High-Throughput Targeted Drug Screening for NF1-associated High-Grade Gliomas with ATRX Deficiency DOI Creative Commons
Swati Dubey,

S.N. Rai,

Fabiola Guillen

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Дек. 17, 2024

Abstract Neurofibromatosis type 1 (NF1)-associated high-grade gliomas (HGGs) harboring ATRX mutations exhibit an aggressive clinical phenotype, driven by heightened genomic instability and metabolic reprogramming. Existing therapies, including chemotherapy radiotherapy, are limited resistance mechanisms formation of secondary malignancy, underscoring the need for novel therapeutic strategies. Here, we report results a high-throughput screening 10,000 small molecules aimed at identifying compounds selectively targeting vulnerabilities associated with concurrent NF1 loss. Among screened compounds, K784-6195 (ChemDiv ID) emerged as promising candidate, exhibiting marked selective cytotoxicity in NF1-associated glioma cell lines deficiency (IC50 = 4.84 µM). In comparison, wild-type sporadic (U251) exhibited significantly reduced sensitivity to 37.03 However, knockout U251 cells recapitulating loss susceptibility 20-23 µM) compared their counterpart. Metabolomic analysis revealed that treatment impairs pathways, pentose phosphate pathway, glutamine metabolism, redox homeostasis, leading oxidative stress impaired survival. These findings highlight candidate development, offering targeted approach NF-1 HGGs deficiency.

Язык: Английский

Identification of Prognostic Genes Related to Cell Senescence and Lipid Metabolism in Glioblastoma Based on Transcriptome and Single-Cell RNA-Seq Data DOI Open Access

Qiong Li,

Hongde Liu

International Journal of Molecular Sciences, Год журнала: 2025, Номер 26(5), С. 1875 - 1875

Опубликована: Фев. 21, 2025

Glioblastoma (GBM) is the most aggressive primary brain cancer, with poor prognosis due to its behavior and high heterogeneity. This study aimed identify cellular senescence (CS) lipid metabolism (LM)-related prognostic genes improve GBM treatment. Transcriptome scRNA-seq data, CS-associated (CSAGs), LM-related (LMRGs) were acquired from public databases. Prognostic identified by intersecting CSAGs, LMRGs, differentially expressed (DEGs), followed WGCNA univariate Cox regression. A risk model nomogram constructed. Analyses covered clinicopathological features, immune microenvironment, somatic mutations, drug sensitivity. data key cells gene expression. SOCS1 PHB2 as markers, contributing construction of a robust excellent predictive ability. High-risk group (HRG) patients had poorer survival, higher stromal scores, distinct mutation profiles. Drug sensitivity analysis revealed significant differences in IC50 values. In microglia differentiation, showed dynamic expression patterns. These findings provide new strategies for

Язык: Английский

Процитировано

0
Targeting metabolic reprogramming in glioblastoma as a new strategy to overcome therapy resistance DOI Creative Commons
Simona D’Aprile, Simona Denaro,

Anna Gervasi

и другие.

Frontiers in Cell and Developmental Biology, Год журнала: 2025, Номер 13

Опубликована: Фев. 26, 2025

Glioblastoma (GBM) is one of the deadliest tumors due to its high aggressiveness and resistance standard therapies, resulting in a dismal prognosis. This lethal tumor carries out metabolic reprogramming order modulate specific pathways, providing metabolites that promote GBM cells proliferation limit efficacy treatments. Indeed, remodels glucose metabolism undergoes Warburg effect, fuelling glycolysis even when oxygen available. Moreover, recent evidence revealed rewiring nucleotide, lipid iron metabolism, not only an increased growth, but also radio- chemo-resistance. Thus, while on hand advantage for GBM, other it may represent exploitable target hamper progression. Lately, number studies focused drugs targeting uncover their effects therapy resistance, demonstrating some these are effective, combination with conventional treatments, sensitizing radiotherapy chemotherapy. However, heterogeneity could lead plethora alterations among subtypes, hence treatment might be effective proneural mesenchymal ones, which more aggressive resistant approaches. review explores key mechanisms involvement highlighting how acts as double-edged sword taking into account pathways seem offer promising options GBM.

Язык: Английский

Процитировано

0
Green chemistry: Modern therapies using nanocarriers for treating rare brain cancer metastasis from colon cancer DOI Creative Commons
Doaa S. R. Khafaga, Ghazala Muteeb,

Darin W Aswa

и другие.

SLAS DISCOVERY, Год журнала: 2025, Номер unknown, С. 100213 - 100213

Опубликована: Янв. 1, 2025

Brain metastasis (BM) from colon cancer is associated with a poor prognosis and restricted treatment alternatives, largely due to issues related blood-brain barrier (BBB) permeability the negative effects of standard chemotherapy. Nanotechnology improves efficacy by enabling targeted controlled drug delivery. This review article evaluates potential nanotechnology-based therapies for treating BM, emphasizing their capacity cross BBB, diminish metastatic growth, enhance overall survival rates. A multiple studies evaluated nanoparticles (NPs) as carriers chemotherapy, focusing on parameters including particle size, surface charge, drug-loading capacity. The study also reviewed that examined BBB penetration, in vitro tumor accumulation, vivo growth inhibition. In findings indicated NPs accumulate more efficiently BM tissue than healthy brain show significant penetration. vivo, nanotherapy markedly inhibited prolonged relative conventional chemotherapy or control treatments while exhibiting reduced side effects. Recent demonstrated plant extracts can effectively safely synthesize nanomaterials, positioning them viable environmentally friendly precursor nanomaterial production. Nanotechnology-based demonstrate minimizing systemic toxicity, enhancing therapeutic efficacy, facilitating Further research required confirm these implement clinical practice.

Язык: Английский

Процитировано

0
Enhancing the Understanding of Ferroptosis Mechanisms in Glioblastoma: An Integrated Approach Utilizing Single-Cell Sequencing and Mendelian Randomization Methods DOI Creative Commons
Menghao Liu, Wencai Wang, Hui Liu

и другие.

Research Square (Research Square), Год журнала: 2025, Номер unknown

Опубликована: Фев. 24, 2025

Abstract Background: Ferroptosis, a novel form of regulated cell death, has emerged as significant research focus due to its involvement in various cancers. This study combines single-cell RNA sequencing with Mendelian randomization (MR) methods identify genetic factors that are associated ferroptosis and explore their potential impact on the pathogenesis glioblastoma (GBM). Methods: MR multiple validation were used ferroptosis-related genes glioblastoma. Single-cell analysis was performed evaluate expression levels markers across different types. Additionally, gene enrichment conducted functions, while survival examined relationship between patient prognosis. Immune infiltration also carried out for Results: sensitivity analyses identified 9 GBM: SIRT1, KDM3B, VCP, GPT2, PRDX6, CISD2, TP53, FLT3, FANCD2. Co-localization showed association VCP GBM. revealed PRDX6 is highly expressed tumor tissues. Gene highlighted biological processes such metabolism, DNA repair, ubiquitination, autophagy occurrence progression suggest CISD2 related CD8+ CD4+ T infiltration, may affect Conclusions: reveal crucial role These influence development GBM by regulating oxidative stress, autophagy. Among them, plays an important microscopic research, ubiquitination key drivers progression. The prognosis thereby promoting immune tolerance mechanisms cells.

Язык: Английский

Процитировано

0
Investigating the antiproliferative properties of Amaryllidaceae plant species and their bioactive compounds on brain tumour cell lines DOI Creative Commons
Sylvester I. Omoruyi, Tanya N. Augustine,

Lawrence Mabasa

и другие.

Advances in Traditional Medicine, Год журнала: 2025, Номер unknown

Опубликована: Фев. 27, 2025

Abstract Glioblastoma multiforme is considered the most aggressive type of brain tumour due to its highly invasive properties that make complete surgical resection almost impossible and treatment very challenging. The current for glioblastoma involves surgery followed by radiotherapy chemotherapy. Despite these options, recurrence toxicity from chemotherapeutic agents remain problematic, which calls novel approaches. In this study, we investigate antiproliferative activities three Amaryllidaceae plant species, Crossyne flava , Amaryllis belladonna Boophone haemanthiodes, as well their isolated bioactive compounds on U87 U251 cell lines, with H9C2 cardiac myocyte used a normal line. effect extracts viability long-term survival was determined using MTT [3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide] clonogenic assay, respectively. Additionally, ATP levels apoptosis-inducing potential were Promega Mitochondrial ToxGlo™ Caspase-Glo™ 3/7 assay kits, results reveal both induce cytotoxicity in also inhibit cells. selective cancer cells when selectivity index calculated. Furthermore, inhibited production cells, while induction apoptosis only evident compound-treated Overall, our findings suggest family could be rich source botanicals phytochemicals might effective against glioblastoma.

Язык: Английский

Процитировано

0
High-Throughput Targeted Drug Screening for NF1-associated High-Grade Gliomas with ATRX Deficiency DOI Creative Commons
Swati Dubey,

S.N. Rai,

Fabiola Guillen

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Дек. 17, 2024

Abstract Neurofibromatosis type 1 (NF1)-associated high-grade gliomas (HGGs) harboring ATRX mutations exhibit an aggressive clinical phenotype, driven by heightened genomic instability and metabolic reprogramming. Existing therapies, including chemotherapy radiotherapy, are limited resistance mechanisms formation of secondary malignancy, underscoring the need for novel therapeutic strategies. Here, we report results a high-throughput screening 10,000 small molecules aimed at identifying compounds selectively targeting vulnerabilities associated with concurrent NF1 loss. Among screened compounds, K784-6195 (ChemDiv ID) emerged as promising candidate, exhibiting marked selective cytotoxicity in NF1-associated glioma cell lines deficiency (IC50 = 4.84 µM). In comparison, wild-type sporadic (U251) exhibited significantly reduced sensitivity to 37.03 However, knockout U251 cells recapitulating loss susceptibility 20-23 µM) compared their counterpart. Metabolomic analysis revealed that treatment impairs pathways, pentose phosphate pathway, glutamine metabolism, redox homeostasis, leading oxidative stress impaired survival. These findings highlight candidate development, offering targeted approach NF-1 HGGs deficiency.

Язык: Английский

Процитировано

0