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Biomedicine & Pharmacotherapy =... Jul 2024The lesson from many studies investigating the efficacy of targeted therapy in glioblastoma (GBM) showed that a future perspective should be focused on combining...
The lesson from many studies investigating the efficacy of targeted therapy in glioblastoma (GBM) showed that a future perspective should be focused on combining multiple target treatments. Our research aimed to assess the efficacy of drug combinations against glioblastoma stem cells (GSCs). Patient-derived cells U3042, U3009, and U3039 were obtained from the Human Glioblastoma Cell Culture resource. Additionally, the study was conducted on a GBM commercial U251 cell line. Gene expression analysis related to receptor tyrosine kinases (RTKs), stem cell markers and genes associated with significant molecular targets was performed, and selected proteins encoded by these genes were assessed using the immunofluorescence and flow cytometry methods. The cytotoxicity studies were preceded by analyzing the expression of specific proteins that serve as targets for selected drugs. The cytotoxicity study using the MTS assay was conducted to evaluate the effects of selected drugs/candidates in monotherapy and combinations. The most cytotoxic compounds for U3042 cells were Disulfiram combined with Copper gluconate (DSF/Cu), Dacomitinib, and Foretinib with IC values of 52.37 nM, 4.38 µM, and 4.54 µM after 24 h incubation, respectively. Interactions were assessed using SynergyFinder Plus software. The analysis enabled the identification of the most effective drug combinations against patient-derived GSCs. Our findings indicate that the most promising drug combinations are Dacomitinib and Foretinib, Dacomitinib and DSF/Cu, and Foretinib and AZD3759. Since most tested combinations have not been previously examined against glioblastoma stem-like cells, these results can shed new light on designing the therapeutic approach to target the GSC population.
Topics: Humans; Glioblastoma; Neoplastic Stem Cells; Drug Repositioning; Protein Kinase Inhibitors; Cell Line, Tumor; Receptor Protein-Tyrosine Kinases; Brain Neoplasms; Antineoplastic Combined Chemotherapy Protocols; Antineoplastic Agents; Cell Survival
PubMed: 38876048
DOI: 10.1016/j.biopha.2024.116892 -
Acta Neurochirurgica Jun 2024Increased use of whole genome sequencing (WGS) in neuro-oncology for diagnostics and research purposes necessitates a renewed conversation about informed consent... (Review)
Review
Increased use of whole genome sequencing (WGS) in neuro-oncology for diagnostics and research purposes necessitates a renewed conversation about informed consent procedures and governance structures for sharing personal health data. There is currently no consensus on how to obtain informed consent for WGS in this population. In this narrative review, we analyze the formats and contents of frameworks suggested in literature for WGS in oncology and assess their benefits and limitations. We discuss applicability, specific challenges, and legal context for patients with (recurrent) glioblastoma. This population is characterized by the rarity of the disease, extremely limited prognosis, and the correlation of the stage of the disease with cognitive abilities. Since this has implications for the informed consent procedure for WGS, we suggest that the content of informed consent should be tailor-made for (recurrent) glioblastoma patients.
Topics: Humans; Glioblastoma; Informed Consent; Brain Neoplasms; Whole Genome Sequencing; Information Dissemination; Neoplasm Recurrence, Local
PubMed: 38874628
DOI: 10.1007/s00701-024-06158-z -
Mathematical Biosciences and... Apr 2024
Topics: Glioblastoma; Humans; Cell Proliferation; Brain Neoplasms
PubMed: 38872553
DOI: 10.3934/mbe.2024250 -
Cell Death & Disease Jun 2024The repurposing of medications developed for central nervous system (CNS) disorders, possessing favorable safety profiles and blood-brain barrier permeability,...
The repurposing of medications developed for central nervous system (CNS) disorders, possessing favorable safety profiles and blood-brain barrier permeability, represents a promising strategy for identifying new therapies to combat glioblastoma (GBM). In this study, we investigated the anti-GBM activity of specific antipsychotics and antidepressants in vitro and in vivo. Our results demonstrate that these compounds share a common mechanism of action in GBM, disrupting lysosomal function and subsequently inducing lysosomal membrane rupture and cell death. Notably, PTEN intact GBMs possess an increased sensitivity to these compounds. The inhibition of lysosomal function synergized with inhibitors targeting the EGFR-PI3K-Akt pathway, leading to an energetic and antioxidant collapse. These findings provide a foundation for the potential clinical application of CNS drugs in GBM treatment. Additionally, this work offers critical insights into the mechanisms and determinants of cytotoxicity for drugs currently undergoing clinical trials as repurposing agents for various cancers, including Fluoxetine, Sertraline, Thioridazine, Chlorpromazine, and Fluphenazine.
Topics: Humans; Glioblastoma; PTEN Phosphohydrolase; Lysosomes; Signal Transduction; Antipsychotic Agents; Animals; Cell Line, Tumor; Mice; Brain Neoplasms; Proto-Oncogene Proteins c-akt; Mice, Nude; Drug Repositioning; Phosphatidylinositol 3-Kinases; ErbB Receptors; Chlorpromazine
PubMed: 38871731
DOI: 10.1038/s41419-024-06779-3 -
Scientific Reports Jun 2024Glioblastoma is a rare and deadly malignancy with a low survival rate. Emerging evidence has shown that aberrantly expressed circular RNAs (circRNAs) play a critical...
Glioblastoma is a rare and deadly malignancy with a low survival rate. Emerging evidence has shown that aberrantly expressed circular RNAs (circRNAs) play a critical role in the initiation and progression of GBM tumorigenesis. The oncogenic function of circZNF609 and circNFIX is involved in several types of cancer, but the role and underlying mechanism of these circRNAs in glioblastoma remain unclear. In this study, we hypothesized that circZNF609 and circNFIX may regulate EGFR through sponging miR-145-5p. Herein, we assessed the expression levels of circZNF609, circNFIX, miR-145-5p, and EGFR using quantitative polymerase chain reaction in glioblastoma patients and normal brain samples. The results showed that circZNF609, circNFIX, and EGFR expression levels were upregulated and miR145-5p was downregulated (p = 0.001, 0.06, 0.002, and 0.0065, respectively), while there was no significant association between clinicopathological features of the patients and the level of these genes expression. We also found a significant inverse correlation between miR145-5p and the expression of cZNF609, cNFIX and EGFR (p = 0.0003, 0.0006, and 0.009, respectively). These findings may open a new window for researchers to better understand the potential pathways involved in GBM pathogenesis. In conclusion, it may provide a new potential pathway for the development of effective drugs for the treatment of GBM patients.
Topics: Humans; MicroRNAs; Glioblastoma; ErbB Receptors; RNA, Circular; Male; Female; Gene Expression Regulation, Neoplastic; Middle Aged; Brain Neoplasms; NFI Transcription Factors; Adult; Aged; Cell Line, Tumor
PubMed: 38866807
DOI: 10.1038/s41598-024-63827-w -
Revista Da Associacao Medica Brasileira... 2024
Review
Topics: Humans; Glioblastoma; Palliative Care; Brain Neoplasms
PubMed: 38865542
DOI: 10.1590/1806-9282.2024S122 -
CNS Oncology Jun 2024Glioblastoma is the most common malignant primary brain tumor. Despite its infiltrative nature, extra-cranial glioblastoma metastases are rare. We present a case of a... (Review)
Review
Glioblastoma is the most common malignant primary brain tumor. Despite its infiltrative nature, extra-cranial glioblastoma metastases are rare. We present a case of a 63-year-old woman with metastatic glioblastoma in the lungs. Sarcomatous histology, a reported risk factor for disseminated disease, was found. Genomic alterations of mutation, mutation, mutation, and +7/-10 were also uncovered. Early evidence suggests these molecular aberrations are common in metastatic glioblastoma. Treatment with third-line lenvatinib resulted in a mixed response. This case contributes to the growing body of evidence for the role of genomic alterations in predictive risk in metastatic glioblastoma. There remains an unmet need for treatment of metastatic glioblastoma.
Topics: Female; Humans; Middle Aged; Brain Neoplasms; Glioblastoma; Lung Neoplasms
PubMed: 38864820
DOI: 10.1080/20450907.2024.2351789 -
Journal of Cellular and Molecular... Jun 2024Deciphering the lncRNA-associated competitive endogenous RNA (ceRNA) network is essential in decoding glioblastoma multiforme (GBM) pathogenesis by regulating miRNA...
Deciphering the lncRNA-associated competitive endogenous RNA (ceRNA) network is essential in decoding glioblastoma multiforme (GBM) pathogenesis by regulating miRNA availability and controlling mRNA stability. This study aimed to explore novel biomarkers for GBM by constructing a lncRNA-miRNA-mRNA network. A ceRNA network in GBM was constructed using lncRNA, mRNA and miRNA expression profiles from the TCGA and GEO datasets. Seed nodes were identified by protein-protein interaction (PPI) network analysis of deregulated-mRNAs (DEmRNAs) in the ceRNA network. A lncRNA-miRNA-seed network was constructed by mapping the seed nodes into the preliminary ceRNA network. The impact of the seed nodes on the overall survival (OS) of patients was assessed by the GSCA database. Functional enrichment analysis of the deregulated-lncRNAs (DElncRNA) in the ceRNA network and genes interacting with OS-related genes in the PPI network were performed. Finally, the positive correlation between seed nodes and their associated lncRNAs and the expression level of these molecules in GBM tissue compared with normal samples was validated using the GEPIA database. Our analyzes revealed that three novel regulatory axes AL161785.1/miR-139-5p/MS4A6A, LINC02611/miR-139-5p/MS4A6A and PCED1B-AS1/miR-433-3p/MS4A6A may play essential roles in GBM pathogenesis. MS4A6A is upregulated in GBM and closely associated with shorter survival time of patients. We also identified that MS4A6A expression positively correlates with genes related to tumour-associated macrophages, which induce macrophage infiltration and immune suppression. The functional enrichment analysis demonstrated that DElncRNAs are mainly involved in neuroactive ligand-receptor interaction, calcium/MAPK signalling pathway, ribosome, GABAergic/Serotonergic/Glutamatergic synapse and immune system process. In addition, genes related to MS4A6A contribute to immune and inflammatory-related biological processes. Our findings provide novel insights to understand the ceRNA regulation in GBM and identify novel prognostic biomarkers or therapeutic targets.
Topics: Humans; Glioblastoma; RNA, Long Noncoding; Gene Regulatory Networks; Gene Expression Regulation, Neoplastic; Prognosis; MicroRNAs; RNA, Messenger; Biomarkers, Tumor; Protein Interaction Maps; Brain Neoplasms; Gene Expression Profiling; Computational Biology; Databases, Genetic; RNA, Competitive Endogenous
PubMed: 38864705
DOI: 10.1111/jcmm.18392 -
Journal of Enzyme Inhibition and... Dec 2024The spices and aromatic herbs were used not only in cooking to add flavour and smell to dishes but also for medicinal use. Nigella sativa, also called black cumin, is...
The spices and aromatic herbs were used not only in cooking to add flavour and smell to dishes but also for medicinal use. Nigella sativa, also called black cumin, is one of the species that contains an important bioactive component, thymoquinone (TQ), which has antioxidant, anti-inflammatory, antimicrobial, and antidiabetic effects. Curcuma longa, which also includes curcumin, has numerous anti-cancer properties. However, the bioavailability of curcumin is lower than that of its analogs. An analog of curcumin (EF-24), which has better bioavailability than curcumin, is capable of exerting a high anti-cancer effect. In our study, we determined the effects of PON1 enzyme activity on the proliferation and aggressiveness of glioblastoma cancer treated with TQ and EF-24 from lysates of the glioblastoma cell line U87MG. The results were determined as increased PON1 activity after treatment with TQ and EF-24 in the U87MG cell line ( < 0.0001).
Topics: Humans; Aryldialkylphosphatase; Glioblastoma; Benzoquinones; Curcumin; Cell Proliferation; Dose-Response Relationship, Drug; Molecular Structure; Structure-Activity Relationship; Drug Screening Assays, Antitumor; Antineoplastic Agents; Cell Line, Tumor; Tumor Cells, Cultured
PubMed: 38864175
DOI: 10.1080/14756366.2024.2339901 -
Cell Biology and Toxicology Jun 2024Vasculogenic mimicry (VM) is an enigmatic physiological feature that influences blood supply within glioblastoma (GBM) tumors for their sustained growth. Previous...
BACKGROUND
Vasculogenic mimicry (VM) is an enigmatic physiological feature that influences blood supply within glioblastoma (GBM) tumors for their sustained growth. Previous studies identify NFATC3, FOSL1 and HNRNPA2B1 as significant mediators of VEGFR2, a key player in vasculogenesis, and their molecular relationships may be crucial for VM in GBM.
AIMS
The aim of this study was to understand how NFATC3, FOSL1 and HNRNPA2B1 collectively influence VM in GBM.
METHODS
We have investigated the underlying gene regulatory mechanisms for VM in GBM cell lines U251 and U373 in vitro and in vivo. In vitro cell-based assays were performed to explore the role of NFATC3, FOSL1 and HNRNPA2B1 in GBM cell proliferation, VM and migration, in the context of RNA interference (RNAi)-mediated knockdown alongside corresponding controls. Western blotting and qRT-PCR assays were used to examine VEGFR2 expression levels. CO-IP was employed to detect protein-protein interactions, ChIP was used to detect DNA-protein complexes, and RIP was used to detect RNA-protein complexes. Histochemical staining was used to detect VM tube formation in vivo.
RESULTS
Focusing on NFATC3, FOSL1 and HNRNPA2B1, we found each was significantly upregulated in GBM and positively correlated with VM-like cellular behaviors in U251 and U373 cell lines. Knockdown of NFATC3, FOSL1 or HNRNPA2B1 each resulted in decreased levels of VEGFR2, a key growth factor gene that drives VM, as well as the inhibition of proliferation, cell migration and extracorporeal VM activity. Chromatin immunoprecipitation (ChIP) studies and luciferase reporter gene assays revealed that NFATC3 binds to the promoter region of VEGFR2 to enhance VEGFR2 gene expression. Notably, FOSL1 interacts with NFATC3 as a co-factor to potentiate the DNA-binding capacity of NFATC3, resulting in enhanced VM-like cellular behaviors. Also, level of NFATC3 protein in cells was enhanced through HNRNPA2B1 binding of NFATC3 mRNA. Furthermore, RNAi-mediated silencing of NFATC3, FOSL1 and HNRNPA2B1 in GBM cells reduced their capacity for tumor formation and VM-like behaviors in vivo.
CONCLUSION
Taken together, our findings identify NFATC3 as an important mediator of GBM tumor growth through its molecular and epistatic interactions with HNRNPA2B1 and FOSL1 to influence VEGFR2 expression and VM-like cellular behaviors.
Topics: Humans; Proto-Oncogene Proteins c-fos; Glioblastoma; Cell Line, Tumor; Heterogeneous-Nuclear Ribonucleoprotein Group A-B; NFATC Transcription Factors; Animals; Cell Proliferation; Neovascularization, Pathologic; Cell Movement; Vascular Endothelial Growth Factor Receptor-2; Gene Expression Regulation, Neoplastic; Mice; Brain Neoplasms; Mice, Nude
PubMed: 38862832
DOI: 10.1007/s10565-024-09890-5