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Objective: This study is targeted at assessing the chemotherapy factor of the ethanol extract of Vernonia amygdalina Delile (VAD)., Methods: U87 glioblastoma cells were treated with extract and a fraction of Vernonia amygdalina Delile (VAD) was harvested from the herbarium. Cytotoxicity was evaluated to determine the IC50 through microscopic observation followed by an MTT assay. Subsequently, flow cytometry with a FACS type was employed to conduct cell cycle and apoptosis analyses. Annexin V/PI and PI markers were used to assess apoptosis and cell cycle progression., Result: The ethanol extract and ethyl acetate fraction of VAD showed promising effects as cancer chemotherapy in glioblastoma cells. The IC50 values for the extract and fraction were notably low, at 37.65 µg/ml and 10.12 µg/ml, respectively, for U87 cells. Analysis of apoptosis using FACS revealed a more pronounced apoptotic effect of the 15 µg/ml fraction of VAD on both early and late apoptosis compared to the 75 µg/ml extract of VAD. Although some differences in cell cycle properties were observed, there were no significant differences in cell cycle analysis between the extract and fraction., Conclusion: These findings underscore the efficacy of VAD's ethanol extract and ethyl acetate fraction as chemotherapeutic agents against U87 cancer cells. The low IC50 values and significant induction of early apoptosis highlight the cytotoxic effects of these treatments on U87 cells.

Objectives: Glioblastoma multiforme (GBM) is considered the most assailant subtype of gliomas, presenting a formidable obstacle because of its inherent resistance to temozolomide (TMZ). This study aimed to characterize the function of lncRNA NEAT1 in facilitating the advancement of gliomas., Methods: The expression level of NEAT1 in glioma tissues and cells was detected by qRT-PCR. RNA interference experiment, cell proliferation assay, FITC/PI detection assay, immunoblotting, bioinformatics prediction, a double luciferase reporter gene assay, RNA immunoprecipitation (RIP) assay, SLDT assay and correlation analysis of clinical samples were performed to explore the regulatory effects of NEAT1, miR-454-3p and Cx43 and their role in malignant progression of GBM. The role of NEAT1 in vivo was investigated by an intracranial tumor formation experiment in mice., Results: The results showed that recurring gliomas displayed elevated levels of NEAT1 compared to primary gliomas. The suppression of NEAT1 led to a restoration of sensitivity in GBM cells to TMZ. NEAT1 functioned as a competitive endogenous RNA against miR-454-3p. Connexin 43 was identified as a miR-454-3p target. NEAT1 was found to regulate gap junctional intercellular communication by modulating Connexin 43, thereby impacting the response of GBM cells to TMZ chemotherapy. Downregulation of NEAT1 resulted in enhanced chemosensitivity to TMZ and extended the survival of mice., Conclusions: Overall, these results indicated that the NEAT1/miR-454-3p/Connexin 43 pathway influences GBM cell response to TMZ and could offer a potential new strategy for treating GBM., (© 2024 The Author(s). Cancer Reports published by Wiley Periodicals LLC.)

Mitogen-Activated Protein Kinase Kinase Kinase 1 (MAP3K1) is overexpressed in gliomas; however, its clinical significance, biological functions, and underlying molecular mechanisms remain unclear. Abnormal overexpression of MAP3K1 in glioma is strongly associated with unfavourable clinicopathological characteristics and disease progression. MAP3K1 could potentially serve as a reliable diagnostic and prognostic biomarker for glioma. MAP3K1 silencing suppressed the migration but had no effect on the proliferation and cell death of Glioblastoma Multiforme (GBM) cells. MAP3K1 knockdown exacerbated the temozolomide (TMZ) induced inhibition of glioma cell proliferation and death of GBM cells. In addition, MAP3K1 knockdown combined with TMZ treatment significantly inhibited the growth and increased cell death in organoids derived from GBM patients. MAP3K1 knockdown reversed TMZ resistance of GBM in intracranial glioma model. In terms of molecular mechanisms, the phosphorylation level of ERK was significantly decreased by MAP3K1 silencing. No significant change in the JNK pathway was found in MAP3K1-silenced GBM cells. Inhibition of ERK phosphorylation suppressed the migration and enhanced the TMZ sensibility of GBM cells. MAP3K1 was correlated with the immune infiltration in glioma. MAP3K1 could facilitate the migration and TMZ resistance of GBM cells through MEK/ERK signalling., (© 2024 The Author(s). Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Background and Aims: Anti-angiogenic therapies prolong patient survival in some malignancies but not glioblastoma. We focused on the relationship between the differentiation of glioma stem like cells (GSCs) into tumor derived endothelial cells (TDECs) and, anti-angiogenic therapy resistance. Especially we aimed to elucidate the mechanisms of drug resistance of TDECs to anti-angiogenic inhibitors and identify novel anti-angiogenic drugs with clinical applications., Results: The mouse GSCs, 005, were differentiated into TDECs under hypoxic conditions, and TDECs had endothelial cell characteristics independent of the vascular endothelial growth factor (VEGF) pathway. In vivo, inhibition of the VEGF pathway had no anti-tumor effect and increased the percentage of TDECs in the 005 mouse model. Novel anti-angiogenic drugs for glioblastoma were evaluated using a tube formation assay and a drug repositioning strategy with existing blood-brain barrier permeable drugs. Drug screening revealed that the antidepressant sertraline inhibited tube formation of TDECs. Sertraline was administered to differentiated TDECs in vitro and 005 mouse models in vivo to evaluate genetic changes by RNA-Seq and tumor regression effects by immunohistochemistry and MRI. Sertraline reduced Lama4 and Ang2 expressions of TDEC, which play an important role in non-VEGF-mediated angiogenesis in tumors. The combination of a VEGF receptor inhibitor axitinib, and sertraline improved survival and reduced tumor growth in the 005 mouse model., Conclusion: Collectively, our findings showed the diversity of tumor vascular endothelial cells across VEGF and non-VEGF pathways led to anti-angiogenic resistance. The combination of axitinib and sertraline can represent an effective anti-angiogenic therapy for glioblastoma with safe, low cost, and fast availability., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Glioblastoma (GBM) is the most common invasive malignant tumor in human brain tumors, representing the most severe grade of gliomas. Despite existing therapeutic approaches, patient prognosis remains dismal, necessitating the exploration of novel strategies to enhance treatment efficacy and extend survival. Due to the restrictive nature of the blood-brain barrier (BBB), small-molecule inhibitors are prioritized in the treatment of central nervous system tumors. Among these, DNA damage response (DDR) inhibitors have garnered significant attention due to their potent therapeutic potential across various malignancies. This review provides a detailed analysis of DDR pathways as therapeutic targets in GBM, summarizes recent advancements, therapeutic strategies, and ongoing clinical trials, and offers perspectives on future directions in this rapidly evolving field. The goal is to present a comprehensive outlook on the potential of DDR inhibitors in improving GBM management and outcomes., (Copyright © 2024 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.)

Objective: Axitinib is a tyrosine kinase inhibitor characterized by a strong affinity for Vascular Endothelial Growth Factor Receptors (VEGFRs). It was approved in 2012 by Food and Drug Administration and European Medicines Agency as a second line treatment for advanced renal cell carcinoma and is currently under evaluation in clinical trial for the treatment of other cancers. Glioblastoma IDH-wild type (GBM) is a highly malignant brain tumor characterized by diffusely infiltrative growth pattern and by a prominent neo-angiogenesis. In GBM, axitinib has demonstrated a limited effectiveness as a monotherapy, while it was recently shown to significantly improve its efficacy in combination treatments. In preclinical models, axitinib has been reported to trigger cellular senescence both in tumor as well as in normal cells, through a mechanism involving intracellular reactive oxygen species (ROS) accumulation and activation of Ataxia Telangiectasia Mutated kinase (ATM). Limiting axitinib-dependent ROS increase by antioxidants prevents senescence specifically in normal cells, without affecting tumor cells., Methods: We used brain tumor xenografts obtained by engrafting Glioma Stem Cells (GSCs) into the brain of immunocompromised mice, to investigate the hypothesis that the antioxidant molecule N-Acetyl-L-Cysteine (NAC) might be used to reduce senescence-associated adverse effects of axitinib treatment without altering its anti-tumor activity., Results: We demonstrate that the use of the antioxidant molecule N-Acetyl-Cysteine (NAC) in combination with axitinib stabilizes tumor microvessels in GBM tumor orthotopic xenografts, eventually resulting in vessel normalization, and protects liver vasculature from axitinib-dependent toxicity., Conclusion: Overall, we found that NAC co-treatment allows vessel normalization in brain tumor vessels and exerts a protective effect on liver vasculature, therefore minimizing axitinib-dependent toxicity., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Autophagy is an innate cellular process characterized by self-digestion, wherein cells degrade or recycle aged proteins, misfolded proteins, and damaged organelles via lysosomal pathways. Its crucial role in maintaining cellular homeostasis, ensuring development and survival is well established. In the context of cancer therapy, autophagy's importance is firmly recognized, given its critical impact on treatment efficacy. Following radiotherapy, several factors can modulate autophagy including parameters related to radiation type and delivery methods. The concomitant use of chemotherapy with radiotherapy further influences autophagy, potentially either enhancing radiosensitivity or promoting radioresistance. This review article discusses some pharmacological agents and drugs capable of modulating autophagy levels in conjunction with radiation in tumor cells, with a focus on those identified as potential radiosensitizers in glioblastoma multiforme treatment., (Copyright © 2024 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

Glioblastoma is a highly aggressive glioma with limited treatment options. Boron neutron capture therapy (BNCT) offers a promising approach for refractory cancers, utilizing boron-10 ( 10 B) and thermal neutrons to generate cytotoxic particles. Effective BNCT depends on selective targeting and retention of 10 B in tumors. Current BNCT drugs face issues with rapid clearance and poor tumor accumulation. To address this, we developed gold nanoparticles (AuNPs) functionalized with cyclic arginine-glycine-aspartic acid (cRGD) peptides as a nanocarrier for Sodium Mercaptododecaborate (BSH), resulting in AuNPs-BSH&PEG-cRGD. In vitro , AuNPs-BSH&PEG-cRGD increased 10 B content in GL261 glioma cells by approximately 2.5-fold compared to unmodified AuNPs-BSH&PEG, indicating enhanced targeting due to cRGD's affinity for integrin receptor α v β 3 . In a subcutaneous glioma mouse model, 6 h post-intratumoral administration, the 10 B concentration in tumors was 17.98 μg/g for AuNPs-BSH&PEG-cRGD, significantly higher than 0.45 μg/g for BSH. The tumor-to-blood (T/B) and tumor-to-normal tissue (T/N) ratios were also higher for AuNPs-BSH&PEG-cRGD, suggesting improved targeting and retention. This indicates that AuNPs-BSH&PEG-cRGD may enhance BNCT efficacy and minimize normal tissue toxicity. In summary, this study provides a novel strategy for BSH delivery and may broaden the design vision of BNCT nano-boron capture agents.

Background: Glioblastoma (GBM) is the most common primary malignant brain tumor with very poor prognosis due to frequent recurrence and short overall survival (OS) time, which according to different sources, is not longer than 17 months after the diagnosis. Infiltrative growth pattern often leads to tumor propagation into functionally significant brain areas while surgery is cytoreductive and does not necessarily alter the prognosis. Many patients are in the working age, thus finding conservative approaches to the treatment of this type of neoplasms is of utmost importance. The aim of the work is to demonstrate the effectiveness of treatment of GBM using cytokine genetic therapy (CGT) and present an algorithm for patient management., Case Description: This paper describes the first case of successful intra-arterial (IA) bevacizumab therapy with following CGT of a 46-year-old patient with recurrent GBM after a combined treatment. Sixteen courses of 15 mg/kg IA bevacizumab with hyperosmolar opening of blood-brain barrier (BBB) resulted in stabilization of the neoplastic process. After that, 9 courses of CGT with recombinant interferon gamma (IFN-γ) and tumor necrosis factor (TNF)-thymosin α1 were performed. Both magnetic resonance imaging (MRI) with contrast and positron emission tomography (PET) confirmed a complete response to the combined treatment. OS time is currently more than 25 months from the diagnosis. The observation continues., Conclusions: This case study expands the range of treatment options for GBM, especially in the context of intolerance and high toxicity of cytostatic drugs, and may lead to improved recurrence-free survival (RFS).

Aim: The aim of our study was to explore the factors influencing cerebral edema and intracranial pressure in glioblastoma multiforme (GBM) patients who undergo photodynamic therapy (PDT) after resection., Approach: This was a retrospective controlled study of GBM patients treated with PDT-assisted resections of varying scope from May 2021 to August 2023. The baseline clinical data, cerebral edema volumes, intracranial pressure values, and imaging data of the GBM patients were collected for statistical analysis., Results: A total of 56 GBM patients were included. Thirty of the patients underwent gross total resection (GTR), and the other 26 patients underwent subtotal resection (STR). We found that the cerebral edema volume and the mean intracranial pressure in patients who underwent GTR were lower than those in patients who underwent STR. Moreover, univariate analysis showed that the scope of tumor resection was an independent factor affecting cerebral edema and intracranial pressure after PDT., Conclusions: Compared with STR, PDT combined with GTR significantly reduced postoperative brain edema volume and intracranial pressure in GBM patients., (© 2024 Wiley Periodicals LLC.)

Glioblastoma (GBM) stands for the most common and aggressive type of brain tumour in adults. It is highly invasive, which explains its short rate of survival. Little is known about its risk factors, and current therapy is still ineffective. Hence, efforts are underway to develop novel and effective treatment approaches against this type of cancer. Exosomes are being explored as a promising strategy for conveying and delivering therapeutic cargo to GBM cells. They can fuse with the GBM cell membrane and, consequently, serve as delivery systems in this context. Due to their nanoscale size, exosomes can cross the blood-brain barrier (BBB), which constitutes a significant hurdle to most chemotherapeutic drugs used against GBM. They can subsequently inhibit oncogenes, activate tumour suppressor genes, induce immune responses, and control cell growth. However, despite representing a promising tool for the treatment of GBM, further research and clinical studies regarding exosome biology, engineering, and clinical applications still need to be completed. Here, we sought to review the application of exosomes in the treatment of GBM through an in-depth analysis of the scientific and clinical studies on the entire process, from the isolation and purification of exosomes to their design and transformation into anti-oncogenic drug delivery systems. Surface modification of exosomes to enhance BBB penetration and GBM-cell targeting is also a topic of discussion., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Glioblastoma multiforme (GBM) remains incurable despite multimodal treatments after surgical debulking. Almost all patients with GBM relapse within a narrow margin (2-3 cm) of the initial resected lesion due to the unreachable residual cancerous cells. Here, a completely biodegradable microneedle for surgical cavity delivery glioblastoma-associated macrophages (GAMs)-activating immune nano-stimulator that mitigates glioblastoma relapse is reported. The residual tumor lesion-directed biocompatible microneedle releases the nano-stimulator and toll-like receptor 9 agonist in a controlled manner until the microneedles completely degrade over 1 week, efferently induce in situ phonotypic shifting of GAMs from anti- to pro-inflammatory and the tumor recurrence is obviously inhibited. The implantable microneedles offer a significant improvement over conventional transdermal ones, as they are 100% degradable, ensuring safe application within surgical cavities. It is also revealed that the T cells are recruited to the tumor niche as the GAMs initiate anti-tumor response and eradicate residual GBM cells. Taken together, this work provides a potential strategy for immunomodulating the postoperative tumor niche to mitigate tumor relapse in GBM patients, which may have broad applications in other malignancies with surgical intervention., (© 2024 Wiley‐VCH GmbH.)

Curcumin (CUR) has received worldwide attention for its beneficial effects on human health. Research report possible cytotoxic activity against various cancers, including glioblastoma. So far, little attention has been given to the binding properties of CUR to lipid membranes, which influences their electrical characteristics and can provide insight into their membrane-permeation abilities. Biophysical interactions between the polyphenol and in vitro models (liposomes and LN-18 human glioblastoma cells) were investigated by monitoring zeta potential and the membrane's surface charge as a function of pH. We focused on practical measurements and undertook a theoretical analysis of interactions in the natural cell membrane. We used the MTT assay to evaluate the viability of CUR-treated cells. Measurements performed using the Electrophoretic Light Scattering method demonstrated the dose-dependent effect of CUR on both membrane surface charge and zeta potential analyzed in vitro models. We determined theoretical parameters characterizing the cell membrane based on a quantitative description of the adsorption equilibria formed due to the binding of solution ions to the membrane of glioblastoma cells. The interaction of CUR with liposomes and human cancer cells is pH-dependent., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Abstract: Glioblastoma multiforme (GBM) is a highly vascularized tumor with reported high prostate-specific membrane antigen (PSMA) expression. On the other hand, bevacizumab as an antiangiogenesis drug is increasingly used in the treatment of GBM recurrence. We present a case of GBM recurrence with significant reduction of 99m Tc-HYNIC-PSMA-11 uptake in her tumor 1 week after administration of 2 doses of bevacizumab with 2 weeks' interval. This case emphasizes the main mechanism of PSMA uptake in GBM secondary to angiogenesis and also implies a potential interaction of bevacizumab with PSMA uptake that should be especially considered during diagnostic and therapeutic application of PSMA radiotracers in GBM., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Glioblastoma (GBM) is a central nervous system cancer with high incidence and poor survival rates. Enhancing drug penetration of the blood-brain barrier (BBB) and targeting efficacy is crucial for improving treatment outcomes. In this study, we developed a redox-sensitive targeted nano-delivery system (HCA-A2) for temozolomide (TMZ) and β-lapachone (β-Lapa). This system used hyaluronic acid (HA) as the hydrophilic group, arachidonic acid (CA) as the hydrophobic group, and angiopep-2 (A2) as the targeting group. Control systems included non-redox sensitive (HDA-A2) and non-targeting (HCA) versions. In vitro, HCA-TMZ-Lapa micelles released 100 % of their payload in a simulated tumor microenvironment within 24 h, compared to 43.97 % under normal conditions. HCA-A2 micelles, internalized via clathrin-mediated endocytosis, showed stronger cytotoxicity and better BBB penetration and cellular uptake than controls. In vivo studies demonstrated superior tumor growth inhibition with HCA-A2 micelles, indicating their potential for GBM treatment., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Glioblastoma stem cells (GSCs) have been implicated in the self-renewal and treatment resistance of glioblastoma (GBM). Our previous study found that 4,5-dimethoxycanthin-6-one has the potential to inhibit GBM cell proliferation. This current study aims to elucidate the molecular mechanism underlying the effects of 4,5-dimethoxycanthin-6-one in GBM development. The effect of 4,5-dimethoxycanthin-6-one on GSC formation and differentiation was explored in human GBM cell lines U251 and U87. Subsequently, 4,5-dimethoxycanthin-6-one binding to tetraspanin 1 (TSPAN1) / transmembrane 4 L six family member 1 (TM4SF1) was analyzed by molecular simulation docking. Co-immunoprecipitation (Co-IP) and immunofluorescence (IF) were used to assess the interactions between TSPAN1 and TM4SF1 in GSCs. Cell proliferation was detected by cell counting kit-8 (CCK-8) and colony formation assay. To evaluate cell migration, invasion and apoptosis, we employed wound healing assay, transwell and flow cytometry, respectively. Furthermore, subcutaneous xenograft tumor models in nude mice were constructed to evaluate the impact of 4,5-dimethoxycanthin-6-one on GSCs in vivo by examining tumor growth and histological characteristics. 4,5-Dimethoxycanthin-6-one inhibited GSC formation and promoted stem cell differentiation in a concentration-dependent manner. Molecular docking models of 4,5-dimethoxycanthin-6-one with TM4SF1 and TSPAN1 were constructed. Then, the interaction between TSPAN1 and TM4SF1 in GSC was clarified. Moreover, 4,5-dimethoxycanthin-6-one significantly inhibited the expressions of TM4SF1 and TSPAN1 in vitro and in vivo. Overexpression of TSPAN1 partially reversed the inhibitory effects of 4,5-dimethoxycanthin-6-one on GSC formation, proliferation, migration and invasion. 4,5-Dimethoxycanthin-6-one inhibited GBM progression by inhibiting TSPAN1/TM4SF1 axis. 4,5-Dimethoxycanthin-6-one might be a novel and effective drug for the treatment of GBM., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Acquired drug resistance in glioblastoma (GBM) presents a major clinical challenge and is a key factor contributing to abysmal prognosis, with less than 15 months median overall survival. Aggressive chemotherapy with the frontline therapeutic, temozolomide (TMZ), ultimately fails to kill residual highly invasive tumor cells after surgical resection and radiotherapy. Here, a 3D engineered model of acquired TMZ resistance is reported using two isogenically matched sets of GBM cell lines encapsulated in gelatin methacrylol hydrogels. Response of TMZ-resistant versus TMZ-sensitive GBM cell lines within the gelatin-based extracellular matrix platform is benchmarked and drug response at physiologically relevant TMZ concentrations is further validated. The changes in drug sensitivity, cell invasion, and matrix-remodeling cytokine production are shown as the result of acquired TMZ resistance. This platform lays the foundation for future investigations targeting key elements of the GBM tumor microenvironment to combat GBM's devastating impact by advancing the understanding of GBM progression and treatment response to guide the development of novel treatment strategies., (© 2024 The Author(s). Advanced Healthcare Materials published by Wiley‐VCH GmbH.)

Glioblastoma (GBM) resection and medication treatment are limited, and local drug therapies are required. This study aims to create a hybrid system comprising liposome-like particles (LLP-DOX) encapsulated in chitosan/hyaluronic acid/polyethyleneimine (CHI/HA/PEI) hydrogels, enabling controlled local delivery of doxorubicin (DOX) into the resection cavity for treating GBM. CHI/HA/PEI hydrogels were characterized morphologically, physically, chemically, mechanically, and thermally. Findings revealed a high network and compact micro-network structure, along with enhanced physical and thermal stability compared to CHI/HA hydrogels. Simultaneously, drug release from CHI/HA/PEI/LLP-DOX hydrogels was assessed, revealing continuous and controlled release up to the 148th hour, with no significant burst release. Cell studies showed that CHI/HA/PEI hydrogels are biocompatible with low genotoxicity. Additionally, LLP-DOX-loaded CHI/HA/PEI hydrogels significantly decreased cell viability and gene expression levels compared to LLP-DOX alone. It was also observed that the viability of GBM spheroids decreased over time when interacting with CHI/HA/PEI/LLP-DOX hydrogels, accompanied by a reduction in total surface area and an increase in apoptotic tendencies. In this study, we hypothesized that creating a hybrid drug delivery system by encapsulating DOX-loaded LLPs within a CHI/HA/PEI hydrogel matrix could achieve sustained drug release, improve anticancer efficacy via localized treatment, and effectively mitigate GBM progression for 3D microtissues., Competing Interests: Declaration of competing interest The authors declare that no known financial interests or any personal that could have influence in the work of this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Glioblastoma is a malignant neoplasm that develops in the central nervous system and is characterized by high rates of cell proliferation and invasion, presenting resistance to treatments and a poor prognosis. Photodynamic therapy (PDT) is a therapeutic modality that can be applied in oncological cases and stands out for being less invasive. Photosensitizers (PS) of natural origin gained prominence in PDT. Curcumin (CUR) is a natural compound that has been used in PDT, considered a promising PS. In this work, we evaluated the effects of PDT-mediated CUR and near-infrared radiation (NIR) in glioblastoma cells. Through trypan blue exclusion analysis, we chose the concentration of 5 μM of CUR and the dose of 2 J/cm 2 of NIR that showed better responses in reducing the viable cell number in the C6 cell line and did not show cytotoxic/cytostatic effects in the HaCat cell line. Our results show that there is a positive interaction between CUR and NIR as a PDT model since there was an increase in ROS levels, a decrease in cell proliferation, increase in cytotoxicity with cell death by autophagy and necrosis, in addition to the presence of oxidative damage to proteins. These results suggest that the use of CUR and NIR is a promising strategy for the antitumor application of PDT., Competing Interests: Declaration of competing interest The authors declare no competing or financial interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The focus of nanoparticles in vivo trafficking has been mostly on their tissue-level biodistribution and clearance. Recent progress in the nanomedicine field suggests that the targeting of nanoparticles to immune cells can be used to modulate the immune response and enhance therapeutic delivery to the diseased tissue. In the presence of tumor lesions, monocytic-myeloid-derived suppressor cells (M-MDSCs) expand significantly in the bone marrow, egress into peripheral blood, and traffic to the solid tumor, where they help maintain an immuno-suppressive tumor microenvironment. In this study, we investigated the interaction between PAMAM dendrimers and M-MDSCs in two murine models of glioblastoma, by examining the cell-level biodistribution kinetics of the systemically injected dendrimers. We found that M-MDSCs in the tumor and lymphoid organs can efficiently endocytose hydroxyl dendrimers. Interestingly, the trafficking of M-MDSCs from the bone marrow to the tumor contributed to the deposition of hydroxyl dendrimers in the tumor. M-MDSCs showed different capacities of endocytosing dendrimers of different functionalities in vivo. This differential uptake was mediated by the unique serum proteins associated with each dendrimer surface functionality. The results of this study set up the framework for developing dendrimer-based immunotherapy to target M-MDSCs for cancer treatment., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Published by Elsevier B.V.)

Glioblastoma (GBM) represents a formidable challenge in oncology, characterized by aggressive proliferation and poor prognosis. Iron metabolism plays a critical player in GBM progression, with dysregulated iron uptake and utilization contributing to tumor growth and therapeutic resistance. Iron's pivotal role in DNA synthesis, oxidative stress, and angiogenesis underscores its significance in GBM pathogenesis. Elevated expression of iron transporters, such as transferrin receptor 1 (TfR1), highlights the tumor's reliance on iron for survival. Innovative treatment strategies targeting iron dysregulation hold promise for overcoming therapeutic challenges in GBM management. Approaches such as iron chelation therapies, induction of ferroptosis to nanoparticle-based drug delivery systems exploit iron-dependent vulnerabilities, offering avenues for enhance treatment efficacy and improve patient outcomes. As research advances, understanding the complexities of iron-mediated carcinogenesis provides a foundation for developing precision medicine approaches tailored to combat GBM effectively. This review explores the intricate relationship between iron metabolism and GBM, elucidating its multifaceted implications and therapeutic opportunities. By consolidating the latest insights into iron metabolism in GBM, this review underscores its potential as a therapeutic target for improving patient care in combination with the standard of care approach., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

α-Pinene (PEN) is a phyto compound present in terpene plants. In traditional medicine, PEN has been used for its anti-inflammatory, pain-relieving, and bronchodilator properties. The effect of PEN in combination with temozolomide (TMZ) in glioblastoma multiforme (GBM) cells has been evaluated. The action of the PEN + TMZ combination on cell migration, soft-agar, and cell death was determined in LN229 and U87MG human glioblastoma cells. In combination, PEN with TMZ showed a synergistic inhibitory effect in the GBM cells. The PEN + TMZ treatment showed a higher fluorescent intensity and reduced the percentage of wound area closure compared to the compound alone. The compounds in combination also resulted in a reduction in single-cell colony formation. To conclude, the study showed that plant-derived PEN enhanced the effectiveness of standard chemotherapeutic, TMZ, in LN229 and U87MG cells.

Glioblastoma multiforme (GBM) is an aggressive, incurable brain tumor with poor prognosis and limited treatment options. Temozolomide (TMZ) is the standard chemotherapeutic treatment for GBM, but its efficacy has drawn strong criticism from clinicians due to short survival gains and frequent relapses. One critical limitation of TMZ therapy is the hyperactivation of DNA repair pathways, which over time neutralizes the cytotoxic effects of TMZ, thus highlighting the urgent need for new treatment approaches. Addressing this, our study explores the therapeutic potential of in-house-designed phenothiazine-based Tousled-like kinase-1 (TLK1) inhibitors for GBM treatment. TLK1, overexpressed in GBM, plays a role in DNA repair. Phenothiazines are known to cross the blood-brain barrier (BBB). Among all molecules, J54 was identified as a potential lead molecule with improved cytotoxicity. In the context of O6-methylguanine-DNA methyltransferase (MGMT)-deficient GBM cells, the combined administration of phenothiazines and TMZ exhibited a collective reduction in clonogenic growth, coupled with anti-migratory and anti-invasion effects. Conversely, in MGMT-proficient cells, phenothiazine monotherapy alone showed reduced clonogenic growth, along with anti-migratory and anti-invasion effects. Notably, a synergistic increase in γH2AX levels and concurrent attenuation of DNA repair upon combinatorial exposure to TMZ and J54 were observed, implying increased cytotoxicity due to sustained DNA strand breaks. Overall, this study provides new insights into TLK1 inhibition for GBM therapy. Collectively, these findings indicate that TLK1 is one of the upregulated kinases in GBM and phenothiazine-based TLK1 inhibitors could be a promising treatment option for GBM patients., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Glioblastoma (GBM) stands as a highly aggressive and deadly malignant primary brain tumor with a median survival time of under 15 months upon disease diagnosis. While immunotherapies have shown promising results in solid cancers, brain cancers are still unresponsive to immunotherapy due to immunological dysfunction and the presence of a blood-brain barrier. Interleukin-12 (IL-12) emerges as a potent cytokine in fostering anti-tumor immunity by triggering interferon-gamma production in T and natural killer cells and changing macrophages to a tumoricidal phenotype. However, systemic administration of IL-12 toxicity in clinical trials often leads to significant toxicity, posing a critical hurdle. To overcome this major drawback, we have formulated a novel nanoadjuvant composed of immunostimulatory nanoparticles (ISN) loaded with IL-12 to decrease IL-12 toxicity and enhance the immune response by macrophages and GBM cancer cells. Our in vitro results reveal that ISN substantially increase the production of pro-inflammatory cytokines in GBM cancer cells (e.g. 2.6 × increase in IL-8 expression compared to free IL-12) and macrophages (e.g. 2 × increase in TNF-α expression and 6 × increase in IL-6 expression compared to the free IL-12). These findings suggest a potential modulation of the tumor microenvironment. Additionally, our study demonstrates the effective intracellular delivery of IL-12 by ISN, triggering alterations in the levels of pro-inflammatory cytokines at both transcriptional and protein expression levels. These results highlight the promise of the nanoadjuvant as a prospective platform for resharing the GBM microenvironment and empowering immunotherapy., (© 2023. The Author(s).)

A potential therapeutic approach for cancer treatment is target oxidative phosphorylation and glycolysis simultaneously. The matrix protein of vesicular stomatitis virus (VSV MP) can target the surface of mitochondria, causing morphological changes that may be associated with mitochondrial dysfunction and oxidative phosphorylation inhibition. Previous research has shown that mitochondrial abnormalities can direct glucose metabolism toward glycolysis. Thus, after treatment with VSV MP, glycolysis inhibition is necessary to completely block glucose metabolism and eradicate cancer. Here, to inhibit glycolysis, the 2-deoxy-D-glucose (2-DG), a synthetic glucose analog was used to combine with VSV MP to treat cancer. This study aims to determine how VSV MP affects the glucose bioenergetic metabolism of cancer cells and to evaluate the synergistic effect of 2-DG when combined with VSV. Our results indicated that in U87 and C6 glioblastoma cell lines, VSV MP caused mitochondrial membrane potential loss, cytochrome c release, and glucose bioenergetics metabolism reprogramming. When combined with 2-DG, VSV MP synergistically aggravated cell viability, apoptosis, and G2/M phase arrest. Meanwhile, the combination therapy exacerbated ATP depletion, activated AMPK, and inhibited mammalian target of rapamycin signaling pathways. In addition, 2-DG treatment alone induced autophagy in glioblastoma cells; however, VSV MP inhibited the autophagy induced by 2-DG in combined treatment and finally contributed to the enhanced cytotoxic effect of the combination strategy in U87 and C6 cancer cells. In the orthotopic U87 glioblastoma model and subcutaneous C6 glioblastoma model, the combined treatment led to significant tumor regression and prolonged survival. A potent therapeutic approach for treating glioblastoma may be found in the combination of VSV MP and glycolytic inhibitors.

Rationale: Glioblastoma (GBM) poses significant challenges regarding complete tumor removal due to its heterogeneity and invasiveness, emphasizing the need for effective therapeutic options. In the last two decades, fluorescence-guided surgery (FGS), employing fluorophores such as 5-aminolevulinic acid (5-ALA) to enhance tumor delineation, has gained attraction among neurosurgeons. However, some low-grade tumors do not show any accumulation of the tracers, and the lack of patient stratification represents an important limitation. Since 2000, endothelin axis has been extensively investigated for its role in cancer progression. More specifically, our team has identified endothelin A receptors (ET A ), overexpressed in glioblastoma cancer stem cells, as a target of interest for GBM imaging. This study aims to evaluate the efficacy of a novel preclinical bimodal imaging agent, [ 89 Zr]Zr-axiRA63-MOMIP, as a theranostic approach to: i) detect ET A + cells in an orthotopic model of human GBM, ii) achieve complete tumoral resection. Methods: Monomolecular multimodal imaging platform (MOMIP) - containing both a fluorophore (IRDye800CW) and a chelator for a positron-emitting radiometal (desferroxamine B, DFO) - was conjugated to the axiRA63 antibody targeting ET A receptors, overexpressed on the surface of GBM stem cells. Mice bearing orthotopic human GBM were imaged 48 h post injection of [ 89 Zr]Zr-axiRA63-MOMIP via positron emission tomography (PET) and optical imaging. Subsequently, post-mortem proof-of-concept FGS was implemented as well as ex vivo analyses (H&E staining, autoradiography, serial block face imaging) on brains with resected or unresected tumor to assess the correlation between PET and fluorescence signals. Results: PET imaging of [ 89 Zr]Zr-axiRA63-MOMIP enabled a clear detection of ET A + cells in an orthotopic model of human GBM. Intraoperative optical imaging allowed a near-complete tumor resection together with the visualization of a weak fluorescence signal, after a prolonged exposure time, that was attributed to residual tumor cells via H&E staining. Besides, a qualitative correlation between the signals of both modalities was observed. Conclusions: The use of [ 89 Zr]Zr-axiRA63-MOMIP provides an effective theranostic approach to detect and treat GBM by surgery in a preclinical mouse model. Thanks to the high correlation between PET and fluorescence signal allowing patients stratification, this bimodal agent should have a great potential for clinical translation and should present a significant advantage over non-targeted fluorophores already used in the clinic., Competing Interests: Competing Interests: DB and AH are scientific cofounders and hold equity in Skymab Biotherapeutics., (© The author(s).)

Glioblastoma (GBL) is one of the more malignant primary brain tumors; it is currently treated by a multimodality strategy including surgery, and radio- and chemotherapy, mainly consisting of temozolomide (TMZ)-based chemotherapy. Tumor relapse often occurs due to the establishment of TMZ resistance, with a patient median survival time of <2 years. The identification of natural molecules with strong anti-tumor activity led to the combination of these compounds with conventional chemotherapeutic agents, developing protocols for integrated anticancer therapies. Curcumin (CUR), resveratrol (RES), and its glucoside polydatin (PLD) are widely employed in the pharmaceutical and nutraceutical fields, and several studies have demonstrated that the combination of these natural products was more cytotoxic than the individual compounds alone against different cancers. Some of us recently demonstrated the synergistic efficacy of the sublingual administration of a new nutraceutical formulation of CUR+PLD in reducing tumor size and improving GBL patient survival. To provide some experimental evidence to reinforce these clinical results, we investigated if pretreatment with a combination of CUR+PLD can improve TMZ cytotoxicity on GBL cells by analyzing the effects on cell cycle, viability, morphology, expression of proteins related to cell proliferation, differentiation, apoptosis or autophagy, and the actin network. Cell viability was assessed using the MTT assay or a CytoSmart cell counter. CalcuSyn software was used to study the CUR+PLD synergism. The morphology was evaluated by optical and scanning electron microscopy, and protein expression was analyzed by Western blot. Flow cytometry was used for the cell cycle, autophagic flux, and apoptosis analyses. The results provide evidence that CUR and PLD, acting in synergy with each other, strongly improve the efficacy of alkylating anti-tumor agents such as TMZ on drug-resistant GBL cells through their ability to affect survival, differentiation, and tumor invasiveness.

Background: Patients with glioblastoma (GBM) have a poor prognosis and limited treatment options. The mRNA decapping enzyme scavenger (DCPS) is a cap-hydrolyzing enzyme. The DCPS inhibitor RG3039 exhibited excellent central nervous system bioavailability in vivo and was safe and well tolerated in healthy volunteers in a phase 1 clinical trial. In this study, we investigated the expression of DCPS in GBM and the anti-tumor activity of RG3039 in various preclinical models of GBM., Methods: DCPS expression was examined in human GBM and paired peritumoral tissues. Its prognostic role was evaluated together with clinicopathological characteristics of patients. The anti-GBM effect of RG3039 was determined using GBM cell lines, patient-derived organoids, and orthotopic mouse models. The therapeutic mechanisms of DCPS inhibition were explored., Results: DCPS is overexpressed in GBM and is associated with poor survival of patients with GBM. The DCPS inhibitor RG3039 exhibited robust anti-GBM activities in GBM cell lines, patient-derived organoids and orthotopic mouse models, with drug exposure achievable in humans. Mechanistically, RG3039 downregulated STAT5B expression, thereby suppressing proliferation, survival and colony formation of GBM cells., Conclusions: DCPS is a promising target for GBM. Inhibition of DCPS with RG3039 at doses achievable in humans downregulates STAT5B expression and reduces proliferation, survival and colony formation of GBM cells. Given the excellent anti-cancer activity and central nervous system bioavailability in vivo and good tolerance in humans, RG3039 warrants further study as a potential GBM therapy., (© 2024. The Author(s).)

Glioblastoma, a highly malignant intracranial tumor, has acquired slow progress in treatment. Previous clinical trials involving targeted therapy and immune checkpoint inhibitors have shown no significant benefits in treating glioblastoma. This ineffectiveness is largely due to the complex immunosuppressive environment of glioblastoma. Glioblastoma cells exhibit low immunogenicity and strong heterogeneity and the immune microenvironment is replete with inhibitory cytokines, numerous immunosuppressive cells, and insufficient effective T cells. Fortunately, recent Phase I clinical trials of CART therapy for glioblastoma have confirmed its safety, with a small subset of patients achieving survival benefits. However, CART therapy continues to face challenges, including blood-brain barrier obstruction, antigen loss, and an immunosuppressive tumor microenvironment (TME). This article provides a detailed examination of glioblastoma's immune microenvironment, both from intrinsic and extrinsic tumor cell factors, reviews current clinical and basic research on multi-targets CART treatment, and concludes by outlining the key challenges in using CART cells for glioblastoma therapy., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Circular RNAs (circRNAs) can influence a variety of biological functions and act as a significant role in the progression and recurrence of glioblastoma (GBM). However, few coding circRNAs have been discovered in cancer, and their role in GBM is still unknown. The aim of this study was to identify coding circRNAs and explore their potential roles in the progression and recurrence of GBM., Methods: CircSPECC1 was screened via circRNAs microarray of primary and recurrent GBM samples. To ascertain the characteristics and coding ability of circSPECC1, we conducted a number of experiments. Afterward, through in vivo and in vitro experiments, we investigated the biological functions of circSPECC1 and its encoded novel protein (SPECC1-415aa) in GBM, as well as their effects on TMZ sensitivity., Results: By analyzing primary and recurrent GBM samples via circRNAs microarray, circSPECC1 was found to be a downregulated circRNA with coding potential in recurrent GBM compared with primary GBM. CircSPECC1 suppressed the proliferation, migration, invasion, and colony formation abilities of GBM cells by encoding a new protein known as SPECC1-415aa. CircSPECC1 restored TMZ sensitivity in TMZ-resistant GBM cells by encoding the new protein SPECC1-415aa. The m 6 A reader protein IGF2BP1 can bind to circSPECC1 to promote its expression and stability. Mechanistically, SPECC1-415aa can bind to ANXA2 and competitively inhibit the binding of ANXA2 to EGFR, thus resulting in the inhibition of the phosphorylation of EGFR (Tyr845) and its downstream pathway protein AKT (Ser473). In vivo experiments showed that the overexpression of circSPECC1 could combine with TMZ to treat TMZ-resistant GBM, thereby restoring the sensitivity of TMZ-resistant GBM to TMZ., Conclusions: CircSPECC1 was downregulated in recurrent GBM compared with primary GBM. The m6A reader protein IGF2BP1 could promote the expression and stability of circSPECC1. The sequence of SPECC1-415aa, which is encoded by circSPECC1, can inhibit the binding of ANXA2 to EGFR by competitively binding to ANXA2 and inhibiting the phosphorylation of EGFR and AKT, thereby restoring the sensitivity of TMZ-resistant GBM cells to TMZ., (© 2024. The Author(s).)

Background: Glioblastoma multiforme (GBM) is among the most aggressive and challenging brain tumors, with limited treatment options. Cimicifuga foetida , a traditional Chinese medicine, has shown promise due to its bioactive components. This study investigates the anti-glioma effects of a methanolic extract of C. foetida (CF-ME) in GBM cell lines., Methods: The effects of CF-ME and its index compounds (caffeic acid, cimifugin, ferulic acid, and isoferulic acid) on GBM cell viability were assessed using MTT assays on U87 MG, A172, and T98G cell lines. The ability of CF-ME to induce cell cycle arrest, apoptosis, and autophagy and inhibit metastasis was evaluated using flow cytometry, Western blotting, and functional assays. Additionally, the synergistic potential of CF-ME with temozolomide (TMZ) was explored., Results: CF-ME significantly reduced GBM cell viability in a dose- and time-dependent manner, induced G1 phase cell cycle arrest, promoted apoptosis via caspase activation, and triggered autophagy. CF-ME also inhibited GBM cell invasion, migration, and adhesion, likely by modulating epithelial-mesenchymal transition (EMT) markers. Combined with TMZ, CF-ME further enhanced reduced GBM cell viability, suggesting a potential synergistic effect. However, the individual index compounds of CF-ME exhibited only modest inhibitory effects, indicating that the full anti-glioma activity may result from the synergistic interactions among its components., Conclusions: CF-ME exhibited potent anti-glioma activity through multiple mechanisms, including cell cycle arrest, apoptosis, autophagy, and the inhibition of metastasis. Combining CF-ME with TMZ further enhanced its therapeutic potential, making it a promising candidate for adjuvant therapy in glioblastoma treatment.

Glioblastoma (GBM) is one of the most common and fatal primary brain tumors, with a 5-year survival rate of 7.2%. The standard treatment for GBM involves surgical resection followed by chemoradiotherapy, and temozolomide (TMZ) is currently the only approved chemotherapeutic agent for the treatment of GBM. However, hydrolytic instability and insufficient drug accumulation are major challenges that limit the effectiveness of TMZ chemotherapy. To overcome these limitations, we have developed a drug delivery platform utilizing porous silicon nanoparticles (pSiNPs) to improve the stability and blood-brain barrier penetration of TMZ. The pSiNPs are synthesized via electrochemical etching and functionalized with octadecane. The octadecyl-modified pSiNP (pSiNP-C 18 ) demonstrates the superiority of loading efficiency, in vivo stability, and brain accumulation of TMZ. Treatment of intracranial tumor-bearing mice with TMZ-loaded pSiNP-C 18 results in a decreased tumor burden and a corresponding increase in survival compared with equivalent free-drug dosing. Furthermore, the mice treated with TMZ-loaded nanoparticles do not exhibit in vivo toxicity, thus underscoring the preclinical potential of the pSiNP-based platform for the delivery of therapeutic agents to gliomas.

For glioblastoma patients, the efficacy-targeted therapy is limited to date. Most of the molecular therapies previously studied are lacking efficacy in this population. More trials are needed to study the actual actionability of biomarkers in (recurrent) glioblastoma. This study aimed to assess the current clinical trial landscape to assess the role of molecular biomarkers in trials on recurrent glioblastoma treatment. The database ClinicalTrials.gov was used to identify not yet completed clinical trials on recurrent glioblastoma in adults. Recruiting studies were assessed to investigate the role of molecular criteria, which were retrieved as detailed as possible. Primary outcome was molecular criteria used as selection criteria for study participation. Next to this, details on moment and method of testing, and targets and drugs studied, were collected. In 76% (181/237) of the included studies, molecular criteria were not included in the study design. Of the remaining 56 studies, at least one specific genomic alteration as selection criterium for study participation was required in 33 (59%) studies. Alterations in EGFR, CDKN2A/B or C, CDK4/6, and RB were most frequently investigated, as were the corresponding drugs abemaciclib and ribociclib. Of the immunotherapies, CAR-T therapies were the most frequently studied therapies. Previously, genomics studies have revealed the presence of potentially actionable alterations in glioblastoma. Our study shows that the potential efficacy of targeted treatment is currently not translated into genome-driven trials in patients with recurrent glioblastoma. An intensification of genome-driven trials might help in providing evidence for (in)efficacy of targeted treatments., (© 2024. The Author(s).)

One of the main causes of poor prognoses in patient with glioblastoma (GBM) is drug resistance to current standard treatment, which includes chemoradiation and adjuvant temozolomide (TMZ). In addition, the concept of cancer stem cells provides new insights into therapy resistance and management also in GBM and glioblastoma stem cell-like cells (GSCs), which might contribute to therapy resistance. Bone morphogenetic protein-4 (BMP4) stimulates astroglial differentiation of GSCs and thereby reduces their self-renewal capacity. Exposure of GSCs to BMP4 may also sensitize these cells to TMZ. A recent phase I trial has shown that local delivery of BMP4 is safe, but a large variation in survival is seen in these treated patients and in features of their cultured tumors. We wanted to combine TMZ and BMP4 (TMZ + BMP4) therapy and assess the inter-tumoral variability in response to TMZ + BMP4 in patient-derived GBM cultures. A phase II trial could then benefit a larger group of patients than those treated with BMP4 only. We first show that simultaneous treatment with TMZ + BMP4 is more effective than sequential treatment. Second, when applying our optimized treatment protocol, 70% of a total of 20 GBM cultures displayed TMZ + BMP4 synergy. This combination induces cellular apoptosis and does not inhibit cell proliferation. Comparative bulk RNA-sequencing indicates that treatment with TMZ + BMP4 eventually results in decreased MAPK signaling, in line with previous evidence that increased MAPK signaling is associated with resistance to TMZ. Based on these results, we advocate further clinical trial research to test patient benefit and validate pathophysiological hypothesis.

Glioblastoma is a Grade 4 primary brain tumor defined by therapy resistance, diffuse infiltration, and near-uniform lethality. The underlying mechanisms are unknown, and no treatment has been curative. Using a recently developed creatine kinase inhibitor (CKi), we explored the role of this inhibitor on GBM biology in vitro. While CKi minimally impacted GBM cell proliferation and viability, it significantly affected migration. In established GBM cell lines and patient-derived xenografts, CKi ablated both the migration and invasion of GBM cells. CKi also hindered radiation-induced migration. RNA-seq revealed a decrease in invasion-related genes, with an unexpected increase in glutathione metabolism and ferroptosis protection genes post-CKi treatment. The effects of CKi could be reversed by the addition of cell-permeable glutathione. Carbon-13 metabolite tracing indicated heightened glutathione biosynthesis post-CKi treatment. Combinatorial CKi blockade and glutathione inhibition or ferroptosis activation abrogated cell survival. Our data demonstrated that CKi perturbs promigratory and anti-ferroptotic roles in GBM, identifying the creatine kinase axis as a druggable target for GBM treatment., (© 2024. The Author(s).)

Glioblastoma (GBM) is a malignant primary brain tumor and an essential contributor to morbidity and mortality globally. Arsenic trioxide (ATO) exerts specific roles in preventing tumor growth. This study investigated the role of ATO in GBM cell behaviors and stemness. The effects of ATO on the malignant behavior of GBM cells, tumor stemness, and epithelial-mesenchymal transition (EMT) factors in mouse tumor tissues were explored. Targets of ATO in GBM were predicted using multiple databases. Subsequently, the expression of retinoic acid-related orphan receptor beta (RORB), WNT-1, β-Catenin, and c-Myc expression were examined in GBM cells before and after ATO treatment.ATO inhibited the malignant behavior of GBM cells in vitro and slowed down the GBM growth in vivo by inhibiting the stemness. The inhibitory effect of ATO on GBM was achieved by promoting RORB levels and strengthening the antagonism to β-Catenin to inhibit Wnt signaling, thus inhibiting tumor growth. Collectively, ATO induced RORB levels in GBM cells and strengthened the antagonistic effect on β-Catenin, thus inhibiting WNT signaling and tumor growth.

The crosstalk between glioma cells and astrocytes plays a crucial role in developing temozolomide (TMZ) resistance of glioblastomas, together with the existence of the BBB contributing to the unsatisfactory clinical treatment of glioblastomas. Herein, we developed a borneol-modified and gastrodin-loaded liposome (Bo-Gas-LP), with the intent of enhancing the efficacy of TMZ therapy after intranasal administration. The results showed that Bo-Gas-LP improved GL261 cells' sensitivity to TMZ and prolonged survival of GL261-bearing mice by blocking the crosstalk between astrocytes and glioblastoma cells with the decrease of Cx43. Our study showed that intranasal Bo-Gas-LP targeting the crosstalk in glioblastoma microenvironments proposed a promising targeted therapy idea to overcome the current therapeutic limitations of TMZ-resistant glioblastomas.

Background: Patients diagnosed with glioblastoma multiforme (GBM) often undergo concurrent temozolomide and radiation therapy. Antineoplastic medication nonadherence continues to be an issue for patients with cancer., Objectives: This quality improvement project aimed to institute an evidence-based standardized educational tool for patients with GBM undergoing concurrent temozolomide and radiation therapy., Methods: To assess medication adherence, patients completed the Brief Adherence Rating Scale at the end of the last radiation therapy visit. Patients and providers completed satisfaction surveys., Findings: Data analysis from the administered Brief Adherence Rating Scale demonstrated a mean of 99.3% (N = 13) medication adherence among participants. Median medication adherence was demonstrated to be 100%, with scores ranging from 93% to 100%.

Antipsychotic drugs have been shown to have antitumor effects but have had limited potency in the clinic. Here, we unveil that pimozide inhibits lysosome hydrolytic function to suppress fatty acid and cholesterol release in glioblastoma (GBM), the most lethal brain tumor. Unexpectedly, GBM develops resistance to pimozide by boosting glutamine consumption and lipogenesis. These elevations are driven by SREBP-1, which we find upregulates the expression of ASCT2, a key glutamine transporter. Glutamine, in turn, intensifies SREBP-1 activation through the release of ammonia, creating a feedforward loop that amplifies both glutamine metabolism and lipid synthesis, leading to drug resistance. Disrupting this loop via pharmacological targeting of ASCT2 or glutaminase, in combination with pimozide, induces remarkable mitochondrial damage and oxidative stress, leading to GBM cell death in vitro and in vivo. Our findings underscore the promising therapeutic potential of effectively targeting GBM by combining glutamine metabolism inhibition with lysosome suppression., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Glioblastoma multiforme is a highly aggressive form of brain cancer, with a median survival time for diagnosed patients of 15 months. Treatment of this cancer is typically a combination of radiation, chemotherapy and surgical removal of the tumour. However, the highly invasive and diffuse nature of glioblastoma makes surgical intrusions difficult, and the diffusive properties of glioblastoma are poorly understood. In this paper, we introduce a stochastic interacting particle system as a model of in vitro glioblastoma migration, along with a maximum likelihood-algorithm designed for inference using microscopy imaging data. The inference method is evaluated on in silico simulation of cancer cell migration, and then applied to a real data set. We find that the inference method performs with a high degree of accuracy on the in silico data, and achieve promising results given the in vitro data set., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Institute of Mathematics and its Applications. All rights reserved.)

Ruthenium compounds offer improved selectivity and fewer side effects compared to platinum-based drugs in glioblastoma treatment. Insights into their interactions with transferrin suggest targeted drug delivery, while photoactivated chemotherapy is a novel cytotoxic approach in tumor tissues.

Glioblastoma (GBM) is the most common form of malignant primary brain tumor and is one of the most lethal cancers. The difficulty in treating GBM stems from its highly developed mechanisms of drug resistance. Our research team has recently identified the fungal secondary metabolite ophiobolin A (OpA) as an agent with significant activity against drug-resistant GBM cells. However, the OpA's mode of action is likely based on covalent modification of its intracellular target(s) and thus possible off-target reactivity needs to be addressed. This work involves the investigation of an acid-sensitive OpA analogue approach that exploits the elevated acidity of the GBM microenvironment to enhance the selectivity for tumor targeting. This project identified analogues that showed selectivity at killing GBM cells grown in cultures at reduced pH compared to those maintained under normal neutral conditions. These studies are expected to facilitate the development of OpA as an anti-GBM agent by investigating its potential use in an acid-sensitive analogue form with enhanced selectivity for tumor targeting., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Naringin, a flavonoid, exhibits diverse therapeutic properties and has been proven to exert cytotoxic effects on cancer cells. Nevertheless, the precise mechanism of naringin maintaining its cytotoxic effect on glioblastoma (GBM) remains unknown. Thus, the current study aimed to establish a plausible cellular mechanism for Naringin's inhibition of GBM. We employed various system biology techniques to forecast the primary targets, including gene ontology and cluster analysis, KEGG enrichment pathway estimation, molecular docking, MD (molecular dynamic) simulation and MMPBSA analysis. Glioblastoma target sequences were obtained via DisGeNet and Therapeutic Target Prediction, aligned with naringin targets, and analyzed for gene enrichment and ontology. Gene enrichment analysis identified the top ten hub genes. Further, molecular docking was conducted on all identified targets. For molecular dynamics modelling, we selected the two complexes that exhibited the most docking affinity and the two most prominent genes of the hub identified through analysis of the enrichment of genes. The PARP1 and ALB1 signalling pathways were found to be the main regulated routes. Naringin exhibited the highest binding potential of - 12.90 kcal/mol with PARP1 (4ZZZ), followed by ABL1 (2ABL), with naringin showing a - 8.4 kcal/mol binding score, as determined by molecular docking. The molecular dynamic approach and MM-PBSA investigation along with PCA study revealed that the complex of Naringin, with 4ZZZ (PARP1) and, 2ABL (ABL1), are highly stable compared to that of imatinib and talazoparib. Analyses of the signalling pathway suggested that naringin may have anticancer effects against GBM by influencing the protein PARP and ALB1 levels. Cytotoxicity assay was performed on two different glioblastoma cell lines C6 and U87MG cells. Naringin demonstrates a higher cytotoxic potency against U87MG human glioblastoma cells compared to C6 rat glioma cells., (© 2024. The Author(s).)

The serine/threonine phosphatase family is important in tumor progression and survival. Due to the high conserved catalytic domain, designing selective inhibitors is challenging. Herein, we obtained compound 28a with 38-fold enhanced PP5 selectivity (PP2A/5 IC 50 = 33.8/0.9 μM) and improved drug-like properties (favorable stability and safety, F = 82.0%) by rational drug design based on a phase II PP2A/5 dual target inhibitor LB-100 . Importantly, we found the spatial conformational restriction of the 28a indole fragment was responsible for the selectivity of PP5. Thus, 28a activated p53 and downregulated cyclin D1 and MGMT, which showed potency in cell cycle arrest and reverse temozolomide (TMZ) resistance in the U87 MG cell line. Furthermore, oral administration of 28a and TMZ was well tolerated to effectively inhibit tumor growth (TGI = 87.7%) in the xenograft model. Collectively, these results implicate 28a could be a drug candidate by reversing TMZ resistance with a selective PP5 inhibition manner.

Background: Glioblastoma is a highly malignant disease with limited treatment options. Ibrutinib, a covalent Bruton tyrosine kinase inhibitor, is an oral agent with manageable side effects used for hematological diseases including Waldenström macroglobulinemia. We present the case of a 69-year-old Caucasian male patient treated with ibrutinib for suspected Bing-Neel syndrome (BNS), which following a biopsy, was reclassified as glioblastoma., Case Presentation: In December 2018, a 69-year-old Caucasian male patient was diagnosed with Waldenström macroglobulinemia. As the patient was asymptomatic, without bone marrow failure or high M-component count, watchful waiting was initiated. Due to increasing neurological symptoms, the patient, based on magnetic resonance imaging, was diagnosed with Bing-Neel syndrome in May 2019. The patient received different treatments before starting ibrutinib monotherapy in August 2019 due to disease progression, both on magnetic resonance imaging and clinically. The patient remained clinically stable for 7 months. In March 2020, the patient developed headaches, and both magnetic resonance imaging and a biopsy revealed glioblastoma IDH-wildtype. Treatment was changed in line with the new diagnosis, but the patient died at the end of 2020., Conclusion: We present a case in which a patient with glioblastoma IDH-wildtype remained clinically stable for 7 months when treated with ibrutinib monotherapy, which is similar to what would be expected for the standard treatment for glioblastoma. To our knowledge, this is the first patient receiving ibrutinib for a glioblastoma IDH-wildtype with a meaningful clinical outcome. Our case may therefore support previous nonclinical findings, indicating a therapeutic value of ibrutinib in patients with glioblastoma and support for further investigation of ibrutinib as a possible treatment for glioblastoma., (© 2024. The Author(s).)

Glioblastoma recurrence is currently inevitable despite extensive standard-of-care treatment. In preclinical studies, an alternative strategy of targeting tumor-associated macrophages and microglia through CSF-1R inhibition was previously found to regress established tumors and significantly increase overall survival. However, recurrences developed in ∼50% of mice in long-term studies, which were consistently associated with fibrotic scars. This fibrotic response is observed following multiple anti-glioma therapies in different preclinical models herein and in patient recurrence samples. Multi-omics analyses of the post-treatment tumor microenvironment identified fibrotic areas as pro-tumor survival niches that encapsulated surviving glioma cells, promoted dormancy, and inhibited immune surveillance. The fibrotic treatment response was mediated by perivascular-derived fibroblast-like cells via activation by transforming growth factor β (TGF-β) signaling and neuroinflammation. Concordantly, combinatorial inhibition of these pathways inhibited treatment-associated fibrosis, and significantly improved survival in preclinical trials of anti-colony-stimulating factor-1 receptor (CSF-1R) therapy., Competing Interests: Declaration of interests A.Z. is a current employee of Genmab; D.C. received consulting fees from Seed Biosciences S.A. and is a current employee of Novigenix; S.N. is a current employee of Roche Pharmaceuticals; A.F.H. has served on advisory boards and speaker’s bureau for Novocure and Bayer; M.E.H. has an advisory role at TME Pharma; J.A.J. received a speaker honorarium from Bristol Meyers Squibb, and served on the scientific advisory board of Pionyr Immunotherapeutics; J.A.J. and D.H. serve on the Cancer Cell editorial advisory board., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Glioblastoma (GBM) stands as the most prevalent and aggressive form of adult gliomas. Despite the implementation of intensive therapeutic approaches involving surgery, radiation, and chemotherapy, Glioblastoma Stem Cells contribute to tumor recurrence and poor prognosis. The induction of Glioblastoma Stem Cells differentiation by manipulating the transcriptional machinery has emerged as a promising strategy for GBM treatment. Here, we explored an innovative approach by investigating the role of the depolarized resting membrane potential (RMP) observed in patient-derived GBM sphereforming cell (GSCs), which allows them to maintain a stemness profile when they reside in the G0 phase of the cell cycle., Methods: We conducted molecular biology and electrophysiological experiments, both in vitro and in vivo, to examine the functional expression of the voltage-gated sodium channel (Na v ) in GSCs, particularly focusing on its cell cycle-dependent functional expression. Na v activity was pharmacologically manipulated, and its effects on GSCs behavior were assessed by live imaging cell cycle analysis, self-renewal assays, and chemosensitivity assays. Mechanistic insights into the role of Na v in regulating GBM stemness were investigated through pathway analysis in vitro and through tumor proliferation assay in vivo., Results: We demonstrated that Na v is functionally expressed by GSCs mainly during the G0 phase of the cell cycle, suggesting its pivotal role in modulating the RMP. The pharmacological blockade of Na v made GBM cells more susceptible to temozolomide (TMZ), a standard drug for this type of tumor, by inducing cell cycle re-entry from G0 phase to G1/S transition. Additionally, inhibition of Na v substantially influenced the self-renewal and multipotency features of GSCs, concomitantly enhancing their degree of differentiation. Finally, our data suggested that Na v positively regulates GBM stemness by depolarizing the RMP and suppressing the ERK signaling pathway. Of note, in vivo proliferation assessment confirmed the increased susceptibility to TMZ following pharmacological blockade of Na v ., Conclusions: This insight positions Na v as a promising prognostic biomarker and therapeutic target for GBM patients, particularly in conjunction with temozolomide treatment., (© 2024. The Author(s).)

Background: Glioblastoma (GBM) is a highly aggressive tumor with unmet therapeutic needs, which can be explained by extensive intra-tumoral heterogeneity and plasticity. In this study, we aimed to investigate the specific metabolic features of Glioblastoma stem cells (GSC), a rare tumor subpopulation involved in tumor growth and therapy resistance., Methods: We conducted comprehensive analyses of primary patient-derived GBM cultures and GSC-enriched cultures of human GBM cell lines using state-of-the-art molecular, metabolic, and phenotypic studies., Results: We showed that GSC-enriched cultures display distinct glycolytic profiles compared with differentiated tumor cells. Further analysis revealed that GSC relies on pyruvate carboxylase (PC) activity for survival and self-renewal capacity. Interestingly, inhibition of PC led to GSC death, particularly when the glutamine pool was low, and increased differentiation. Finally, while GSC displayed resistance to the chemotherapy drug etoposide, genetic or pharmacological inhibition of PC restored etoposide sensitivity in GSC, both in vitro and in orthotopic murine models., Conclusions: Our findings demonstrate the critical role of PC in GSC metabolism, survival, and escape to etoposide. They also highlight PC as a therapeutic target to overcome therapy resistance in GBM., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)