Search Results (86)

Background: Enhancer RNAs (eRNAs), a subclass of long non-coding RNAs transcribed from enhancer regions, have emerged as dynamic regulators of gene expression, tumor progression, and therapeutic response. In gliomas, their biological and clinical significance is only recently being elucidated. This systematic review aimed to synthesize current evidence regarding the role of eRNAs in gliomagenesis, chemoresistance, and prognosis. Methods: We conducted a systematic review following PRISMA 2020 guidelines. PubMed/MEDLINE and Scopus databases were searched on September 2025 using a predefined strategy. Eligible studies included clinical or pre-clinical analyses of eRNAs in gliomas, reporting associations with tumorigenicity, survival, or resistance to temozolomide (TMZ). Risk of bias was assessed using ROBINS-I (Version 2), and findings were qualitatively synthesized. Results: From 26 retrieved records, 10 studies were included, encompassing 22 unique eRNAs. Two studies demonstrated that TMZR1-eRNA and LINC02454* modulate TMZ sensitivity by regulating STAT3, SORBS2, and DDR1 pathways. Seven studies evaluated prognostic implications: 12 eRNAs (e.g., AC003092.1, CYP1B1-AS1, CRNDE) were consistently associated with poor survival, while seven (e.g., LINC00844, ENSR00000260547) correlated with favorable outcomes, particularly in low-grade gliomas. One mechanistic study showed that HOXDeRNA directly promotes gliomagenesis by displacing PRC2 repression at key transcription factor promoters and activating oncogenic super-enhancers. Conclusions: eRNAs are not passive transcriptional by-products but active modulators of glioma biology. They influence tumor initiation, therapeutic resistance, and survival outcomes, underscoring their potential as prognostic biomarkers and therapeutic targets. Future research should validate these findings in larger clinical cohorts and explore strategies for eRNA-directed therapies in precision neuro-oncology. Full article

Glioblastoma multiforme (GBM) is an aggressive brain tumor with limited treatment options and a poor prognosis. Natural phytochemicals from Dendrobium species, particularly bibenzyl derivatives, possess diverse pharmacological activities, yet their potential against GBM remains largely unexplored. Here, we investigated the anticancer activity of 4,5,4′-trihydroxy-3,3′-dimethoxybibenzyl (TDB), a potent antioxidant bibenzyl derivative isolated from Dendrobium pachyglossum. In U87MG cells, TDB reduced viability in a dose- and time-dependent manner, suppressed clonogenic growth, induced apoptosis via Bax upregulation and Bcl-xL/Mcl-1 downregulation, and inhibited both mTORC1 and mTORC2 signaling. TDB also impaired cell migration and downregulated epithelial–mesenchymal transition (EMT)-associated proteins. Notably, TDB enhanced the cytotoxicity of temozolomide (TMZ), the current standard of care for GBM. These TMZ-sensitizing properties were further confirmed in patient-derived xenograft (PDX) Jx22 cells. To assess its potential for central nervous system delivery, blood–brain barrier (BBB) permeability was predicted using four independent in silico platforms—ADMETlab 3.0, LogBB_Pred, LightBBB, and BBB Predictor (Tree2C)—all of which consistently classified TDB as BBB-permeable. This predicted CNS accessibility, together with its potent anticancer profile, underscores TDB’s translational promise. Collectively, our findings identify TDB as a plant-derived antioxidant with multifaceted anti-GBM activity and favorable BBB penetration potential, warranting further in vivo validation and preclinical development as a novel therapeutic candidate for GBM. Full article

Extracellular vesicles (EVs) secreted by glioblastoma multiforme and other types of cancer cells are key factors contributing to the aggressiveness of the disease and its resistance to therapy. Chloroquine (CHQ), a lysosomal inhibitor, has shown potential as an enhancer of temozolomide (TMZ) cytotoxicity against glioblastoma cells. Since both CHQ and TMZ are known to modulate EV secretion, we sought to investigate their potential interplay in this process. Simultaneous treatment of TMZ-sensitive (U87-MG) and TMZ-resistant (U138-MG) glioblastoma cells with TMZ and CHQ led to a synergistic upregulation of EV secretion. Although CHQ did not enhance the TMZ cytotoxicity in U87-MG cells, it synergized with the latter to upregulate the release of extracellular nucleic acids implicating activation of unconventional secretory pathways. Synergistic upregulation of the autophagy markers LC3B-II and p62 by CHQ and TMZ in both cells and EVs indicates that secretory autophagy is likely involved in the observed unconventional secretion. Moreover, a significant enrichment of caveolin-1 in small EVs highlights their potential role in modulating tumor aggressiveness. The synergy in EV upregulation was not confined to the specific biological activity of TMZ and CHQ; similar effects were observed upon co-treatments with CHQ and etoposide (a topoisomerase inhibitor) and TMZ and Bafilomycin A1 (another lysosomal inhibitor). Heightened EV release was also observed in THP-1 monocytes and macrophages treated with Bafilomycin and TMZ, highlighting a broader, cell-type-independent mechanism. These findings indicate that combined DNA damage and lysosomal inhibition synergistically stimulate secretory autophagy and EV release, potentially impacting the tumor microenvironment and driving disease progression. Full article

Glioblastoma (GBM) is one of the deadliest types of cancer, characterized by a short life expectancy after diagnosis, mostly related to therapy resistance and recurrence. GBM stem-like cells (GSCs) reside within the tumor and contribute to these features; therefore, finding drugs that specifically target such cells holds promise to halt GBM progression. The primary objective of this work is to comprehensively review and discuss the potential of hard drug repurposing to target GSCs. Several studies evaluating drugs showing anti-GSC activity, originally approved for non-cancer indications, were identified. These mainly included antidiabetics (e.g., Metformin, Phenformin, and Sitagliptin), antihypertensives (e.g., Nicardipine, Doxazosin, and Prazosin), antimicrobials (e.g., Pyrvinium pamoate, Flubendazole, and Clofazimine), and central nervous system-acting drugs (e.g., Chlorpromazine, Fluvoxamine, and Disulfiram). Relevant candidates include those that disrupt GSC metabolism, namely impairing mitochondrial function, such as Metformin, Chlorpromazine, and Pyrvinium pamoate. Multiple signaling pathways may be involved, namely the Wnt, PI3K/AKT, and STAT3 pathways, among others. Also significant were those drugs tested in combination, resulting in increased sensitivity to Temozolomide (TMZ), the standard pharmacological treatment available for GBM. Some repurposed agents, such as Disulfiram and Metformin, have already reached clinical testing, although none have yet been incorporated into clinical practice. Importantly, major translational barriers remain, like limited blood–brain barrier penetration and the lack of robust clinical trials. In conclusion, drug repurposing is an affordable and suitable strategy to target GSCs, impairing cell viability, reducing stemness, and enhancing their sensitivity to TMZ, which has potential that should be further explored to improve patients’ clinical outcomes. Full article

Background/Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD) represents a significant global public health issue, affecting approximately 25% of the population and currently offering limited treatment options. Trimetazidine (TMZ) serves as a metabolic modulator that shifts cellular energy metabolism from fatty acid oxidation to glucose oxidation, thereby providing a novel therapeutic strategy aimed at addressing the underlying metabolic dysfunctions that contribute to the pathogenesis of MASLD. Our study aims to assess the efficacy of trimetazidine in improving hepatic steatosis, inflammation, and various metabolic parameters. Methods: In this double-masked, randomized controlled trial, 60 patients with confirmed MASLD diagnoses were randomly assigned in a 1:1 ratio to receive either trimetazidine 20 mg three times daily or a placebo, alongside lifestyle modifications, for 24 weeks. The trial was conducted in accordance with the Declaration of Helsinki and approved by the ethics committees of both participating institutions. We measured changes in hepatic steatosis, non-invasive fibrosis scores, inflammatory markers (including interleukin-6, tumor necrosis factor-alpha, and highly sensitive C-reactive protein), liver enzymes, and lipid profiles at baseline and at the end of the 24 weeks. Results: Hepatic steatosis decreased significantly, with controlled attenuation parameter scores from 352.5 to 302 dB/m in the TMZ group compared to the control (p < 0.001). TNF-α was reduced significantly in the TMZ group compared to the control group (p = 0.001). Fibrosis to AST score decreased from 0.49 to 0.25 in the TMZ group (p < 0.001). Aspartate aminotransferase decreased significantly compared to the control group (p 0.032). Notably, TMZ also imparted cardioprotective benefits, reducing total cholesterol by 14%, LDL by 17% (both p < 0.05), and triglycerides by 16% (p = 0.176). Conclusions: This groundbreaking trial supports the potential of trimetazidine as a promising therapeutic agent for MASLD, indicating substantial improvements in hepatic steatosis, inflammation, and metabolic disturbances. These findings underscore the urgency and importance of further multicenter trials to validate trimetazidine’s efficacy as a disease-modifying therapy for MASLD. Full article

Glioblastoma multiforme (GBM) is an aggressive and molecularly heterogeneous brain cancer with a poor prognosis. Despite advancements in standard-of-care therapies, including surgery, radiotherapy, and temozolomide (TMZ), the median survival remains approximately 15 months, with a 5-year survival rate of less than 10%. We and others have demonstrated that FOXM1 is a critical oncogenic driver of GBM cell proliferation. However, the role of FOXM1 and its interaction with other oncogenic signaling pathways in GBM remains incompletely understood. In this study, we identified FOXM1, AXL, and eEF2K as highly upregulated oncogenes in GBM patient tumors. We demonstrated, for the first time, that FOXM1 directly interacts with AXL and eEF2K, regulating their expression and promoting GBM cell proliferation, migration, and invasion. Knockdown of these genes disrupted cell proliferation, spheroid formation, migration, and invasion, and induced apoptosis and ferroptosis. Additionally, inhibiting the FOXM1–AXL/eEF2K signaling axis sensitized GBM cells to TMZ, further enhancing apoptotic and ferroptotic responses. These findings highlight the critical role of the FOXM1–AXL/eEF2K signaling pathway in GBM progression and suggest that targeting this axis may offer a novel multitargeted therapeutic strategy in GBM. Full article

Background/Objectives: Isocitrate dehydrogenase (IDH) mutations are hallmark features in subsets of gliomas, producing the oncometabolite D-2-hydroxyglutarate (2HG). Although IDH mutations are associated with better clinical outcomes, their relationship with tumor progression is complex. This study aimed to investigate, in vitro and in vivo, the phenotypic consequences of IDH mutation and 2HG exposure in glioblastoma (GBM) under normoxic and hypoxic conditions and under temozolomide (TMZ) and radiation exposure. Methods: Experiments were conducted using IDH-wildtype (IDH-wt) and IDH-mutant (IDH-mut) glioma cell lines under controlled oxygen conditions. Functional assays included cell viability, cell cycle analysis, apoptosis profiling, migration, and surface marker expression via flow cytometry. Orthotopic xenografts were established in immunocompromised mice to assess in vivo tumor growth and morphology, followed by MRI and histological analysis. Treatments included TMZ, radiation, and 2HG at varying concentrations. Statistical analyses were performed using SPSS and RStudio. Results:IDH-wt cells exhibited faster proliferation and greater adaptability under hypoxia, while IDH-mut cells showed cell cycle arrest and limited growth. 2HG recapitulated IDH-mut features in IDH-wt cells, including increased apoptosis under TMZ, reduced proliferation, and altered CD24/CD44 expression. In vivo, IDH-wt tumors were larger and more infiltrative, while 2HG administration reduced tumor volume and promoted compact morphology. Notably, migration was initially similar across genotypes but increased in IDH-mut and 2HG-treated IDH-wt cells over time, though suppressed under therapeutic stress. Conclusions: IDH mutation and 2HG modulate glioma cell biology, including cell cycle dynamics, proliferation rates, migration, and apoptosis. While the IDH mutation and its metabolic product confer initial growth advantages, they enhance treatment sensitivity and reduce invasiveness, highlighting potential vulnerabilities for targeted therapy. Full article

Glioblastoma (GBM), a highly malignant brain tumor, arises within a complex microenvironment that plays a critical role in facilitating tumor progression, ensuring survival, and enabling immune evasion, ultimately contributing to therapeutic resistance. Cancer-associated fibrosis is increasingly recognized as a key factor in the tumor pathophysiology, particularly in extracranial cancers, and reported therapeutic strategies in several cancers consist of the current use of the standard-of-care treatment combined with anti-fibrotic drugs. However, it remains unclear how the fibrotic changes associated with the GBM microenvironment contribute to the transformation of GBM from a chemosensitive state to a chemoresistant one. Here, we developed an in vitro model that mimics a fibrosis-like mechanism using the U-87MG GBM cell line. To achieve this, we identified the optimal experimental conditions (i.e., U-87MG cultured in serum-deprivation medium in the presence of recombinant TGF-B1 at 5 ng/mL for 72 h) that effectively induced fibrosis, as suggested by the counter-regulated expression of E- and N-cadherin and sustained levels of α-SMA and collagen I. As expected, U-87MG fibrotic cells were demonstrated to be more resistant to TMZ (predicted EC₅₀ = 35 µM) as compared to the non-fibrotic counterpart (EC₅₀ not achieved here; predicted EC₅₀ = 351 µM). Accordingly, the anti-fibrotic uPAcyclin—a new derivative cyclic compound inspired as a A6 decapeptide drug—showed a significant cytotoxic effect, sensitizing resistant U-87MG fibrotic cells to TMZ. This highlights that targeting fibrosis may help to overcome TMZ resistance in GBM. Full article

Glioblastoma multiforme (GBM) is a highly aggressive primary brain tumor with a dismal prognosis despite advances in multimodal treatment. Conventional therapies fail to achieve durable responses due to GBM’s molecular heterogeneity and capacity to evade therapeutic pressures. Epigenetic alterations have emerged as critical contributors to GBM pathobiology, including aberrant DNA methylation, histone modifications, and non-coding RNA (ncRNA) dysregulation. These mechanisms drive oncogenesis, therapy resistance, and immune evasion. This scoping review evaluates the current state of knowledge on epigenetic modifications in GBM, synthesizing findings from original articles and preclinical and clinical trials published over the last decade. Particular attention is given to MGMT promoter hypermethylation status as a biomarker for temozolomide (TMZ) sensitivity, histone deacetylation and methylation as modulators of chromatin structure, and microRNAs as regulators of pathways such as apoptosis and angiogenesis. Therapeutically, epigenetic drugs, like DNA methyltransferase inhibitors (DNMTis) and histone deacetylase inhibitors (HDACis), appear as promising approaches in preclinical models and early trials. Emerging RNA-based therapies targeting dysregulated ncRNAs represent a novel approach to reprogram the tumor epigenome. Combination therapies, pairing epigenetic agents with immune checkpoint inhibitors or chemotherapy, are explored for their potential to enhance treatment response. Despite these advancements, challenges such as tumor heterogeneity, the blood–brain barrier (BBB), and off-target effects remain significant. Future directions emphasize integrative omics approaches to identify patient-specific targets and refine therapies. This article thus highlights the potential of epigenetics in reshaping GBM treatment paradigms. Full article

Glioblastoma Multiforme (GBM) is one of the most common brain tumors and is associated with aggressive tumor characteristics and extremely poor patient survival. The median survival time for GBM patients is around 12–15 months. Temozolomide (TMZ) is a key chemotherapeutic drug used in the treatment of GBM. However, at least 50% of GBM patients do not respond to TMZ, necessitating the identification of novel therapeutic strategies sensitizing patients to TMZ. In this study, we aimed to investigate the effects of two different tumor suppressor microRNAs (miR-329 and miR-449b) on cell proliferation and migration of GBM cells, and their potential for sensitizing GBM cells to TMZ. Our findings show that MiR-329/449b treatments suppressed spheroid formation and migration of GBM (LN229 and U87) cells. When miR treatments were combined with Temozolomide (TMZ), we also observed that they synergistically enhanced the suppressive effects of TMZ and inhibited the activity of clinically significant NF-KB and Src/FAK signaling pathways, making the combination therapy a viable option to treat GBM, with greater impact on patient survival. Full article

Background: Glioblastoma (GBM) remains almost uniformly fatal, owing in part to therapy-resistant cancer stem-like cells (CSCs) and to temozolomide (TMZ) resistance driven by O⁶-methylguanine-DNA methyltransferase (MGMT). Differentiation therapy with all-trans retinoic acid (ATRA) has the potential to attenuate stemness and sensitize GBM to TMZ. We therefore asked whether ATRA reduces expression of key CSC markers and MGMT in established GBM lines. Methods: Two established human GBM cell lines, U87-MG and A172, were cultured under neurosphere-promoting conditions to enrich for potential stem-like subpopulations. Cells were treated with either 1 µM ATRA or vehicle control (DMSO) for 5 days. Total RNA was extracted, and cDNA was synthesized. Quantitative Real-Time PCR (qPCR) assessed relative mRNA expression levels of key stemness transcription factors (SOX2, NES) and the DNA repair gene MGMT and corresponding protein levels were measured by an Enzyme-Linked Immunosorbent Assay (ELISA). Gene expression was normalized to the geometric mean of two validated housekeeping genes (GAPDH, ACTB). Relative quantification was calculated using the ΔΔCt method, and statistical significance was determined using Student’s t-tests. Results: ATRA markedly suppressed stemness and MGMT in both lines. In U87-MG, SOX2 mRNA fell 3.7-fold (p = 0.0008) and protein 2.99-fold (148.3 ± 6.0 → 49.7 ± 2.7 pg µg⁻¹; p = 0.0002); Nestin dropped 4.1-fold (p = 0.0005) and 3.51-fold (450.0 ± 17.3 → 128.3 ± 4.4 pg µg⁻¹; p = 0.00008). MGMT decreased 2.6-fold at transcript level (p = 0.0065) and 2.11-fold at protein level (81.7 ± 4.4 → 38.7 ± 1.8 pg µg⁻¹; p = 0.0005). In A172, SOX2 was reduced 2.9-fold (p = 0.0041) and 2.31-fold (p = 0.0007); Nestin 3.3-fold (p = 0.0028) and 2.79-fold (p = 0.00009). MGMT declined 2.2-fold (p = 0.0132) and 1.82-fold (p = 0.0015), respectively. Conclusions: Five-day exposure to ATRA diminishes SOX2, Nestin, and MGMT at both mRNA and protein levels in stem-enriched GBM cultures, supporting the premise that ATRA-induced differentiation can concurrently blunt CSC traits and TMZ-resistance mechanisms. These data provide a molecular rationale for testing ATRA in combination regimens aimed at improving GBM therapy. Full article

Glioblastoma (GBM) presents significant therapeutic challenges due to its invasive nature and resistance to standard chemotherapy, i.e., temozolomide (TMZ). This study aimed to identify gene signatures that predict poor TMZ response and high PD−L1/PD−1 tumor expression, and explore potential sensitivity to alternative drugs. We analyzed The Cancer Genome Atlas (TCGA) biopsy data to identify differentially expressed genes (DEGs) linked to these characteristics. Among 33 upregulated DEGs, 5 were significantly correlated with overall survival. A risk score model was built using these 5 DEGs, classifying patients into low-, medium-, and high-risk groups. We assessed immune cell infiltration, immunosuppressive mediators, and epithelial–mesenchymal transition (EMT) markers in each group using correlation analysis, Gene Set Enrichment Analysis (GSEA), and machine learning. The model demonstrated strong predictive power, with high-risk patients exhibiting poorer survival and increased immune infiltration. GSEA revealed upregulation of immune and EMT-related pathways in high-risk patients. Our analyses suggest that high-risk patients may exhibit limited response to PD−1 inhibitors, but could show sensitivity to etoposide and paclitaxel. This risk score model provides a valuable tool for guiding therapeutic decisions and identifying alternative chemotherapy options to enable the development of personalized and cost-effective treatments for GBM patients. Full article

Background/Objectives: Human glioblastoma (GBM) is the most aggressive brain cancer in adults and a highly treatment-refractory malignancy. The overall prognosis for the GBM is extremely poor, with a median survival of 12–14 months after initial diagnosis. Many GBM patients initially respond to the DNA alkylating agent temozolomide (TMZ), but patients often become therapy-resistant, and tumors recur. We previously reported that treatment with PFI-3, which is a small molecule inhibitor of the bromodomain of the BRG1 subunit of the SW1/SNF chromatin remodeling complex, enhanced the sensitivity of GBM cells to TMZ in vitro and in vivo GBM animal models. Our general objective was to perform an SAR study of new diphenyl PFI-3 analogs. Methods: New structural analogs of PFI-3 were developed, synthesized, and tested for their ability to enhance TMZ-induced GBM cell death by ELISA. Results: Following on the enhanced activity of compounds 2a and 2b, new diphenyl PFI-3 analogs with specific structural adjustments were made to better understand the structural requirements to optimize function. Additionally, several new structurally different candidates (e.g., 4a, 4b, and 5) showed much better efficacy in sensitizing GBM cells to TMZ-induced GBM cell death. Conclusions: Four series of PFI-3 analogs (2, 3, 4, and 5) were designed, synthesized, and tested for the ability to sensitize GBM cells to TMZ-induced cell death. Series 2 optimized the A-ring and R-isomer chirality. Series 3 used a 5-membered linker with weak activity. Series 4’s di-phenyl urea compounds showed better bromodomain inhibition. Series 5’s methoxyphenyl-B-ring analogs were exceptionally strong inhibitors. Full article

Oxidative stress critically influences the pathophysiology of glioblastoma (GBM), a deadly and aggressive brain tumor. Reactive oxygen species (ROS) regulate cancer cell homeostasis, influencing the treatment response. The transcription factor Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2) activates antioxidant defenses, protecting GBM cells from therapy-induced oxidative stress and contributing to Temozolomide (TMZ) resistance. Cyclooxygenase-2 (COX-2) plays a key role in GBM chemoresistance by modulating the tumor microenvironment and supporting a pro-survival phenotype. The impact of COX-2 inhibition by celecoxib (CXB), a selective COX-2 inhibitor, combined with TMZ on oxidative stress modulation linked to resistance was investigated in GBM primary cultures and cell lines. The drug combination CXB+TMZ was tested on TMZ-sensitive and -resistant cells, and ROS levels and Nrf2 activation were evaluated via a DCFH-DA probe and Western blotting, respectively. The oxidative stress marker malondialdehyde and antioxidant enzymes were assayed using standard methods. COX-2 inhibition combined with TMZ significantly increased ROS, while TMZ alone induced a compensatory antioxidant response, sustaining resistance. Drug combination reduced this response, restoring oxidative stress even in TMZ-resistant cells. Prostaglandin E2 reversed these effects, confirming the role of the COX-2/PGE2 axis in redox balance. Drug combination increased ROS, disrupted redox homeostasis and overcame TMZ resistance, supporting COX-2 inhibition as a promising GBM therapy strategy. Full article

A novel composite voltammetric biosensor has been developed for the first time, utilizing a glassy carbon electrode modified with yttria-stabilized zirconia doped with titanium dioxide and carbon black (YSZTiO₂-CB/GCE), specifically designed for the detection of trimetazidine (TMZ). The measurement conditions, including both the supporting electrolyte and instrumental settings, were optimized to enhance performance. In the concentration range of 0.5 to 7 µM, it is not necessary to use preconcentration time for the determination of TMZ. The limit of detection (for 60 s of preconcentration time) was equal to 5.5 nM (1.87 ng mL⁻¹), outperforming other voltammetric methods in terms of sensitivity. The reproducibility of the trimetazidine signal (with a concentration of 0.05 µM) exhibited a relative standard deviation (RSD) of 3.3% over 10 measurements. Additionally, our biosensor is characterized by excellent stability, ease of use, and straightforward preparation. The proposed biosensor and method have proven effective in analyzing TMZ in a variety of matrices, including urine, blood plasma, pharmaceutical formulations, as well as gastric and intestinal fluids, yielding recovery rates ranging from 97.7 to 102.3%. Full article