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1.
Pan Afr Med J ; 39: 191, 2021.
Artigo em Francês | MEDLINE | ID: mdl-34603572

RESUMO

Glioblastoma is the most common primary malignant brain tumour. Despite advances in diagnostic and therapeutic treatments, it is still associated with poor outcome The purpose of this study of cases is to describe the epidemiological, clinical, therapeutic and evolutionary features of patients with glioblastoma admitted to the Department of Hematology-Oncology (DHO) in Marrakech in 2016 and 2017. We conducted a literature review of epidemiological, clinical, radiological, anatomopathological, therapeutic and evolutionary data from 40 patients. Glioblastoma accounted for 47.6% of treated intracranial tumours. The average age of patients was 52.4±12.3 years. Functional impotence and signs of intracranial hypertension were the main symptoms. Tumours mainly occurred in the parietal region (44%) and were large (57.5%). Aphasia was related to tumour size (p=0.042). Nine cases had glioblastomas-IDH1-wild and one case had glioblastoma-IDH1-mutant. On admission, patients had poor performance-status. This was due to a prolonged time between surgery and DHO admission (p= 0.034). Patients with sensory impairments were older (62.5±3 years) than those without sensory impairments (51.2±12 years) (p=0,045). In-patient women received chemoradiotherapy (1.5±1 month) earlier than men (2.3±1.2 months) (p=0.03). Survival was 13.6±5.3 months; it was unrelated to the time to surgery (p=0.076), the time to DHO (p=0.058), and the time to chemoradiotherapy (p=0.073). The epidemiological, clinical, radiological and evolutionary features of our sample were comparable to literature data. The molecular profiling was not systematically realized. Despite prolonged treatment times, no link to survival was detected.


Assuntos
Neoplasias Encefálicas/epidemiologia , Glioblastoma/epidemiologia , Hipertensão Intracraniana/etiologia , Adulto , Fatores Etários , Afasia/epidemiologia , Afasia/etiologia , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/terapia , Feminino , Glioblastoma/patologia , Glioblastoma/terapia , Hospitais Universitários , Humanos , Masculino , Pessoa de Meia-Idade , Marrocos , Estudos Retrospectivos , Fatores Sexuais , Taxa de Sobrevida , Tempo para o Tratamento
2.
Expert Opin Pharmacother ; 22(15): 2019-2031, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34605345

RESUMO

Introduction: Treatments for brain cancer have radically evolved in the past decade due to a better understanding of the interplay between the immune system and tumors of the central nervous system (CNS). However, glioblastoma multiforme (GBM) remains the most common and lethal CNS malignancy affecting adults.Areas covered: The authors review the literature on glioblastoma pharmacologic therapies with a focus on trials of combination chemo-/immunotherapies and drug delivery platforms from 2015 to 2021.Expert opinion: Few therapeutic advances in GBM treatment have been made since the Food and Drug Administration (FDA) approval of the BCNU-eluting wafer, Gliadel, in 1996 and oral temozolomide (TMZ) in 2005. Recent advances in our understanding of GBM have promoted a wide assortment of new therapeutic approaches including combination therapy, immunotherapy, vaccines, and Car T-cell therapy along with developments in drug delivery. Given promising preclinical data, these novel pharmacotherapies for the treatment of GBM are currently being evaluated in various stages of clinical trials.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Neoplasias Encefálicas/tratamento farmacológico , Sistema Nervoso Central , Glioblastoma/tratamento farmacológico , Humanos , Prognóstico , Temozolomida/uso terapêutico , Estados Unidos
3.
BMC Bioinformatics ; 22(1): 420, 2021 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-34482818

RESUMO

BACKGROUND: Glioblastoma multiforme (GBM) is the most common and aggressive primary malignant brain tumor with grim prognosis. Aberrant DNA methylation is an epigenetic mechanism that promotes GBM carcinogenesis, while the function of DNA methylation at enhancer regions in GBM remains poorly described. RESULTS: We integrated multi-omics data to identify differential methylation enhancer region (DMER)-genes and revealed global enhancer hypomethylation in GBM. In addition, a DMER-mediated target genes regulatory network and functional enrichment analysis of target genes that might be regulated by hypomethylation enhancer regions showed that aberrant enhancer regions could contribute to tumorigenesis and progression in GBM. Further, we identified 22 modules in which lncRNAs and mRNAs synergistically competed with each other. Finally, through the construction of drug-target association networks, our study identified potential small-molecule drugs for GBM treatment. CONCLUSIONS: Our study provides novel insights for understanding the regulation of aberrant enhancer region methylation and developing methylation-based biomarkers for the diagnosis and treatment of GBM.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Biomarcadores Tumorais , Neoplasias Encefálicas/genética , Metilação de DNA , Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Glioblastoma/genética , Humanos
4.
Mater Sci Eng C Mater Biol Appl ; 128: 112261, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34474820

RESUMO

Glioblastoma multiforme (GBM) remains a major cause of mortality because treatments are precluded by to the limited transport and penetration of chemotherapeutics across the blood-brain barrier. Pitavastatin (PTV) is a hydrophobic Food and Drug Administration (FDA)-approved anticholesterolemic agent with reported anti-GBM activity. In the present study, we encapsulate PTV in silica-coated polymeric micelles (SiO2 PMs) surface-modified with the cyclic peptide Arg-Gly-Asp-Phe-Val (cRGDfV) that actively targets the αvß3 integrin overexpressed in the BBB endothelium and GBM. A central composite design is utilized to optimize the preparation process and improve the drug encapsulation ratio from 131 to 780 µg/mL. The silica shell provides full colloidal stability upon extreme dilution and enables a better control of the release kinetics in vitro with 28% of the cargo released after 12 h. Furthermore, SiO2 PMs show excellent compatibility and are internalized by human BBB endothelial cells, astrocytes and pericytes, as shown by confocal laser scanning fluorescence microscopy and flow cytometry. Finally, the anticancer efficacy is assessed in a pediatric patient-derived glioma cell line expressing high levels of the integrin subunits αv, ß3 and ß5. This PTV-loaded nanocarrier triggers apoptosis by reducing the mRNA level of anti-apoptotic genes NF-kß, IL-6, BIRC1 and BIRC5 by 89%, 33%, 81% and 63%, respectively, and the cell viability by >60%. Overall, our results suggest the potential of these hybrid nanocarriers for the targeted therapy of GBM and other tumors overexpressing integrin receptors.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Neoplasias Encefálicas/tratamento farmacológico , Linhagem Celular Tumoral , Criança , Células Endoteliais , Glioblastoma/tratamento farmacológico , Humanos , Integrinas , Micelas , Dióxido de Silício
5.
Mater Sci Eng C Mater Biol Appl ; 128: 112330, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34474881

RESUMO

Glioblastoma multiforme (GBM) is one of the most malignant types of central nervous system tumours. Despite advances in treatment modalities, it remains largely incurable with an extremely poor prognosis. Treatment of GBM is associated with several difficulties such as the risk of damaging healthy brain tissues during surgery, drug resistance and inadequate drug delivery across the blood brain barrier. The new nanomaterial graphene, has recently attracted great attention due to its unique physico-chemical characteristics, good biocompatibility, specific targeting and small size. Starting from simple drug delivery systems, the application of graphene-based nanomaterials has been extended to a versatile platform of multiple therapeutic modalities, including immunotherapy, gene therapy, photothermal therapy and photodynamic therapy. Graphene-based materials can also be engineered to integrate multiple functions into a single platform for combination therapy for enhanced anticancer activity and reduced side effects. This review aims to discuss the state-of-the-art applications of graphene-based materials in GBM diagnosis and therapy. In addition, future challenges and prospects regarding this promising field are discussed, which may pave the way towards improving the safety and efficacy of graphene-based therapeutics.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Grafite , Nanoestruturas , Fotoquimioterapia , Neoplasias Encefálicas/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Glioblastoma/tratamento farmacológico , Grafite/uso terapêutico , Humanos
6.
Neurol India ; 69(4): 856-860, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34507401

RESUMO

Aim: Glioblastoma (GBM) is one of the most aggressive neoplasms of the central nervous system with dismal survival. In recent years, different variants of GBM have been described in the literature. GBM with areas of neuroectodermal differentiation (GBM-PNET) is a relatively new entity in GBM. Presence of the neuroectodermal component increases the propensity of systemic dissemination as with other intracranial primitive neuroectodermal tumors (PNET). The optimal treatment for these patients remains a controversy, with authors reporting local radiotherapy to craniospinal irradiation and chemotherapy. We intend to analyze the pattern of care for GBM with neuroectodermal component. Materials and Methods: We retrieved data of four patients with GBM-PNET treated in our institute; data were also retrieved from published series to derive treatment and outcome results. Results: In this series, we report the outcome of a series of four patients of GBM-PNET treated with adjuvant radiotherapy and temozolomide. All but one patient underwent gross total resection of the tumor. Adjuvant hypofractionated radiation with concurrent and adjuvant temozolomide was used in all cases. The median follow-up was 12.9 months in the present series. One patient experienced local recurrence 18 months after the treatment. A review of published literature on GBM-PNET was done; studies with details of patient outcome were used for an independent analysis. Twenty-three patients were identified, and the pooled analysis revealed a median progression free and overall survival of 10 and 25, months respectively. Extent of surgery, local radiation vs. craniospinal irradiation, and age at presentation had no impact on the survival. Conclusion: GBM PNET is a new entity with only few cases reported so far. Clinical behavior and treatment outcome of these tumors are not different from conventional GBM. However, these patients are at higher risk of CSF dissemination. Hence, an individualized treatment approach is best suited.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Tumores Neuroectodérmicos Primitivos , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/radioterapia , Glioblastoma/tratamento farmacológico , Glioblastoma/radioterapia , Humanos , Recidiva Local de Neoplasia , Tumores Neuroectodérmicos Primitivos/tratamento farmacológico , Tumores Neuroectodérmicos Primitivos/radioterapia , Radioterapia Adjuvante , Estudos Retrospectivos , Temozolomida/uso terapêutico
7.
Neurol India ; 69(4): 894-901, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34507408

RESUMO

Background: Biomarkers of systemic inflammation (BMSIs), including haemogram cell counts (CC, e.g., absolute neutrophil count) and cell count-ratios (CCR, e.g., the neutrophil-lymphocyte ratio, etc.), have been found to have prognostic significance in many solid-organ cancers. Aims: In this three-part study, we first examined if the CCs and CCRs were altered in patients with glioblastoma (GBM) when compared with healthy controls. Second, we evaluated for any correlation between the BMSIs and patient- and tumour-related factors. Third, we evaluated the influence of the CCs and CCRs on survival. Methods: This was a retrospective analysis of patients who underwent surgery/biopsy for a newly diagnosed brain tumour that was subsequently confirmed to be GBM (Cases). Controls were healthy individuals who underwent pre-employment screening blood tests. Statistical Methods: Parametric tests were used to compare normally distributed continuous variables, whereas non-normally distributed variables were compared using non-parametric tests. Thresholds for the BMSIs were determined using X-tile analysis. Cox regression using the proportional hazards model was used for survival analyses around the determined thresholds. Results: All CCs and CCRs were altered in Cases compared with Controls. Presentation with raised intracranial pressure, altered sensorium, poor performance status, loss of ATRX, and lack of p53 overexpression was associated with an inflammatory phenotype of changes in the BMSIs. The inflammatory phenotype of changes was associated with poor survival. Conclusions: A significant inflammatory response was found in patients with GBM and correlated with clinical features, the molecular profile of the tumour and poor survival.


Assuntos
Glioblastoma , Biomarcadores , Humanos , Inflamação , Linfócitos , Prognóstico , Estudos Retrospectivos
8.
Nan Fang Yi Ke Da Xue Xue Bao ; 41(8): 1171-1176, 2021 Aug 20.
Artigo em Chinês | MEDLINE | ID: mdl-34549707

RESUMO

OBJECTIVE: To investigate neuregulin 2 (NRG2) expression in gliomas and its role in glioma development. METHODS: We compared the expression levels of NRG2 and glial fibrillary acidic protein (GFAP) in low-grade glioma (LGG) and glioblastoma multiforme (GBM) with those in normal control samples using GEPIA database.The correlation between NRG2 and GFAP expression and their association with the overall survival of patients with LGG and GBM were analyzed.Immunohistochemical staining was used to detect NRG2 protein expression levels in a tissue microarray consisting of human gliomas of different grades, and potential co-localization of NRG2 and GFAP was analyzed using a double-labeling immunofluorescence assay.Western blotting was used to investigate the effect of perifosine (an AKT inhibitor) on the regulation of GFAP expression by NRG2 in human glioblastoma U-87 MG cells. RESULTS: Both LGG and GBM tissues, especially the former, exhibited high expressions of NRG2 (P < 0.01).In GBM samples, patients with low NRG2 levels had slightly higher overall survival after 30 months than patients with high NRG2 levels.The expression level of NRG2 mRNA was negatively correlated with that of GFAP in LGG samples (P < 0.01) but positively correlated with GFAP expression in GBM samples (P < 0.01).Immunofluorescence assay showed that NRG2 and GFAP were co-expressed in the same tumor cells of LGG tissues but were separately expressed in different tumor cells in GBM tissues.In U-87 MG cells, treatment with recombinant human NRG2 obviously promoted the expression of GFAP, and this effect was significantly inhibited by perifosine (P < 0.01). CONCLUSION: NRG2 is highly expressed in gliomas of different grades and regulates GFAP expression in glioma cells at least partly via the Akt signaling pathway to affect the survival of glioma patients.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Glioma , Fatores de Crescimento Neural/genética , Biomarcadores Tumorais/genética , Proteína Glial Fibrilar Ácida , Humanos , Neurregulinas , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais
9.
Chem Pharm Bull (Tokyo) ; 69(9): 832-839, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34470947

RESUMO

Thiamine (vitamin B1), which is synthesized only in bacteria, fungi and plants and which humans should take with diet, participates in basic biochemical and physiological processes in a versatile way and its deficiency is associated with neurological problems accompanied by cognitive dysfunctions. The rat glioblastoma (C6) model was used, which was exposed to a limited environment and toxicity with glutamate. The cells were stressed by exposure to glutamate in the presence and absence of thiamine. The difference in cell proliferation was evaluated in the XTT assay. Oxidative stress (OS) markers malondialdehyde (MDA), superoxide dismutase (SOD), and catalase (CAT) levels, as well as endoplasmic reticulum (ER) stress markers 78-kDa glucose-regulated protein (GRP78), activating transcription factor-4 (ATF-4), and C/EBP homologous protein (CHOP) levels, were measured with commercial kits. Apoptosis determined by flow cytometry was confirmed by 4',6-diamidino-2-phenylindole (DAPI) staining. At all concentrations, thiamine protects the cells and increased the viability against glutamate-induced toxicity. Thiamine also significantly decreased the levels of MDA, while increasing SOD and CAT levels. Moreover, thiamine reduced ER stress proteins' levels. Moreover, it lessened the apoptotic cell amount and enhanced the live-cell percentage in the flow cytometry and DAPI staining. As a result, thiamine may be beneficial nutritional support for individuals with a predisposition to neurodegenerative disorders due to its protective effect on glutamate cytotoxicity in glioblastoma cells by suppressing OS and ER stress.


Assuntos
Glioblastoma/tratamento farmacológico , Substâncias Protetoras/farmacologia , Tiamina/farmacologia , Animais , Sobrevivência Celular/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Glioblastoma/induzido quimicamente , Glioblastoma/patologia , Ácido Glutâmico , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/química , Ratos , Tiamina/química , Células Tumorais Cultivadas
10.
FASEB J ; 35(10): e21906, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34490940

RESUMO

Glioblastoma (GBM) is a refractory disease that has a highly infiltrative characteristic. Over the past decade, GBM perivascular niche (PVN) has been described as a route of dissemination. Here, we investigated that trailed membrane structures, namely retraction fibers (RFs), are formed by perivascular extracellular matrix (ECM) proteins. By using the anatomical GBM database, we validated that the ECM-related genes were highly expressed in the cells within the PVN where fibronectin (FN) induced RF formation. By disrupting candidates of FN-binding integrins, integrin α5ß1 was identified as the main regulator of RF formation. De novo RFs were produced at the trailing edge, and focal adhesions were actively localized in RFs, indicating that adhesive force makes RFs remain at the bottom surface. Furthermore, we observed that GBM cells more frequently migrated along the residual RFs formed by preceding cells in microfluidic channels in comparison to those in the channels without RFs, suggesting that the infiltrative characteristics GBM could be attributed to RFs formed by the preceding cells in concert with chemoattractant cues. Altogether, we demonstrated that shedding membrane structures of GBM cells are maintained by FN-integrin α5ß1 interaction and promoted their motility .


Assuntos
Neoplasias Encefálicas/metabolismo , Movimento Celular , Fibronectinas/metabolismo , Glioblastoma/metabolismo , Proteínas de Neoplasias/metabolismo , Receptores de Vitronectina/metabolismo , Animais , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , Feminino , Glioblastoma/patologia , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus
11.
ACS Chem Neurosci ; 12(18): 3477-3486, 2021 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-34472849

RESUMO

A number of studies have shown high levels of thymidine phosphorylase (TP) expression in glioblastoma (GBM), with trace or undetectable TP levels in normal developed brain tissue. TP catalyzes the reversible phosphorolysis of thymidine to thymine and 2-deoxyribose-1-phosphate, maintaining nucleoside homeostasis for efficient DNA replication and cell division. The TP-mediated catabolism of thymidine is responsible for multiple protumor processes and can support angiogenesis, glycation of proteins, and alternative metabolism. In this study, we examined the effect of TP inhibition in GBM using the known nanomolar TP inhibitors 5-chloro-6-[1-(2'-iminopyrrolidin-1'-yl)methyl]uracil (TPI) and the analogous 6-[(2'-aminoimidazol-1'-yl)methyl]uracils. Although these TP inhibitors did not demonstrate any appreciable cytotoxicity in GBM cell lines as single agents, they did enhance the cytotoxicity of temozolomide (TMZ). This pontetiated action of TMZ by TP inhibition may be due to limiting the availability of thymine for DNA repair and replication. These studies support that TP inhibitors could be used as chemosensitizing agents in GBM to improve the efficacy of TMZ.


Assuntos
Glioblastoma , Timidina Fosforilase , Linhagem Celular , Glioblastoma/tratamento farmacológico , Humanos , Temozolomida/farmacologia , Uracila
12.
Nanoscale ; 13(35): 14745-14759, 2021 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-34474460

RESUMO

MicroRNA-21 (miR-21) is involved in the progression of glioblastoma through inhibition of pro-apoptotic genes. Antisense RNA against miR-21 (antagomir-21) has been developed as a potential therapeutic reagent for the treatment of glioblastoma. The receptor for advanced glycation end-products (RAGE) is also involved in the progression of glioblastoma through induction of angiogenic factors. Therefore, RAGE-antagonist peptide (RAP) is proposed to be an anti-tumor reagent. In this study, self-assembled nanoparticles were produced solely with therapeutic agents, antagomir-21 and RAP, with no additional carrier. The therapeutic effects of the nanoparticles by intranasal delivery were evaluated in intracranial glioblastoma animal models. First, physical characterizations such as size/zeta-potential study, scanning electron microscopy, and gel retardation assays showed that antagomir-21 and RAP formed stable nanoparticles without any additional reagents. The ratio between antagomir-21 and RAP was optimized by an in vitro cellular uptake study. The antagomir-21/RAP nanoparticles were administrated intranasally in the intracranial glioblastoma animal models to bypass the blood-brain-barrier. As a result, the nanoparticles reduced the miR-21 levels in tumors. Inhibition of miR-21 by the nanoparticles induced the expression of pro-apoptotic genes, such as PTEN and PDCD4, which enhanced tumor cell apoptosis. In addition, the expression of RAGE was suppressed by the nanoparticles, resulting in decreased levels of vascular endothelial growth factor in the tumor. The reduction of CD31-positive endothelial cells confirmed the anti-angiogenic effects of the nanoparticles. The results indicate that the intranasal delivery of the self-assembled nanoparticles of antagomir-21 and RAP is an efficient treatment of glioblastoma.


Assuntos
Glioblastoma , MicroRNAs , Nanopartículas , Animais , Antagomirs , Linhagem Celular Tumoral , Células Endoteliais , Glioblastoma/tratamento farmacológico , Peptídeos , Receptor para Produtos Finais de Glicação Avançada , Fator A de Crescimento do Endotélio Vascular
13.
Nat Commun ; 12(1): 5203, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34471141

RESUMO

Aurora kinase A (AURKA) has emerged as a drug target for glioblastoma (GBM). However, resistance to therapy remains a critical issue. By integration of transcriptome, chromatin immunoprecipitation sequencing (CHIP-seq), Assay for Transposase-Accessible Chromatin sequencing (ATAC-seq), proteomic and metabolite screening followed by carbon tracing and extracellular flux analyses we show that genetic and pharmacological AURKA inhibition elicits metabolic reprogramming mediated by inhibition of MYC targets and concomitant activation of Peroxisome Proliferator Activated Receptor Alpha (PPARA) signaling. While glycolysis is suppressed by AURKA inhibition, we note an increase in the oxygen consumption rate fueled by enhanced fatty acid oxidation (FAO), which was accompanied by an increase of Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α). Combining AURKA inhibitors with inhibitors of FAO extends overall survival in orthotopic GBM PDX models. Taken together, these data suggest that simultaneous targeting of oxidative metabolism and AURKAi might be a potential novel therapy against recalcitrant malignancies.


Assuntos
Aurora Quinase A/genética , Aurora Quinase A/metabolismo , Glioblastoma/genética , Glioblastoma/metabolismo , Efeito Warburg em Oncologia , Linhagem Celular Tumoral , Proliferação de Células , Ácidos Graxos/metabolismo , Glicólise/efeitos dos fármacos , Humanos , PPAR alfa/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Proteômica , Transdução de Sinais/efeitos dos fármacos , Transcriptoma , Efeito Warburg em Oncologia/efeitos dos fármacos
14.
Molecules ; 26(17)2021 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-34500622

RESUMO

Glucosinolates (GSLs) from Lepidium graminifolium L. were analyzed qualitatively and quantitatively by their desulfo-counterparts using UHPLC-DAD-MS/MS technique and by their volatile breakdown products-isothiocyanates (ITCs) using GC-MS analysis. Thirteen GSLs were identified with arylaliphatic as the major ones in the following order: 3-hydroxybenzyl GSL (glucolepigramin, 7), benzyl GSL (glucotropaeolin, 9), 3,4,5-trimethoxybenzyl GSL (11), 3-methoxybenzyl GSL (glucolimnanthin, 12), 4-hydroxy-3,5-dimethoxybenzyl GSL (3,5-dimethoxysinalbin, 8), 4-hydroxybenzyl GSL (glucosinalbin, 6), 3,4-dimethoxybenzyl GSL (10) and 2-phenylethyl GSL (gluconasturtiin, 13). GSL breakdown products obtained by hydrodistillation (HD) and CH2Cl2 extraction after hydrolysis by myrosinase for 24 h (EXT) as well as benzyl ITC were tested for their cytotoxic activity using MTT assay. Generally, EXT showed noticeable antiproliferative activity against human bladder cancer cell line UM-UC-3 and human glioblastoma cell line LN229, and can be considered as moderately active, while IC50 of benzyl ITC was 12.3 µg/mL, which can be considered as highly active.


Assuntos
Proliferação de Células/efeitos dos fármacos , Glucosinolatos/química , Glucosinolatos/farmacologia , Lepidium/química , Linhagem Celular Tumoral , Cromatografia Gasosa-Espectrometria de Massas/métodos , Glioblastoma/tratamento farmacológico , Humanos , Hidrólise , Isotiocianatos/química , Isotiocianatos/farmacologia , Espectrometria de Massas em Tandem/métodos , Tiocianatos/química , Tiocianatos/farmacologia , Tioglucosídeos/química , Tioglucosídeos/farmacologia , Neoplasias da Bexiga Urinária/tratamento farmacológico
15.
Medicina (Kaunas) ; 57(9)2021 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-34577802

RESUMO

Background and Objectives: Malignant glioblastoma (GBM) is caused by abnormal proliferation of glial cells, which are found in the brain. The therapeutic effects of surgical treatment, radiation therapy, and chemo-therapy against GBM are relatively poor compared with their effects against other tumors. Luteolin is abundant in peanut shells and is also found in herbs and other plants, such as thyme, green pepper, and celery. Luteolin is known to be effective against obesity and metabolic syndrome. The anti-inflammatory, and anti-cancer activities of luteolin have been investigated. Most studies have focused on the antioxidant and anti-inflammatory effects of luteolin, which is a natural flavonoid. However, the association between the induction of apoptosis by luteolin in GBM and autophagy has not yet been investigated. This study thus aimed to confirm the occurrence of luteolin-induced apoptosis and autophagy in GBM cells and to assess their relationship. Materials and Methods: A172 and U-373MG glioblastoma cell lines were used for this experiment. We confirmed the apoptosis effect of Luteolin on GBM cells using methods such as 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, immunofluorescence, Flow cytometry (FACS) western blot, and real-time quantitative PCR (qPCR). Results: In the luteolin-treated A172 and U-373MG cells, cell viability decreased in a concentration- and time-dependent manner. In addition, in A172 and U-373MG cells treated with luteolin at concentrations greater than 100 µM, nuclear fragmentation, which is a typical morphological change characterizing apoptosis, as well as fragmentation of caspase-3 and Poly (ADP-ribose) polymerase (PARP), which are apoptosis-related factors, were observed. Autophagy was induced after treatment with at least 50 µM luteolin. Inhibition of autophagy using 3MA allowed for a low concentration of luteolin to more effectively induce apoptosis in A172 and U-373MG cells. Conclusions: Results showed that luteolin induces apoptosis and autophagy and that the luteolin-induced autophagy promotes cell survival. Therefore, an appropriate combination therapy involving luteolin and an autophagy inhibitor is expected to improve the prognosis of GBM treatment.


Assuntos
Glioblastoma , Luteolina , Apoptose , Autofagia , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular , Glioblastoma/tratamento farmacológico , Humanos , Luteolina/farmacologia , Luteolina/uso terapêutico
16.
Medicina (Kaunas) ; 57(9)2021 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-34577831

RESUMO

Background: Glioblastoma is the most frequent and aggressive malignant brain tumor among adults. Unfortunately, its symptoms can vary considerably depending on the size, location and the anatomic structures of the involved brain. Case report: A 58-year-old male amateur cyclist who suffered from sharp arm pain was examined for a thoracic outlet syndrome due to a previous clavicle fracture. Because of ambiguous results of the neck and nerve plexus imaging, he was referred to a neurosurgeon who properly suspected a brain tumor. The neuroimaging of the brain shown a 3 cm disploriferative mass with a blood enhancement within the left parietal lobe. The mass was urgently removed, and its histologic analysis stated a grade 4 glioblastoma. Conclusion: This case report highlights the differential diagnosis process and the teamwork approach needed to diagnose a rare presentation of a brain glioblastoma, which started its symptoms mimicking a thoracic outlet syndrome caused by a previous bone fracture.


Assuntos
Fraturas Ósseas , Glioblastoma , Síndrome do Desfiladeiro Torácico , Adulto , Clavícula , Diagnóstico Diferencial , Glioblastoma/diagnóstico , Glioblastoma/diagnóstico por imagem , Humanos , Masculino , Pessoa de Meia-Idade , Síndrome do Desfiladeiro Torácico/diagnóstico por imagem
17.
Molecules ; 26(17)2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34500575

RESUMO

Glioblastoma (GB), is the most common and aggressive malignant primary brain tumour in adults. Intra- and inter-tumour heterogeneity, infiltrative GB cell invasion and presence of therapy-resistant GB stem cells (GSCs) represent major obstacles to favourable prognosis and poor therapy response. Identifying the biomarkers of the most aggressive tumour cells and their more efficient targeting strategies are; therefore, crucial. Recently, transcription factor TRIM28 has been identified as a GB biomarker and, in this study, we have shown high expression of TRIM28 in GB and in low grade gliomas as well as higher expression in GSCs vs. differentiated GB cells, although in both cases not significant. We demonstrated significant in vitro inhibition of GB cells and GSCs invasiveness and spread in zebrafish brains in vivo by anti-TRIM28 selective nanobody NB237. TRIM28 was also enriched in GB (tumour) core and associated with the expression of stem cell genes, but was not prognostic for overall survival. However, based on the above results, we conclude that TRIM28 nanobody NB237 offers a new opportunity as a GB therapeutic tool.


Assuntos
Neoplasias Encefálicas/metabolismo , Glioblastoma/metabolismo , Proteína 28 com Motivo Tripartido/metabolismo , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Glioblastoma/patologia , Humanos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Prognóstico , Peixe-Zebra/metabolismo
19.
Nanomedicine (Lond) ; 16(23): 2095-2115, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34523353

RESUMO

Aim: To develop and characterize bozepinib-loaded lipid-core nanocapsules (BZP-LNC+) as a potential treatment for glioblastoma (GBM). Methods: Characterization of nanocapsules was performed by diameter, polydispersity index, Zeta potential, pH and encapsulation efficiency. GBM cell viability, cell cycle and Annexin/PI were evaluated after BZP-LNC+ treatment. Synergism between BZP-LNC+ and temozolomide (TMZ) was performed by CompuSyn software and confirmed in vitro and in vivo. Results: BZP-LNC+ showed adequate particle sizes, positive Zeta potential, narrow size distribution and high encapsulation efficiency. BZP-LNC+ reduces GBM growth by inducing apoptosis. BZP-LNC+ and TMZ showed synergistic effect in vitro and reduced the in vivo glioma growth by approximately 81%. Conclusion: The present study provides proof-of-principle insights for the combination of these drugs for GBM treatment.


Assuntos
Glioblastoma , Nanocápsulas , Encéfalo , Linhagem Celular Tumoral , Glioblastoma/tratamento farmacológico , Humanos , Nanocápsulas/uso terapêutico , Oxazepinas , Purinas
20.
Nat Commun ; 12(1): 5551, 2021 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-34548489

RESUMO

While dysregulation of RNA splicing has been recognized as an emerging target for cancer therapy, the functional significance of RNA splicing and individual splicing factors in brain tumors is poorly understood. Here, we identify SON as a master regulator that activates PTBP1-mediated oncogenic splicing while suppressing RBFOX2-mediated non-oncogenic neuronal splicing in glioblastoma multiforme (GBM). SON is overexpressed in GBM patients and SON knockdown causes failure in intron removal from the PTBP1 transcript, resulting in PTBP1 downregulation and inhibition of its downstream oncogenic splicing. Furthermore, SON forms a complex with hnRNP A2B1 and antagonizes RBFOX2, which leads to skipping of RBFOX2-targeted cassette exons, including the PTBP2 neuronal exon. SON knockdown inhibits proliferation and clonogenicity of GBM cells in vitro and significantly suppresses tumor growth in orthotopic xenografts in vivo. Collectively, our study reveals that SON-mediated RNA splicing is a GBM vulnerability, implicating SON as a potential therapeutic target in brain tumors.


Assuntos
Neoplasias Encefálicas/genética , Proteínas de Ligação a DNA/genética , Glioblastoma/genética , Ribonucleoproteínas Nucleares Heterogêneas/genética , Antígenos de Histocompatibilidade Menor/genética , Proteínas do Tecido Nervoso/genética , Proteína de Ligação a Regiões Ricas em Polipirimidinas/genética , Fatores de Processamento de RNA/genética , Splicing de RNA , Proteínas Repressoras/genética , Animais , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células , Proteínas de Ligação a DNA/antagonistas & inibidores , Proteínas de Ligação a DNA/metabolismo , Éxons , Regulação Neoplásica da Expressão Gênica , Glioblastoma/metabolismo , Glioblastoma/mortalidade , Glioblastoma/patologia , Ribonucleoproteínas Nucleares Heterogêneas Grupo A-B/genética , Ribonucleoproteínas Nucleares Heterogêneas Grupo A-B/metabolismo , Ribonucleoproteínas Nucleares Heterogêneas/metabolismo , Xenoenxertos , Humanos , Íntrons , Camundongos , Antígenos de Histocompatibilidade Menor/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Neuroglia/metabolismo , Neuroglia/patologia , Neurônios/metabolismo , Neurônios/patologia , Proteína de Ligação a Regiões Ricas em Polipirimidinas/metabolismo , Fatores de Processamento de RNA/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Proteínas Repressoras/metabolismo , Transdução de Sinais , Esferoides Celulares/metabolismo , Esferoides Celulares/patologia , Análise de Sobrevida
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