Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.997
Filtrar
1.
Life Sci ; 256: 117897, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32502543

RESUMO

Glioma is the most common brain malignancy and surgical resection is the primary option for patient with glioma. Anesthetics could be used to inhibit cancer dissemination and metastasis during surgery. This study aims to assess the function of volatile anesthetic sevoflurane in glioma migration and invasion and explore the potential mechanism. Twenty-five patients with glioma were recruited in this study. LN229 and U251 cells were used in vitro experiments. Cell viability was analyzed by MTT analysis. Cell migration and invasion were examined via transwell analysis. microRNA-34a-5p (miR-34a-5p) and matrix metalloproteinase-2 (MMP-2) levels were measured via quantitative real-time polymerase chain reaction. The relationship of miR-34a-5p and MMP-2 was tested via bioinformatics analysis, luciferase reporter analysis, RNA immunoprecipitation and RNA pull-down. Sevoflurane decreased glioma cell migration and invasion. In glioma cells, sevoflurane up-regulated miR-34a-5p abundance and down-regulated MMP-2 level. Overexpression of miR-34a-5p contributed to sevoflurane-caused suppression of migration and invasion, while its knockdown played an opposite effect. MMP-2 was targeted via miR-34a-5p and MMP-2 silence reversed the influence of miR-34a-5p knockdown under sevoflurane. Sevoflurane exposure represses cell migration and invasion, which might be related to inhibition of MMP-2 by up-regulating miR-34a-5p. This study provides a novel mechanism for understanding the pharmacological effects of sevoflurane on glioma.


Assuntos
Neoplasias Encefálicas/patologia , Movimento Celular/efeitos dos fármacos , Glioma/patologia , Metaloproteinase 2 da Matriz/metabolismo , MicroRNAs/metabolismo , Sevoflurano/farmacologia , Sequência de Bases , Neoplasias Encefálicas/enzimologia , Neoplasias Encefálicas/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Inativação Gênica/efeitos dos fármacos , Glioma/enzimologia , Glioma/genética , Humanos , MicroRNAs/genética , Invasividade Neoplásica , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Regulação para Cima/efeitos dos fármacos
2.
Brain Tumor Pathol ; 37(2): 69-75, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32297014

RESUMO

Dysembryoplastic neuroepithelial tumors (DNTs) are regarded as benign glioneuronal neoplasms because of their excellent outcomes; however, rare DNTs show malignant transformation. We herein described a case of DNT showing malignant transformation. The patient had intractable epilepsy caused by a tumor at 1 year of age and partial resection was performed. After surgery, the residual tumor showed regrowth and surgery was performed again at 4 years of age. The resected tumor showed the typical histological features of DNT, such as specific glioneuronal elements and alveolar structures. Tumor regrowth was detected again at 6 years of age, and the patient underwent gross total resection. Histologically, the tumor was composed of a high-grade glial component mixed with atypical neuronal cells, and the diagnosis of an anaplastic glioneuronal tumor was made. Genetically, DNT and the anaplastic glioneuronal tumor both shared a copy number gain of the tyrosine kinase domain of fibroblast growth factor receptor 1 (FGFR1), as demonstrated by multiplex ligation-dependent probe amplification (MLPA), corresponding to internal tandem duplication (ITD). A frequent FGFR1-ITD in DNT was previously reported. To the best of our knowledge, an identical mutation between primary and transformed DNT has not yet been demonstrated by MLPA.


Assuntos
Neoplasias Encefálicas/enzimologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Transformação Celular Neoplásica , Dosagem de Genes , Neoplasias Neuroepiteliomatosas/genética , Neoplasias Neuroepiteliomatosas/patologia , Proteínas Tirosina Quinases/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Pré-Escolar , Feminino , Humanos , Neoplasias Neuroepiteliomatosas/enzimologia
3.
Adv Exp Med Biol ; 1221: 365-403, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32274718

RESUMO

Brain tumors are aggressive and devastating diseases. The most common type of brain tumor, glioblastoma (GBM), is incurable and has one of the worst five-year survival rates of all human cancers. GBMs are invasive and infiltrate healthy brain tissue, which is one main reason they remain fatal despite resection, since cells that have already migrated away lead to rapid regrowth of the tumor. Curative therapy for medulloblastoma (MB), the most common pediatric brain tumor, has improved, but the outcome is still poor for many patients, and treatment causes long-term complications. Recent advances in the classification of pediatric brain tumors reveal distinct subgroups, allowing more targeted therapy for the most aggressive forms, and sparing children with less malignant tumors the side-effects of massive treatment. Heparan sulfate proteoglycans (HSPGs), main components of the neurogenic niche, interact specifically with a large number of physiologically important molecules and vital roles for HS biosynthesis and degradation in neural stem cell differentiation have been presented. HSPGs are composed of a core protein with attached highly charged, sulfated disaccharide chains. The major enzyme that degrades HS is heparanase (HPSE), an important regulator of extracellular matrix (ECM) remodeling which has been suggested to promote the growth and invasion of other types of tumors. This is of clinical interest because GBM are highly invasive and children with metastatic MB at the time of diagnosis exhibit a worse outcome. Here we review the involvement of HS and HPSE in development of the nervous system and some of its most malignant brain tumors, glioblastoma and medulloblastoma.


Assuntos
Neoplasias Encefálicas/enzimologia , Neoplasias Encefálicas/patologia , Glucuronidase/metabolismo , Heparitina Sulfato/metabolismo , Glioblastoma/enzimologia , Glioblastoma/patologia , Proteoglicanas de Heparan Sulfato , Humanos , Meduloblastoma/enzimologia , Meduloblastoma/patologia
4.
Am Soc Clin Oncol Educ Book ; 40: 1-8, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32186930

RESUMO

Since the first discovery of isocitrate dehydrogenase (IDH) mutations in cancer, considerable progress has been made in our understanding of their contribution to cancer development. For glioma, this has helped to identify two diagnostic groups of tumors (oligodendroglioma and astrocytoma IDHmt) with distinct clinical characteristics and that are now diagnosed by the presence of the IDH mutations. The metabolic changes occurring as the consequence of the altered substrate affinity of the mutant IDH protein results in a cascade of intracellular changes, also inducing a relative sensitivity to chemotherapy and radiotherapy compared with IDHwt tumors. Pharmacologic blockade of the mutant enzyme with first-in-class inhibitors has been efficacious for the treatment of IDH-mutant acute myeloid leukemia (AML) and is currently being evaluated in phase III trials for IDH-mutant glioma (INDIGO) and cholangiocarcinoma (ClarIDHy). It seems likely that acquired resistance to mutant IDH inhibitors will eventually emerge, and combination therapies to augment the antitumor activity of mutant IDH inhibitors have already been initiated. Approaches to exploit, rather than inhibit, the unique metabolism of IDH-mutant cancer cells have emerged from laboratory studies and are now also being tested in the clinic. Results of these clinical trials are eagerly awaited and will likely provide new key insights and direction of the treatment of IDH-mutant human cancer.


Assuntos
Neoplasias Encefálicas/genética , Glioma/genética , Substância Cinzenta/patologia , Isocitrato Desidrogenase/genética , Mutação , Neoplasias Encefálicas/enzimologia , Neoplasias Encefálicas/patologia , Glioma/enzimologia , Glioma/patologia , Humanos
5.
Biochem Biophys Res Commun ; 524(3): 723-729, 2020 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-32035622

RESUMO

Recent research has revealed that glioblastoma (GBM) avoids the immune system via strong expression of indoleamine 2,3-dioxygenase 1 (IDO1). IDO1, an enzyme involved in tryptophan metabolism, is now proposed as a new target in GBM treatment, since several reports have demonstrated that IDO1 expression is related to GBM malignancy. On the other hand, it is well known that glioma stem cells (GSCs) are strongly related to the malignancy of GBM. However, there is as yet no report evaluating the relationship between GSCs and IDO1. We therefore examined the expression levels of IDO1 in GSCs in order to identify a new therapeutic target for GBM based on the immune systems of GSCs. In the present study, we employed human GBM cell lines (U-138MG, U-251MG) and patient-derived GSC model cell lines (0125-GSC, 0222-GSC). GSC model cell lines Rev-U-138MG and Rev-U-251MG were established by culturing U-138MG and U-251MG in serum-free media, while differentiated GBM model cell lines 0125-DGC and 0222-DGC were established by culturing 0125-GSC and 0222-GSC in serum-containing media. The expression levels of stem cell markers (Nanog, Nestin, Oct4 and Sox2) and IDO1 protein and mRNA were determined. Rev-U-138MG and Rev-U-251MG formed spheres and their expression levels of stem cell markers were increased as compared to U-138MG and U-251MG. On the other hand, 0125-DGC and 0222-DGC suffered breakdown of sphere formation, despite the original 0125-GSC and 0222-GSC forming spheres, and their expression levels of the markers were decreased. IDO1 expressions were strongly recognized in Rev-U-138MG, Rev-U-251MG, 0125-GSC and 0222-GSC as compared to U-138MG, U-251MG, 0125-DGC and 0222-DGC. These findings demonstrate that GSCs exhibit treatment resistance with immunosuppression via high expression levels of IDO1, and could represent a novel target for GBM treatment.


Assuntos
Neoplasias Encefálicas/enzimologia , Neoplasias Encefálicas/patologia , Glioma/enzimologia , Glioma/patologia , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Células-Tronco Neoplásicas/enzimologia , Células-Tronco Neoplásicas/patologia , Linhagem Celular Tumoral , Meios de Cultura Livres de Soro , Glioblastoma/patologia , Humanos , Interferon beta/metabolismo
6.
Adv Exp Med Biol ; 1202: 151-178, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32034713

RESUMO

Protein tyrosine kinases are enzymes that are capable of adding a phosphate group to specific tyrosines on target proteins. A receptor tyrosine kinase (RTK) is a tyrosine kinase located at the cellular membrane and is activated by binding of a ligand via its extracellular domain. Protein phosphorylation by kinases is an important mechanism for communicating signals within a cell and regulating cellular activity; furthermore, this mechanism functions as an "on" or "off" switch in many cellular functions. Ninety unique tyrosine kinase genes, including 58 RTKs, were identified in the human genome; the products of these genes regulate cellular proliferation, survival, differentiation, function, and motility. Tyrosine kinases play a critical role in the development and progression of many types of cancer, in addition to their roles as key regulators of normal cellular processes. Recent studies have revealed that RTKs such as epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), c-Met, Tie, Axl, discoidin domain receptor 1 (DDR1), and erythropoietin-producing human hepatocellular carcinoma (Eph) play a major role in glioma invasion. Herein, we summarize recent advances in understanding the role of RTKs in glioma pathobiology, especially the invasive phenotype, and present the perspective that RTKs are a potential target of glioma therapy.


Assuntos
Neoplasias Encefálicas/enzimologia , Neoplasias Encefálicas/patologia , Glioma/enzimologia , Glioma/patologia , Receptores Proteína Tirosina Quinases/metabolismo , Animais , Neoplasias Encefálicas/tratamento farmacológico , Movimento Celular , Proliferação de Células , Glioma/tratamento farmacológico , Humanos , Fosforilação , Fosfotirosina/metabolismo , Receptores Proteína Tirosina Quinases/antagonistas & inibidores
7.
Adv Exp Med Biol ; 1202: 259-279, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32034718

RESUMO

Signal transduction pathways directly communicate and transform chromatin to change the epigenetic landscape and regulate gene expression. Chromatin acts as a dynamic platform of signal integration and storage. Histone modifications and alteration of chromatin structure play the main role in chromatin-based gene expression regulation. Alterations in genes coding for histone modifying enzymes and chromatin modifiers result in malfunction of proteins that regulate chromatin modification and remodeling. Such dysregulations culminate in profound changes in chromatin structure and distorted patterns of gene expression. Gliomagenesis is a multistep process, involving both genetic and epigenetic alterations. Recent applications of next generation sequencing have revealed that many chromatin regulation-related genes, including ATRX, ARID1A, SMARCA4, SMARCA2, SMARCC2, BAF155 and hSNF5 are mutated in gliomas. In this review we summarize newly identified mechanisms affecting expression or functions of selected histone modifying enzymes and chromatin modifiers in gliomas. We focus on selected examples of pathogenic mechanisms involving ATRX, histone methyltransferase G9a, histone acetylases/deacetylases and chromatin remodeling complexes SMARCA2/4. We discuss the impact of selected epigenetics alterations on glioma pathobiology, signaling and therapeutic responses. We assess the attempts of targeting defective pathways with new inhibitors.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Cromatina/metabolismo , Glioma/tratamento farmacológico , Glioma/patologia , Histonas/metabolismo , Neoplasias Encefálicas/enzimologia , Neoplasias Encefálicas/genética , Cromatina/genética , Montagem e Desmontagem da Cromatina/efeitos dos fármacos , Epigênese Genética/efeitos dos fármacos , Glioma/enzimologia , Glioma/genética , Código das Histonas/efeitos dos fármacos , Histonas/química , Humanos
8.
Nature ; 578(7793): 166-171, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31996845

RESUMO

Glioblastoma is a universally lethal form of brain cancer that exhibits an array of pathophysiological phenotypes, many of which are mediated by interactions with the neuronal microenvironment1,2. Recent studies have shown that increases in neuronal activity have an important role in the proliferation and progression of glioblastoma3,4. Whether there is reciprocal crosstalk between glioblastoma and neurons remains poorly defined, as the mechanisms that underlie how these tumours remodel the neuronal milieu towards increased activity are unknown. Here, using a native mouse model of glioblastoma, we develop a high-throughput in vivo screening platform and discover several driver variants of PIK3CA. We show that tumours driven by these variants have divergent molecular properties that manifest in selective initiation of brain hyperexcitability and remodelling of the synaptic constituency. Furthermore, secreted members of the glypican (GPC) family are selectively expressed in these tumours, and GPC3 drives gliomagenesis and hyperexcitability. Together, our studies illustrate the importance of functionally interrogating diverse tumour phenotypes driven by individual, yet related, variants and reveal how glioblastoma alters the neuronal microenvironment.


Assuntos
Neoplasias Encefálicas/enzimologia , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Glioblastoma/enzimologia , Animais , Neoplasias Encefálicas/patologia , Carcinogênese/genética , Carcinogênese/metabolismo , Classe I de Fosfatidilinositol 3-Quinases/química , Classe I de Fosfatidilinositol 3-Quinases/genética , Modelos Animais de Doenças , Glioblastoma/patologia , Glipicanas/metabolismo , Camundongos
9.
J Clin Pathol ; 73(2): 112-115, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31422371

RESUMO

AIMS: O(6)-methylguanine-DNA-methyltransferase (MGMT) promoter methylation is a high predictive factor for therapy results of temozolomide in patients with glioma. The objective of this work was to analyse the impact of MGMT promoter methylation in patients with primary diagnosed glioblastoma (GBM) relating to survival using a quantitative method (methylation quantification of endonuclease-resistant DNA, MethyQESD) by verifying a cut-off point for MGMT methylation provided by the literature (

Assuntos
Biomarcadores Tumorais/genética , Neoplasias Encefálicas/genética , Metilação de DNA , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Glioblastoma/genética , Regiões Promotoras Genéticas , Proteínas Supressoras de Tumor/genética , Adulto , Idoso , Antineoplásicos Alquilantes/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/enzimologia , Neoplasias Encefálicas/mortalidade , Feminino , Glioblastoma/tratamento farmacológico , Glioblastoma/enzimologia , Glioblastoma/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Temozolomida/uso terapêutico , Fatores de Tempo
10.
World Neurosurg ; 133: e421-e427, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31526886

RESUMO

BACKGROUND: In the era of integrated genomic-histologic analysis of brain tumors, new biomarkers have been introduced as diagnostic, prognostic, and therapeutic indicators. The analysis of the mutation in the isocitrate dehydrogenase (IDH) genes IDH1 and IDH2 has provided important diagnostic and prognostic information for patients affected by diffuse glioma (i.e., the presence of the mutation has been related to an increased survival rate). The reference standard of IDH mutation detection has been its assessment in surgical specimens, immunohistochemistry, and/or genetic sequencing. Knowing the IDH status information preoperatively would be of great importance, because it has been related to tumor progression and the response to treatment. The oncometabolite 2-hydroxyglutarate (2HG), accumulated in gliomas with IDH mutation status, can be detected in vivo using magnetic resonance spectroscopy (MRS). METHODS: The 2HG-MRS technique remains technically challenging. We have summarized the results of the first pilot study in Australia, which included 10 patients affected by glioma. The data recorded from May 2017 to November 2018 were analyzed. RESULTS: In our exploratory study, we reached a sensitivity and specificity of 100%, confirming the strong predictive role of 2HG, as detected using MRS, in the diagnosis of glioma. CONCLUSION: In the present study, we have focused on methodological tips and future perspectives of the technique in the neuroimaging and neuro-oncological scenario. We would advocate the integration of 2HG-MRS into standard clinical practice.


Assuntos
Neoplasias Encefálicas/enzimologia , Análise Mutacional de DNA/métodos , Glioma/enzimologia , Isocitrato Desidrogenase/análise , Espectroscopia de Ressonância Magnética/métodos , Proteínas de Neoplasias/análise , Neuroimagem/métodos , Adulto , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Feminino , Previsões , Glioma/diagnóstico por imagem , Glioma/genética , Glioma/patologia , Humanos , Isocitrato Desidrogenase/genética , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Mutação , Proteínas de Neoplasias/genética , Neuroimagem/tendências , Projetos Piloto , Sensibilidade e Especificidade , Adulto Jovem
11.
Anticancer Res ; 39(12): 6731-6741, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31810938

RESUMO

BACKGROUND/AIM: Histone deacetylase 6 (HDAC6) is considered as one of the most promising targets in drug development for cancer therapy. Drug resistance is a major cause of treatment failure in many cancers including glioblastoma (GBM), the most lethal malignant tumor. The role of HDAC6 in GBM resistance and its underlying mechanisms have not been well elucidated. Herein, we investigated the function of HDAC6 in modulating GBM resistance. MATERIALS AND METHODS: The anticancer effects of four structurally distinct selective HDAC6 inhibitors were addressed using western blot, flow cytometry, CCK-8 assay, and CI in temozolomide (TMZ)-resistant GBM cells. RESULTS: We showed that HDAC6-selecitve inhibitors block activation of the EGFR and p53 pathways in TMZ-resistant GBM cells. Importantly, the inhibition of HDAC6 correlates with increased levels of MSH2 and MSH6, key DNA mismatch repair proteins, in TMZ-resistant GBM cells. In addition to the MSH, HDAC6 inhibitors decrease MGMT expression in TMZ-resistant GBM cells. Furthermore, HDAC6 inhibitors increase TMZ sensitivity and efficiently induce apoptosis in TMZ-resistant GBM cells. CONCLUSION: Selective inhibition of HDAC6 may be a promising strategy for the treatment of TMZ-resistant GBM.


Assuntos
Neoplasias Encefálicas/enzimologia , Proteínas de Ligação a DNA/metabolismo , Resistencia a Medicamentos Antineoplásicos , Glioblastoma/enzimologia , Desacetilase 6 de Histona/antagonistas & inibidores , Proteína 2 Homóloga a MutS/metabolismo , Antineoplásicos Alquilantes/uso terapêutico , Derivados de Benzeno/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Linhagem Celular Tumoral , Sobrevivência Celular , Reparo de Erro de Pareamento de DNA/fisiologia , Metilases de Modificação do DNA/metabolismo , Enzimas Reparadoras do DNA/metabolismo , Receptores ErbB/metabolismo , Glioblastoma/tratamento farmacológico , Desacetilase 6 de Histona/metabolismo , Inibidores de Histona Desacetilases/farmacologia , Humanos , Ácidos Hidroxâmicos/farmacologia , Indóis/farmacologia , Pirimidinas/farmacologia , Temozolomida/uso terapêutico , Proteína Supressora de Tumor p53/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Regulação para Cima
12.
Ann Saudi Med ; 39(6): 410-416, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31804140

RESUMO

BACKGROUND: Treatment of glioblastoma (GB), the most common malignant primary brain tumor in adults, can include alkylating chemo-therapeutic agents. Two molecular biomarkers of treatment response are MGMT (O6-methylguanine-DNA methyltransferase) promoter methylation and IDH (isocitrate dehydrogenase) mutations, which prevent repair of tumor cell DNA damage caused by alkylating chemotherapy. The status of MGMT promoter methylation and IDH mutation are associated with longer survival and a better response to chemotherapy. OBJECTIVE: Assess the prognostic value of MGMT methylation status and IDH mutation in adult Saudi glioblastoma patients. DESIGN: Retrospective, comparative survival analysis. SETTING: Tertiary care center. PATIENTS AND METHODS: The status of the MGMT promoter methylation and IDH mutation was assessed in adult patients diagnosed with GB between 2006 and 2019. A PCR-based assay was used to analyze for methylation of the MGMT promoter. A qualitative assay combining PCR clamping and amplification refractory mutation system technology was used to search for any of the 12 most common mutations in IDH1 and IDH2. Differences in survival were compared between those with and without MGMT promoter methylation and IDH mutation and between other subgroups. MAIN OUTCOME MEASURES: Survival of GB patients relative to MGMT promoter methylation and IDH mutation status. SAMPLE SIZE: 146 patients (80 males and 66 females). RESULTS: Of 43 (29.5%) cases tested for MGMT promoter methylation, 14 (32.5%) were positive. Of 65 (44.5%) cases screened for IDH mutation, 6 cases (9.2%) tested positive. The 36-month survival rate was 47% for the MGMT methylated cohort compared to 27% for their unmethylated counterparts. The 18-month survival rate for the IDH-mutant was 75% compared to 48% for their IDH-wildtype counterparts. CONCLUSION: The findings confirm the positive impact of both MGMT promoter methylation and IDH mutation on the overall survival of Saudi GB patients. LIMITATIONS: Single institute study with relatively few tested cases. CONFLICT OF INTEREST: None.


Assuntos
Neoplasias Encefálicas/diagnóstico , Metilação de DNA , Glioblastoma/diagnóstico , Isocitrato Desidrogenase/genética , O(6)-Metilguanina-DNA Metiltransferase/genética , Regiões Promotoras Genéticas/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/enzimologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidade , Metilação de DNA/genética , Feminino , Marcadores Genéticos/genética , Glioblastoma/enzimologia , Glioblastoma/genética , Glioblastoma/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Arábia Saudita/epidemiologia , Análise de Sobrevida , Adulto Jovem
13.
Molecules ; 24(23)2019 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-31771098

RESUMO

The identification of signaling pathways that are involved in gliomagenesis is crucial for targeted therapy design. In this study we assessed the biological and therapeutic effect of ingenol-3-dodecanoate (IngC) on glioma. IngC exhibited dose-time-dependent cytotoxic effects on large panel of glioma cell lines (adult, pediatric cancer cells, and primary cultures), as well as, effectively reduced colonies formation. Nevertheless, it was not been able to attenuate cell migration, invasion, and promote apoptotic effects when administered alone. IngC exposure promoted S-phase arrest associated with p21CIP/WAF1 overexpression and regulated a broad range of signaling effectors related to survival and cell cycle regulation. Moreover, IngC led glioma cells to autophagy by LC3B-II accumulation and exhibited increased cytotoxic sensitivity when combined to a specific autophagic inhibitor, bafilomycin A1. In comparison with temozolomide, IngC showed a mean increase of 106-fold in efficacy, with no synergistic effect when they were both combined. When compared with a known compound of the same class, namely ingenol-3-angelate (I3A, Picato®), IngC showed a mean 9.46-fold higher efficacy. Furthermore, IngC acted as a potent inhibitor of protein kinase C (PKC) activity, an emerging therapeutic target in glioma cells, showing differential actions against various PKC isotypes. These findings identify IngC as a promising lead compound for the development of new cancer therapy and they may guide the search for additional PKC inhibitors.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Encefálicas/enzimologia , Diterpenos/farmacologia , Euphorbia/química , Glioma/enzimologia , Proteína Quinase C/antagonistas & inibidores , Antineoplásicos/química , Autofagia , Neoplasias Encefálicas/tratamento farmacológico , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Diterpenos/química , Ensaios de Seleção de Medicamentos Antitumorais , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioma/tratamento farmacológico , Humanos , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Transdução de Sinais/efeitos dos fármacos
14.
Anal Bioanal Chem ; 411(30): 7929-7933, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31754769

RESUMO

Knowledge of the isocitrate dehydrogenase (IDH) mutation status of glioma patients could provide insights for decision-making during brain surgery. However, pathology is not able to provide such information intraoperatively. Here we describe the first application of a miniature mass spectrometer (MS) to the determination of IDH mutation status in gliomas intraoperatively. The instrumentation was modified to be compatible with use in the operating room. Tandem MS was performed on the oncometabolite, 2-hydroxyglutarate, and a reference metabolite, glutamate, which is not involved in the IDH mutation. Ratios of fragment ion intensities were measured to calculate an IDH mutation score, which was used to differentiate IDH mutant and wild-type tissues. The results of analyzing 25 biopsies from 13 patients indicate that reliable determination of IDH mutation status was achieved (p = 0.0001, using the Kruskal-Wallis non-parametric test). With its small footprint and low power consumption and noise level, this application of miniature mass spectrometers represents a simple and cost-effective platform for an important intraoperative measurement. Graphical abstract.


Assuntos
Neoplasias Encefálicas/enzimologia , Glioma/enzimologia , Isocitrato Desidrogenase/genética , Mutação , Espectrometria de Massas por Ionização por Electrospray/instrumentação , Espectrometria de Massas em Tandem/instrumentação , Biópsia , Neoplasias Encefálicas/patologia , Estudos de Coortes , Glioma/patologia , Humanos , Período Intraoperatório
15.
Mol Cell ; 76(6): 885-895.e7, 2019 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-31629659

RESUMO

Hypoxia, which occurs during tumor growth, triggers complex adaptive responses in which peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) plays a critical role in mitochondrial biogenesis and oxidative metabolism. However, how PGC-1α is regulated in response to oxygen availability remains unclear. We demonstrated that lysine demethylase 3A (KDM3A) binds to PGC-1α and demethylates monomethylated lysine (K) 224 of PGC-1α under normoxic conditions. Hypoxic stimulation inhibits KDM3A, which has a high KM of oxygen for its activity, and enhances PGC-1α K224 monomethylation. This modification decreases PGC-1α's activity required for NRF1- and NRF2-dependent transcriptional regulation of TFAM, TFB1M, and TFB2M, resulting in reduced mitochondrial biogenesis. Expression of PGC-1α K224R mutant significantly increases mitochondrial biogenesis, reactive oxygen species (ROS) production, and tumor cell apoptosis under hypoxia and inhibits brain tumor growth in mice. This study revealed that PGC-1α monomethylation, which is dependent on oxygen availability-regulated KDM3A, plays a critical role in the regulation of mitochondrial biogenesis.


Assuntos
Neoplasias Encefálicas/enzimologia , Histona Desmetilases com o Domínio Jumonji/metabolismo , Mitocôndrias/enzimologia , Biogênese de Organelas , Oxigênio/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Processamento de Proteína Pós-Traducional , Animais , Apoptose , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Proliferação de Células , Feminino , Regulação Neoplásica da Expressão Gênica , Células HEK293 , Células HeLa , Células Hep G2 , Humanos , Histona Desmetilases com o Domínio Jumonji/genética , Metilação , Camundongos Endogâmicos BALB C , Camundongos Nus , Mitocôndrias/patologia , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Carga Tumoral , Hipóxia Tumoral , Microambiente Tumoral
16.
Radiology ; 293(3): 633-643, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31592732

RESUMO

Background Tumor location is a main prognostic parameter in patients with glioblastoma. Probabilistic MRI-based brain atlases specifying the probability of tumor location associated with important demographic, clinical, histomolecular, and management data are lacking for isocitrate dehydrogenase (IDH) wild-type glioblastomas. Purpose To correlate glioblastoma location with clinical phenotype, surgical management, and outcomes by using a probabilistic analysis in a three-dimensional (3D) MRI-based atlas. Materials and Methods This retrospective study included all adults surgically treated for newly diagnosed IDH wild-type supratentorial glioblastoma in a tertiary adult surgical neuro-oncology center (2006-2016). Semiautomated tumor segmentation and spatial normalization procedures to build a 3D MRI-based atlas were validated. The authors performed probabilistic analyses by using voxel-based lesion symptom mapping technology. The Liebermeister test was used for binary data, and the generalized linear model was used for continuous data. Results A total of 392 patients (mean age, 61 years ± 13; 233 men) were evaluated. The authors identified the preferential location of glioblastomas according to subventricular zone, age, sex, clinical presentation, revised Radiation Therapy Oncology Group-Recursive Partitioning Analysis class, Karnofsky performance status, O6-methylguanine DNA methyltransferase promoter methylation status, surgical management, and survival. The superficial location distant from the eloquent area was more likely associated with a preserved functional status at diagnosis (348 of 392 patients [89%], P < .05), a large surgical resection (173 of 392 patients [44%], P < .05), and prolonged overall survival (163 of 334 patients [49%], P < .05). In contrast, deep location and location within eloquent brain areas were more likely associated with an impaired functional status at diagnosis (44 of 392 patients [11%], P < .05), a neurologic deficit (282 of 392 patients [72%], P < .05), treatment with biopsy only (183 of 392 patients [47%], P < .05), and shortened overall survival (171 of 334 patients [51%], P < .05). Conclusion The authors identified the preferential location of isocitrate dehydrogenase wild-type glioblastomas according to parameters of interest and provided an image-based integration of multimodal information impacting survival results. This suggests the role of glioblastoma location as a surrogate and multimodal parameter integrating several known prognostic factors. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Huang in this issue.


Assuntos
Mapeamento Encefálico/métodos , Neoplasias Encefálicas/diagnóstico por imagem , Glioblastoma/diagnóstico por imagem , Imageamento Tridimensional , Imagem por Ressonância Magnética/métodos , Atlas como Assunto , Neoplasias Encefálicas/enzimologia , Neoplasias Encefálicas/cirurgia , Feminino , Glioblastoma/enzimologia , Glioblastoma/cirurgia , Humanos , Isocitrato Desidrogenase , Masculino , Pessoa de Meia-Idade , Fenótipo , Estudos Retrospectivos
17.
Eur J Pharmacol ; 863: 172665, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31542479

RESUMO

Glioma is one of the most lethal malignancies and molecular regulators driving gliomagenesis are incompletely understood. Although temozolomide (TMZ) has been applied for malignant gliomas as a canonical chemotherapy, the treatment of glioma still remains limited due to frequently developed resistance to TMZ. Therefore, promising strategies that sensitize glioma cells to temozolomide are overwhelming to develop. Here we found that the expression of dihydrofolate reductase (DHFR) and thymidylate synthetase (TYMS), which played an essential role in folate metabolism and several types of tumors, were up-regulated in both human glioma tissues and cell lines, and overexpression of DHFR/TYMS promoted the proliferation of glioma cells. Notably, inhibition of DHFR/TYMS by pemetrexed exhibited synergistic anti-glioma activity with TMZ in both cell lines and U251 xenografts, which suggested potential combined chemotherapy for glioma. Mechanistically, the synergistic effect of inhibition of DHFR/TYMS with TMZ was due to activated AMPK and subsequently suppressed mTOR signaling pathway. Taken together, these findings identify an uncharacterized role of DHFR/TYMS in glioma growth and TMZ sensitivity mediated by AMPK-mTOR signal pathway, and provide a prospective approach for improving the anti-tumor activity of TMZ in glioma.


Assuntos
Glioma/patologia , Temozolomida/farmacologia , Tetra-Hidrofolato Desidrogenase/metabolismo , Timidilato Sintase/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/enzimologia , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Antagonistas do Ácido Fólico/farmacologia , Glioma/tratamento farmacológico , Glioma/enzimologia , Humanos , Camundongos , Terapia de Alvo Molecular , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Timidilato Sintase/antagonistas & inibidores , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Mol Cell ; 76(3): 516-527.e7, 2019 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-31492635

RESUMO

The PTEN tumor suppressor is frequently mutated or deleted in cancer and regulates glucose metabolism through the PI3K-AKT pathway. However, whether PTEN directly regulates glycolysis in tumor cells is unclear. We demonstrate here that PTEN directly interacts with phosphoglycerate kinase 1 (PGK1). PGK1 functions not only as a glycolytic enzyme but also as a protein kinase intermolecularly autophosphorylating itself at Y324 for activation. The protein phosphatase activity of PTEN dephosphorylates and inhibits autophosphorylated PGK1, thereby inhibiting glycolysis, ATP production, and brain tumor cell proliferation. In addition, knockin expression of a PGK1 Y324F mutant inhibits brain tumor formation. Analyses of human glioblastoma specimens reveals that PGK1 Y324 phosphorylation levels inversely correlate with PTEN expression status and are positively associated with poor prognosis in glioblastoma patients. This work highlights the instrumental role of PGK1 autophosphorylation in its activation and PTEN protein phosphatase activity in governing glycolysis and tumorigenesis.


Assuntos
Neoplasias Encefálicas/enzimologia , Glioblastoma/enzimologia , Glucose/metabolismo , Glicólise , PTEN Fosfo-Hidrolase/metabolismo , Fosfoglicerato Quinase/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Glioblastoma/genética , Glioblastoma/patologia , Células HEK293 , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , PTEN Fosfo-Hidrolase/genética , Fosfoglicerato Quinase/genética , Fosforilação , Prognóstico , Transdução de Sinais , Fatores de Tempo , Carga Tumoral , Tirosina
19.
Biomed Pharmacother ; 118: 109369, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31545229

RESUMO

The main characteristic of glioma is recurrence, even after intensive multidisciplinary treatment. Studies show that enhanced invasive ability will increase the ability of tumor cells to escape from the primary tumor mass, which is a key factor contributing to tumor relapse and recurrence. In this study, we assessed the expression of MMP-2, MMP-9, two important matrix metallopeptidases that increase the invasive ability of glioma, and their suppressors, TIMP-1, TIMP-2 in glioma tissues from primary and recurrent glioma patients by immunohistochemistry. Glioma cells and nude mice were used for in vitro and in vivo studies. Results showed that the expression of MMP-2 and MMP-9 in recurrent gliomas were significantly higher than those in primary gliomas (P = 3.075 × 10-11, P = 1.510 × 10-5, respectively). We also found that radiotherapy increased the expression of MMP-9, but had no effect on MMP-2 and TIMP-1/2. With glioma cell line U251, we found that irradiation increased the expression of MMP-9 in vitro. Tumor tissues from an orthotopic xenograft model showed that after irradiation treatment, the expression of MMP-9 increased significantly in vivo. We also found that knocking down MMP-9 decreased irradiation-induced invasion obviously. Above all, we concluded that higher expressions of MMP-2/-9 indicate poor prognosis in glioma recurrence. The increased expression of MMP-9 after radiotherapy suggests that MMP-9 might be an important target in the radiosensitization of glioma.


Assuntos
Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/enzimologia , Glioma/diagnóstico , Glioma/enzimologia , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Adolescente , Adulto , Idoso , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Criança , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Invasividade Neoplásica , Recidiva Local de Neoplasia/enzimologia , Recidiva Local de Neoplasia/patologia , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Prognóstico , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Inibidor Tecidual de Metaloproteinase-2/metabolismo , Adulto Jovem
20.
Pathol Res Pract ; 215(11): 152617, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31563286

RESUMO

BACKGROUND: Recent studies have demonstrated that aberrant expression or activation of kinases results in oncogenesis of a wide range of cancers including GBM. Inhibition of kinases expression induces a reduction of therapy resistance. In this study, we investigate the underlying mechanism by which glioblastoma (GBM) cells acquire resistance to Temozolomide (TMZ) through Aurora kinase B (AURKB) thus to identify novel therapeutic targets and prognostic biomarkers for GBM. METHODS: AURKB was identified as a key candidate kinase-encoding gene in chemoresistance regulation by using kinome-wide bioinformatic analysis. Afterwards, the potential biological functions of AURKB in oncogenesis and chemoresistance were investigated by lentivirus-dependent silencing of AURKB combined with qRT-PCR, western blot and in vivo intra-cranial xenograft mice models. Additionally, immunohistochemistry (IHC) assays were performed to explore the clinical significance of AURKB in glioma patients. Lastly, Chou-Talalay method was used to confirm the synergistic effect of TMZ combined with AURKB inhibitor. RESULTS: AURKB was among the most significantly up-regulated kinase-coding genes in TMZ resistant GBM cells according to database GSE68029, moreover, an increased expression of AURKB was closely associated with poor prognosis in glioma and GBM patients. AURKB knock-down resensitized U87 resistant cells to TMZ both in vitro and in vivo. Additionally, the combination of TMZ and Hesperadin, a specific AURKB inhibitor, significantly suppressed the proliferation of TMZ resistant GBM cells thus dramatically prolonged the survival of xenograft mice viaa synergistic effect with TMZ. CONCLUSION: Elevated AURKB expression was strongly correlated to TMZ resistant acquisition and poor prognosis, furthermore, targeting AURKB would be a potential therapeutic target for GBM patients.


Assuntos
Aurora Quinase B/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Glioblastoma/patologia , Indóis/farmacologia , Sulfonamidas/farmacologia , Temozolomida/farmacologia , Animais , Antineoplásicos/farmacologia , Aurora Quinase B/efeitos dos fármacos , Neoplasias Encefálicas/enzimologia , Neoplasias Encefálicas/patologia , Resistencia a Medicamentos Antineoplásicos/fisiologia , Sinergismo Farmacológico , Glioblastoma/enzimologia , Humanos , Camundongos , Ensaios Antitumorais Modelo de Xenoenxerto
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA