetuximab/efeitos adversos
Cloridrato de Erlotinib/administração & dosagem
Cloridrato de Erlotinib/efeitos adversos
Exantema/sangue
Feminino
Seres Humanos
Masculino
Meia-Idade
Neoplasias/genética
Neoplasias/metabolismo
Estudos Prospectivos
Inibidores de Proteínas Quinases/efeitos adversos
Quinazolinas/administração & dosagem
Quinazolinas/efeitos adversos
Receptor do Fator de Crescimento Epidérmico/antagonistas & inibidores
Receptor do Fator de Crescimento Epidérmico/genética
Transdução de Sinais/efeitos dos fármacos
Análise de Sobrevida
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (AREG protein, human); 0 (Amphiregulin); 0 (Biomarkers, Tumor); 0 (HGF protein, human); 0 (Protein Kinase Inhibitors); 0 (Quinazolines); 67256-21-7 (Hepatocyte Growth Factor); DA87705X9K (Erlotinib Hydrochloride); EC 2.7.10.1 (EGFR protein, human); EC 2.7.10.1 (MET protein, human); EC 2.7.10.1 (Proto-Oncogene Proteins c-met); EC 2.7.10.1 (Receptor, Epidermal Growth Factor); P6YZ13C99Q (Calcifediol); PQX0D8J21J (Cetuximab); S65743JHBS (gefitinib)
[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:170501
[St] Status:MEDLINE
[do] DOI:10.18632/oncotarget.17060


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[PMID]:28460431
[Au] Autor:Du J; Wu X; Tong X; Wang X; Wei J; Yang Y; Chang Z; Mao Y; Shao YW; Liu B
[Ad] Endereço:The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University, Clinical Cancer Institute of Nanjing University, Nanjing, Jiangsu, 210008, China.
[Ti] Título:Circulating tumor DNA profiling by next generation sequencing reveals heterogeneity of crizotinib resistance mechanisms in a gastric cancer patient with MET amplification.
[So] Source:Oncotarget;8(16):26281-26287, 2017 Apr 18.
[Is] ISSN:1949-2553
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Crizotinib has been used to counter MET gene amplification in a number of different human malignancies. Transient response to crizotinib in MET-amplified gastric cancer has been reported, but the mechanisms of resistance are not well studied. Here, we reported a stage IV gastric cancer patient with high levels of MET amplification. The implementation of crizotinib treatment led to significant symptomatic improvement in the first 2 months, but was followed by rapid disease progression. Periodic mutation profiling of patient's circulating tumor DNA (ctDNA) by next generation sequencing (NGS) revealed a number of genetic alterations including re-occurrence of MET amplification, multiple secondary MET mutations, a dramatic increase of FGFR2 gene relative copy number as well as mutations in other downstream and bypassing elements, which may collectively related to the patient's cancer progression. Our results illustrate the complex and heterogeneous molecular mechanisms for crizotinib resistance in this patient, and demonstrate the great potential of ctDNA profiling for treatment decision-making and prognosis in clinical practice.
[Mh] Termos MeSH primário: DNA Tumoral Circulante
Resistência a Medicamentos Antineoplásicos/genética
Amplificação de Genes
Proteínas Proto-Oncogênicas c-met/genética
Pirazóis/farmacologia
Piridinas/farmacologia
Neoplasias Gástricas/genética
[Mh] Termos MeSH secundário: Adulto
Linhagem Celular Tumoral
Feminino
Perfilação da Expressão Gênica
Sequenciamento de Nucleotídeos em Larga Escala
Seres Humanos
Modelos Biológicos
Modelos Moleculares
Mutação
Estadiamento de Neoplasias
Tomografia Computadorizada com Tomografia por Emissão de Pósitrons
Conformação Proteica
Inibidores de Proteínas Quinases/farmacologia
Inibidores de Proteínas Quinases/uso terapêutico
Proteínas Proto-Oncogênicas c-met/química
Pirazóis/uso terapêutico
Piridinas/uso terapêutico
Neoplasias Gástricas/diagnóstico
Neoplasias Gástricas/tratamento farmacológico
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Circulating Tumor DNA); 0 (Protein Kinase Inhibitors); 0 (Pyrazoles); 0 (Pyridines); 53AH36668S (crizotinib); EC 2.7.10.1 (Proto-Oncogene Proteins c-met)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180305
[Lr] Data última revisão:
180305
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170503
[St] Status:MEDLINE
[do] DOI:10.18632/oncotarget.15457


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[PMID]:27779203
[Au] Autor:Villalobos-Hernandez A; Bobbala D; Kandhi R; Khan MG; Mayhue M; Dubois CM; Ferbeyre G; Saucier C; Ramanathan S; Ilangumaran S
[Ad] Endereço:Immunology Division, Department of Pediatrics, Faculty of Medicine and Health Sciences, University of Sherbrooke, Sherbrooke, Quebec, Canada.
[Ti] Título:SOCS1 inhibits migration and invasion of prostate cancer cells, attenuates tumor growth and modulates the tumor stroma.
[So] Source:Prostate Cancer Prostatic Dis;20(1):36-47, 2017 Mar.
[Is] ISSN:1476-5608
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: The suppressor of cytokine signaling 1 (SOCS1) gene is repressed in prostate cancer (PCa) by epigenetic silencing and microRNA miR30d. Increased expression of the SOCS1-targeting miR30d correlates with higher biochemical recurrence, suggesting a tumor suppressor role of SOCS1 in PCa, but the underlying mechanisms are unclear. We have shown that SOCS1 inhibits MET receptor kinase signaling, a key oncogenic pathway in cancer progression. Here we evaluated the role of SOCS1 in attenuating MET signaling in PCa cells and tumor growth in vivo. METHODS: MET-overexpressing human DU145 and PC3 PCa cell lines were stably transduced with SOCS1, and their growth, migration and invasion of collagen matrix were evaluated in vitro. Cells expressing SOCS1 or the control vector were evaluated for tumor growth in NOD.scid.gamma mice as xenograft or orthotopic tumors. RESULTS: HGF-induced MET signaling was attenuated in SOCS1-expressing DU145 and PC3 cells. Compared with vector control cells, SOCS1-expressing cells showed reduced proliferation and impaired migration following HGF stimulation. DU145 and PC3 cells showed marked ability to invade the collagen matrix following HGF stimulation and this was attenuated by SOCS1. As xenografts, SOCS1-expressing PCa cells showed significantly reduced tumor growth compared with vector control cells. In the orthotopic tumor model, SOCS1 reduced the growth of primary tumors and metastatic spread. Intriguingly, the SOCS1-expressing DU145 and PC3 tumors showed increased collagen deposition, associated with increased frequency of myofibroblasts. CONCLUSIONS: Our findings support the tumor suppressor role of SOCS1 in PCa and suggest that attenuation of MET signaling is one of the underlying mechanisms. SOCS1 in PCa cells also appears to prevent the tumor-promoting functions of cancer-associated fibroblasts.
[Mh] Termos MeSH primário: Neoplasias da Próstata/metabolismo
Neoplasias da Próstata/patologia
Células Estromais/metabolismo
Proteína 1 Supressora da Sinalização de Citocina/metabolismo
[Mh] Termos MeSH secundário: Animais
Linhagem Celular Tumoral
Movimento Celular
Proliferação Celular
Transformação Celular Neoplásica/genética
Transformação Celular Neoplásica/metabolismo
Colágeno/metabolismo
Metilação de DNA
Modelos Animais de Doenças
Epigênese Genética
Expressão Gênica
Fator de Crescimento de Hepatócito/metabolismo
Xenoenxertos
Seres Humanos
Masculino
Camundongos
Invasividade Neoplásica
Metástase Neoplásica
Neoplasias da Próstata/genética
Proteínas Proto-Oncogênicas c-met/metabolismo
Transdução de Sinais
Células Estromais/patologia
Proteína 1 Supressora da Sinalização de Citocina/genética
Carga Tumoral
Microambiente Tumoral
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (HGF protein, human); 0 (SOCS1 protein, human); 0 (Suppressor of Cytokine Signaling 1 Protein); 67256-21-7 (Hepatocyte Growth Factor); 9007-34-5 (Collagen); EC 2.7.10.1 (Proto-Oncogene Proteins c-met)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180305
[Lr] Data última revisão:
180305
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161026
[St] Status:MEDLINE
[do] DOI:10.1038/pcan.2016.50


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[PMID]:29331754
[Au] Autor:Wang W; Xu S; Duan Y; Liu X; Li X; Wang C; Zhao B; Zheng P; Zhu W
[Ad] Endereço:Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, PR China.
[Ti] Título:Synthesis and bioevaluation and doking study of 1H-pyrrolo[2,3-b]pyridine derivatives bearing aromatic hydrazone moiety as c-Met inhibitors.
[So] Source:Eur J Med Chem;145:315-327, 2018 Feb 10.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:Two series of aromatic hydrazone derivatives bearing 1H-pyrrolo[2,3-b]pyridine moiety (7a-r, 8a-i, 12a-b, 13a-c, 16a-d and 17a-e) were designed, synthesized and evaluated for the IC values against four cancer cell lines (A549, HepG2, MCF-7and PC-3). Two selected compounds (7c and 17e) were further evaluated for the activity against c-Met, Flt-3, VEGFR-2 and EGFR kinases. The data indicated that targets compounds were selective for c-Met kinase. And the most promising compound 7c was further studied in terms of dose-dependent, time-dependent and cell apoptosis. Most of the compounds showed excellent cytotoxicity activity, especially the most promising compound 7c with the IC values of 0.82 ±â€¯0.08 µM, 1.00 ±â€¯0.11 µM, 0.93 ±â€¯0.28 µM and 0.92 ±â€¯0.17 µM against A549, HepG2, MCF-7 and PC-3 cell lines and 0.506 µM against c-Met kinase. Structure-activity relationships (SARs) and docking studies indicated that the activities of the phenyl hydrazone derivatives (7a-r and 8a-i) were superior to that of the heterocyclic hydrazone series (12a-b, 13a-c, 16a-d and 17a-e). What's more, the further studies indicated that the target compounds can induce apoptosis of A549 cells and arrest efficiently the cell cycle progression in G2/M phase of A549 cells.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Hidrazonas/farmacologia
Simulação de Acoplamento Molecular
Inibidores de Proteínas Quinases/farmacologia
Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores
Piridinas/farmacologia
Pirróis/farmacologia
[Mh] Termos MeSH secundário: Antineoplásicos/síntese química
Antineoplásicos/química
Apoptose/efeitos dos fármacos
Ciclo Celular/efeitos dos fármacos
Proliferação Celular/efeitos dos fármacos
Relação Dose-Resposta a Droga
Ensaios de Seleção de Medicamentos Antitumorais
Seres Humanos
Hidrazonas/química
Estrutura Molecular
Inibidores de Proteínas Quinases/síntese química
Inibidores de Proteínas Quinases/química
Proteínas Proto-Oncogênicas c-met/metabolismo
Piridinas/síntese química
Piridinas/química
Pirróis/síntese química
Pirróis/química
Relação Estrutura-Atividade
Fatores de Tempo
Células Tumorais Cultivadas
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Hydrazones); 0 (Protein Kinase Inhibitors); 0 (Pyridines); 0 (Pyrroles); EC 2.7.10.1 (Proto-Oncogene Proteins c-met); QX4465NR9T (pyrrolo(2, 3-b)pyridine)
[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:180115
[St] Status:MEDLINE


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[PMID]:28464908
[Au] Autor:Chia SK; Ellard SL; Mates M; Welch S; Mihalcioiu C; Miller WH; Gelmon K; Lohrisch C; Kumar V; Taylor S; Hagerman L; Goodwin R; Wang T; Sakashita S; Tsao MS; Eisenhauer E; Bradbury P
[Ad] Endereço:Medical Oncology, British Columbia Cancer Agency (BCCA), Vancouver, BC, Canada. schia@bccancer.bc.ca.
[Ti] Título:A phase-I study of lapatinib in combination with foretinib, a c-MET, AXL and vascular endothelial growth factor receptor inhibitor, in human epidermal growth factor receptor 2 (HER-2)-positive metastatic breast cancer.
[So] Source:Breast Cancer Res;19(1):54, 2017 May 02.
[Is] ISSN:1465-542X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: The mechanisms of resistance to anti-human epidermal growth factor receptor 2 (HER 2) therapies are unclear but may include the tyrosine-protein kinase Met (c-Met), vascular endothelial growth factor (VEGF) and AXL pathways. Foretinib is an inhibitor of c-Met, VEGF receptor 2 (VEGFR-2), platelet-derived growth factor receptor beta (PDGFRB), AXL, Fms-like tyrosine kinase 3 (FLT3), angiopoiten receptor (TIE-2), RET and RON kinases. This phase Ib study sought to establish the associated toxicities, pharmacokinetics (PK) and recommended phase II doses (RP2D) of foretinib and lapatinib in a cohort of HER-2-positive patients with metastatic breast cancer (MBC). METHODS: Women with HER-2 positive MBC, Performance status (PS 0-2), and no limit on number of prior chemotherapies or lines of anti-HER-2 therapies were enrolled. A 3 + 3 dose escalation design was utilized. Four dose levels were intended with starting doses of foretinib 30 mg and lapatinib 750 mg orally once a day (OD) on a 4-weekly cycle. Assessment of c-MET status from the primary archival tissue was performed. RESULTS: We enrolled 19 patients, all evaluable for toxicity assessment and for response evaluation. Median age was 60 years (34-86 years), 95% were PS 0-1, 53% were estrogen receptor-positive and 95% had at least one prior anti-HER-2-based regimen. The fourth dose level was reached (foretinib 45 mg/lapatinib 1250 mg) with dose-limiting toxicities of grade-3 diarrhea and fatigue. There was only one grade-4 non-hematological toxicity across all dose levels. There were no PK interactions between the agents. A median of two cycles was delivered across the dose levels (range 1-20) with associated progression-free survival of 3.2 months (95% CI 1.61-4.34 months). By immunohistochemical assessment with a specified cutoff, none of the 17 samples tested were classified as positive for c-Met. CONCLUSIONS: The RP2D of the combined foretinib and lapatinib is 45 mg and 1000 mg PO OD, respectively. Limited activity was seen with this combination in a predominantly unselected cohort of HER-2-positive patients with MBC.
[Mh] Termos MeSH primário: Anilidas/administração & dosagem
Neoplasias da Mama/tratamento farmacológico
Inibidores de Proteínas Quinases/administração & dosagem
Quinazolinas/administração & dosagem
Quinolinas/administração & dosagem
[Mh] Termos MeSH secundário: Adulto
Idoso
Idoso de 80 Anos ou mais
Protocolos de Quimioterapia Combinada Antineoplásica
Neoplasias da Mama/genética
Neoplasias da Mama/patologia
Intervalo Livre de Doença
Feminino
Seres Humanos
Meia-Idade
Metástase Neoplásica
Proteínas Proto-Oncogênicas/antagonistas & inibidores
Proteínas Proto-Oncogênicas/genética
Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores
Proteínas Proto-Oncogênicas c-met/genética
Receptores Proteína Tirosina Quinases/antagonistas & inibidores
Receptores Proteína Tirosina Quinases/genética
Receptor ErbB-2/genética
Receptor 1 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores
Receptor 1 de Fatores de Crescimento do Endotélio Vascular/genética
[Pt] Tipo de publicação:CLINICAL TRIAL, PHASE I; CLINICAL TRIAL, PHASE II; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anilides); 0 (GSK 1363089); 0 (Protein Kinase Inhibitors); 0 (Proto-Oncogene Proteins); 0 (Quinazolines); 0 (Quinolines); 0VUA21238F (lapatinib); EC 2.7.10.1 (ERBB2 protein, human); EC 2.7.10.1 (MET protein, human); EC 2.7.10.1 (Proto-Oncogene Proteins c-met); EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases); EC 2.7.10.1 (Receptor, ErbB-2); EC 2.7.10.1 (Vascular Endothelial Growth Factor Receptor-1); EC 2.7.10.1 (axl receptor tyrosine kinase)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180301
[Lr] Data última revisão:
180301
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170504
[St] Status:MEDLINE
[do] DOI:10.1186/s13058-017-0836-3


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[PMID]:29254294
[Au] Autor:Bednarczyk M; Muc-Wierzgon M; Waniczek D; Fatyga E; Klakla K; Mazurek U; Wierzgon J
[Ad] Endereço:School of Pharmacy with the Division of Laboratory Medicine in Sosnowiec, Medical University of Silesia, Department of Molecular Biology, Sosnowiec, Poland.
[Ti] Título:Autophagy-related gene expression in colorectal cancer patients.
[So] Source:J Biol Regul Homeost Agents;31(4):923-927, 2017 Oct-Dec.
[Is] ISSN:0393-974X
[Cp] País de publicação:Italy
[La] Idioma:eng
[Ab] Resumo:There is evidence that autophagy can play a dual role in tumor cells – as a tumor suppressor, and a process involved in tumor cell survival. The aim of this work was to assess the expression of the genes engaged in the autophagy process in biopsies taken from the colon, confirmed as adenocarcinoma, and normal tissue and to relate them to the clinical stage of the tumor. A total of 20 pairs of surgically removed tumors and healthy (marginal) tissue samples from colorectal cancer patients at clinical stages (CS) I-IV were analyzed. Gene expression profile analysis was performed using HG-U133A microarrays. Differentially expressed genes were identified, using the PL-Grid Infrastructure. Only for CSI, there were two specific genes: FOXO1 and BNIP1; further in CSII – LAMP2, MET and BCL2L, in CSIII – HIF1A and 2 ID mRNAs for HGF and 18 genes were specific for CSIV in comparison to controls. PINK1 is the only gene that differentiates all transcriptome groups from controls. Furthermore, examination of the expression of genes associated with the autophagy process may allow for better knowledge and understanding of the processes occurring during the development of colon cancer. The presented genes may be used as prognostic markers of clinical stages of colorectal cancer, contributing to the development of new lines of therapy focused on reducing metastasis of the primary tumor.
[Mh] Termos MeSH primário: Adenocarcinoma/genética
Autofagia/genética
Colo/metabolismo
Neoplasias Colorretais/genética
Regulação Neoplásica da Expressão Gênica
Transcriptoma
[Mh] Termos MeSH secundário: Adenocarcinoma/metabolismo
Adenocarcinoma/patologia
Adulto
Idoso
Idoso de 80 Anos ou mais
Colo/patologia
Neoplasias Colorretais/metabolismo
Neoplasias Colorretais/patologia
Feminino
Proteína Forkhead Box O1/genética
Proteína Forkhead Box O1/metabolismo
Perfilação da Expressão Gênica
Seres Humanos
Subunidade alfa do Fator 1 Induzível por Hipóxia/genética
Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo
Proteína 2 de Membrana Associada ao Lisossomo/genética
Proteína 2 de Membrana Associada ao Lisossomo/metabolismo
Masculino
Meia-Idade
Estadiamento de Neoplasias
Análise de Sequência com Séries de Oligonucleotídeos
Proteínas Quinases/genética
Proteínas Quinases/metabolismo
Proteínas Proto-Oncogênicas c-bcl-2/genética
Proteínas Proto-Oncogênicas c-bcl-2/metabolismo
Proteínas Proto-Oncogênicas c-met/genética
Proteínas Proto-Oncogênicas c-met/metabolismo
Proteína bcl-X/genética
Proteína bcl-X/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (BCL2L1 protein, human); 0 (BNIP1 protein, human); 0 (FOXO1 protein, human); 0 (Forkhead Box Protein O1); 0 (HIF1A protein, human); 0 (Hypoxia-Inducible Factor 1, alpha Subunit); 0 (LAMP2 protein, human); 0 (Lysosomal-Associated Membrane Protein 2); 0 (Proto-Oncogene Proteins c-bcl-2); 0 (bcl-X Protein); EC 2.7.- (Protein Kinases); EC 2.7.10.1 (MET protein, human); EC 2.7.10.1 (Proto-Oncogene Proteins c-met); EC 2.7.11.1 (PTEN-induced putative kinase)
[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:171220
[St] Status:MEDLINE


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[PMID]:29199218
[Au] Autor:Mohareb RM; Abbas NS; Ibrahim RA
[Ad] Endereço:Department of Chemistry, Faculty of Science, Cairo University.
[Ti] Título:Uses of Cyclohexan-1,4-dione for the Synthesis of 2-Amino-4,5-dihydrobenzo[b]thiophen-6(7H)-one Derivatives with Anti-proliferative and Pim-1 Kinase Activities.
[So] Source:Chem Pharm Bull (Tokyo);65(12):1117-1131, 2017.
[Is] ISSN:1347-5223
[Cp] País de publicação:Japan
[La] Idioma:eng
[Ab] Resumo:The reaction of cyclohexan-1,4-dione with elemental sulfur and any of the 2-cyano-N-arylacetamide derivatives 2a-c gave the 2-amino-4,5-dihydrobenzo[b]thiophen-6(7H)-one derivatives 3a-c to be used in some heterocyclization reactions. The multicomponent reactions of any of compounds 3a-c with aromatic aldehydes 6a-c and either of malononitrile or ethylcyanoacetate gave the 5,9-dihydro-4H-thieno[2,3-f]chromene derivatives 9a-r, respectively. The anti-proliferative evaluation of the newly synthesized compounds against the six cancer cell lines A549, HT-29, MKN-45, U87MG, SMMC-7721 and H460 showed that the nine compounds 3c, 5c, 9e, 9h, 9i, 9j, 9l, 9q, 11e and 13e with highest cytotoxcity. Toxicity of these compounds against shrimp larvae revealed that compounds 3c, 9j, 9q, and 13e showed no toxicity against the tested organisms. The c-Met kinase inhibition of the most potent compounds showed that compounds 9j, 9q, 10e, 12e and 13e have the highest activities. Compounds 9j, 9l, 9q and 11e showed high activity towards tyrosine kinases. Moreover, compounds 9j, 9q and 13e showed the highest inhibitor activity towards Pim-1 kinase.
[Mh] Termos MeSH primário: Cicloexanonas/química
Inibidores de Proteínas Quinases/síntese química
Proteínas Proto-Oncogênicas c-pim-1/antagonistas & inibidores
Tiofenos/química
[Mh] Termos MeSH secundário: Células A549
Animais
Antineoplásicos/síntese química
Antineoplásicos/química
Antineoplásicos/farmacologia
Artemia/efeitos dos fármacos
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Ensaios de Seleção de Medicamentos Antitumorais
Células HT29
Seres Humanos
Inibidores de Proteínas Quinases/química
Inibidores de Proteínas Quinases/farmacologia
Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores
Proteínas Proto-Oncogênicas c-met/metabolismo
Proteínas Proto-Oncogênicas c-pim-1/metabolismo
Relação Estrutura-Atividade
Tiofenos/síntese química
Tiofenos/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Cyclohexanones); 0 (Protein Kinase Inhibitors); 0 (Thiophenes); 073790YQ2G (benzothiophene); EC 2.7.10.1 (Proto-Oncogene Proteins c-met); EC 2.7.11.1 (Proto-Oncogene Proteins c-pim-1)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180110
[Lr] Data última revisão:
180110
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171205
[St] Status:MEDLINE
[do] DOI:10.1248/cpb.c17-00582


  9 / 4463 MEDLINE  
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[PMID]:29203143
[Au] Autor:Wang L; Xu S; Chen X; Liu X; Duan Y; Kong D; Zhao D; Zheng P; Tang Q; Zhu W
[Ad] Endereço:Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, PR China.
[Ti] Título:Synthesis and bioevaluation study of novel N-methylpicolinamide and thienopyrimidine derivatives as selectivity c-Met kinase inhibitors.
[So] Source:Bioorg Med Chem;26(1):245-256, 2018 01 01.
[Is] ISSN:1464-3391
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Four series of N-methylpicolinamide moiety and thienopyrimidine moiety bearing pyridazinone were designed and synthesized and evaluated for the IC values against three cancer cell lines (A549, HepG2 and MCF-7) and some selected compounds were further evaluated for the activity against c-Met, Flt-3, VEGFR-2, c-Kit and EGFR kinases. Three compounds (35, 39 and 43) showed more active than positive control Foretinib against A549, HepG2 and MCF-7 cell lines. The most promising compound 43 showed superior activity against A549, HepG2 and MCF-7, with the IC values of 0.58 ±â€¯0.15 µM, 0.47 ±â€¯0.06 µM and 0.74 ±â€¯0.12 µM, which were 3.73-5.39-fold more activity than Foretinib, respectively. The experiments of enzyme-based showed that 43 restrain the c-Met selectively, with the IC values of 16 nM, which showed equal activity to Foretinib (14 nM) and better than the compound 5 (90 nM). Moreover, AO and Annexin V/PI staining and docking studies were carried out.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Ácidos Picolínicos/farmacologia
Inibidores de Proteínas Quinases/farmacologia
Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores
Pirimidinas/farmacologia
[Mh] Termos MeSH secundário: Amidas/síntese química
Amidas/química
Amidas/farmacologia
Antineoplásicos/síntese química
Antineoplásicos/química
Apoptose/efeitos dos fármacos
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Relação Dose-Resposta a Droga
Ensaios de Seleção de Medicamentos Antitumorais
Seres Humanos
Simulação de Acoplamento Molecular
Estrutura Molecular
Ácidos Picolínicos/síntese química
Ácidos Picolínicos/química
Inibidores de Proteínas Quinases/síntese química
Inibidores de Proteínas Quinases/química
Proteínas Proto-Oncogênicas c-met/metabolismo
Pirimidinas/síntese química
Pirimidinas/química
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Amides); 0 (Antineoplastic Agents); 0 (Picolinic Acids); 0 (Protein Kinase Inhibitors); 0 (Pyrimidines); 0 (thienopyrimidine); EC 2.7.10.1 (Proto-Oncogene Proteins c-met); I3550CCL59 (picolinamide)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180106
[Lr] Data última revisão:
180106
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171206
[St] Status:MEDLINE


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[PMID]:29202410
[Au] Autor:Yuan H; Liu Q; Zhang L; Hu S; Chen T; Li H; Chen Y; Xu Y; Lu T
[Ad] Endereço:Laboratory of Molecular Design and Drug Discovery, School of Science, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China; State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, Institute of Pharmaceutical Research, China Pharma
[Ti] Título:Discovery, optimization and biological evaluation for novel c-Met kinase inhibitors.
[So] Source:Eur J Med Chem;143:491-502, 2018 Jan 01.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:The c-Met kinase has emerged as an attractive target for developing antitumor agents because of its close relationship with the development of many human cancers, poor clinical outcomes and even drug resistance. A series of novel c-Met kinase inhibitors have been identified with multiple workflow in this work, including virtual screening, X-ray crystallography, biological evaluation and structural optimization. The experimentally determined crystal structure of the best hit compound HL-11 in c-Met kinase domain was highly consistent with the computational prediction. Comparison of the hit compounds with different c-Met kinase inhibitory activity by molecular dynamics simulations suggested the key protein-ligand interactions for structural optimization. Based on these, structural optimization produced compound 11e with better c-Met kinase inhibitory activity and improved anti-proliferative activity. These experimental findings proved the reliability and efficiency of our in silico methods. This strategy will facilitate further lead discovery and optimization for novel c-Met kinase inhibitors.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Descoberta de Drogas
Inibidores de Proteínas Quinases/farmacologia
Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores
[Mh] Termos MeSH secundário: Antineoplásicos/síntese química
Antineoplásicos/química
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Cristalografia por Raios X
Relação Dose-Resposta a Droga
Ensaios de Seleção de Medicamentos Antitumorais
Seres Humanos
Modelos Moleculares
Estrutura Molecular
Inibidores de Proteínas Quinases/química
Proteínas Proto-Oncogênicas c-met/metabolismo
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Protein Kinase Inhibitors); EC 2.7.10.1 (MET protein, human); EC 2.7.10.1 (Proto-Oncogene Proteins c-met)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180101
[Lr] Data última revisão:
180101
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171205
[St] Status:MEDLINE



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