Glioblastoma Multiforme Cells Research Articles

Hyaluronan decorated layer-by-layer assembled lipid nanoparticles for miR-181a delivery in glioblastoma treatment

Glioblastoma multiforme (GBM) is the most common and lethal primary brain cancer. Current pharmacological interventions marginally increase the 12-month overall survival of patients with GBM. Among the novel therapeutic strategies being pursued, micro-RNAs, a class of non-coding RNAs, are receiving considerable attention for their regulation of several pathways implicated in tumorigenesis and survival. Notably, microRNA-181a-5p (miR-181a) has consistently been reported to be downregulated in GBM clinical samples, and its overexpression negatively affects tumor growth both in vitro and in vivo. To improve the delivery of miR-181a to GBM cells, we sought to develop a modified lipid-based nanocarrier capable of encapsulating and delivering miR-181a to GBM cells in vitro and in vivo. Optimized ionizable-lipid containing lipid nanoparticles (LNP) were constructed by covering the miR-181a-loaded LNP with alternating layers of miR-181a, poly-l-arginine and hyaluronic acid through the layer-by-layer technique. The resulting hyaluronan-decorated lipid nanoparticles (HA-LNP) targeted GBM cells more efficiently than non-modified LNP and mediated siRNA and miRNA transfection in vitro. Finally, delivery of miR-181a by HA-LNP induced significant cellular death of U87 GBM cells in vitro and delayed tumor growth in an in vivo subcutaneous tumor model.

Glioblastoma cellular MAP4K1 facilitates tumor growth and disrupts T effector cell infiltration.

MAP4K1 has been identified as a cancer immunotherapy target. Whether and how cancer cell-intrinsic MAP4K1 contributes to glioblastoma multiforme (GBM) progression remains unclear. We found that MAP4K1 was highly expressed in the glioma cells of human GBM specimens. High levels of MAP4K1 mRNA were prevalent in IDH-WT and 1p/19q non-codeletion gliomas and correlated with poor prognosis of patients. MAP4K1 silencing inhibited GBM cell proliferation and glioma growth. Transcriptome analysis of GBM cells and patient samples showed that MAP4K1 modulated cytokine‒cytokine receptor interactions and chemokine signaling pathway, including IL-18R and IL-6R Importantly, MAP4K1 loss down-regulated membrane-bound IL-18R/IL-6R by inhibiting the PI3K-AKT pathway, whereas MAP4K1 restoration rescued this phenotype and therefore GBM cell proliferation. MAP4K1 deficiency abolished GBM cell pro-proliferation responses to IL-18, suggesting an oncogenic role of MAP4K1 via the intrinsic IL-18/IL-18R pathway. In addition, GBM cell-derived MAP4K1 impaired T-cell migration and reduced CD8+ T-cell infiltration in mouse glioma models. Together, our findings provide novel insight into the pathological significance of GBM cell-intrinsic MAP4K1 in driving tumor growth and immune evasion by remodeling cytokine-chemokine networks.

The Antitumor Effect of the DNA Polymerase Alpha Inhibitor ST1926 in Glioblastoma: A Proteomics Approach.

Glioblastoma Multiforme (GBM) is the most aggressive form of malignant brain tumor. The median survival rate does not exceed two years, indicating an imminent need to develop novel therapies. The atypical adamantyl retinoid ST1926 induces apoptosis and growth inhibition in different cancer types. We have shown that ST1926 is an inhibitor of the catalytic subunit of DNA polymerase alpha (POLA1), which is involved in initiating DNA synthesis in eukaryotic cells. POLA1 levels are elevated in GBM versus normal brain tissues. Therefore, we studied the antitumor effects of ST1926 in several human GBM cell lines. We further explored the global protein expression profiles in GBM cell lines using liquid chromatography coupled with tandem mass spectrometry to identify new targets of ST1926. Low sub-micromolar concentrations of ST1926 potently decreased cell viability, induced cell damage and apoptosis, and reduced POLA1 protein levels in GBM cells. The proteomics profiles revealed 197 proteins significantly differentially altered upon ST1926 treatment of GBM cells involved in various cellular processes. We explored the differential gene and protein expression of significantly altered proteins in GBM compared to normal brain tissues.

P02.20.B PLASMA MEMBRANE-ASSOCIATED 70 KDA HEAT SHOCK PROTEIN (HSP70) INVOLVED IN GLIOBLASTOMA CELLS INVASION AS A TARGET FOR TUMOR THERANOSTICS

Abstract BACKGROUND Heat shock proteins (HSPs) represent a large family of highly conserved proteins serving as molecular chaperones that play an important role in intracellular homeostasis. Apart from their intracellular localization, members of various HSPs families such as HSP70 have been reported to be expressed on the plasma membrane of malignant cells, including glioblastoma multiforme (GBM). However, the role of the membrane-bound protein Hsp70 has not yet been investigated in the pathophysiology of GBM. MATERIAL AND METHODS mHsp70 expression as related to GBM cell invasive potential was analyzed in biopsies obtained from neurooncological patients using CellVoyager CQ1 Benchtop High-Content Analysis System (Yokogawa) and inverted confocal microscopy (Leica Microsystems). Application of membrane-associated chaperone for targeted therapies was assessed in the intracranial human NCH644, NCH421k, and U87 GBM models in immunodeficient mice employing various chaperone inhibitors (i.e., JG-98, MKT-077, pifithrin-μ (PES)) as a monotherapy or in combination with a single dose of stereotactic irradiation (10Gy) (SARRP). RESULTS Live-cell imaging of the patient-derived biopsies demonstrated the increased cellular density of mHsp70+ GBM cells particularly in the tissue along the tumor-brain margin. Time-lapse evaluation of the tumor sample further proved the migration of mHsp70+ cells into the surrounding normal brain tissues. Subsequent high-powered multiplex immunofluorescence analysis (Akoya Biosystems) confirmed significantly increased single-cell infiltration of mHsp70+ tumor cells (also positively stained for Nestin, Oct4, and SOX2) in the normal brain tissues. When mHsp70 inhibitors were applied in GBM animal models as a monotherapy or in combination with radiotherapy dramatic inhibition of tumor progression (as shown by MRI) and increased animal survival were observed. CONCLUSION Expression of the mHsp70 on the plasma membrane of GBM cells corresponds to the highly invasive potential of the tumor cells in neuro-oncological patients. Administration of the HSP70 small molecular inhibitors significantly decreased the GBM growth and invasion thus prolonging the overall survival of tumor-bearing mice. Further development of mHsp70-targeted agents represents a promising approach in treatment of multiforme glioblastoma.

Flavopiridol Suppresses Cell Proliferation and Migration and Induces Apoptotic Cell Death by Inhibiting Oncogenic FOXM1 Signaling in IDH Wild-Type and IDH-Mutant GBM Cells.

Glioblastoma multiforme (GBM) remains one of the most challenging solid cancers to treat due to its highly aggressive and drug-resistant nature. Flavopiridol is synthetic flavone that was recently approved by the FDA for the treatment of acute myeloid leukemia. Flavopiridol exhibits antiproliferative activity in several solid cancer cells and currently evaluated in clinical trials in several solid and hematological cancers. In this study, we investigated the molecular mechanisms underlying antiproliferative effects of flavopiridol in GBM cell lines with wild-type and mutant encoding isocitrate dehydrogenase 1 (IDH1). We found that flavopiridol inhibits proliferation, colony formation, and migration and induces apoptosis in IDH1 wild-type and IDH-mutant cells through inhibition of FOXM1 oncogenic signaling. Furthermore, flavopiridol treatment also inhibits of NF-KB, mediators unfolded protein response (UPR), including, GRP78, PERK and IRE1α, and DNA repair enzyme PARP, which have been shown to be potential therapeutic targets by downregulating FOXM1 in GBM cells. Our findings suggest for the first time that flavopiridol suppresses proliferation, survival, and migration and induces apoptosis in IDH1 wild-type and IDH1-mutant GBM cells by targeting FOXM1 oncogenic signaling which also regulates NF-KB, PARP, and UPR response in GBM cells. Flavopiridol may be a potential novel therapeutic strategy in the treatment of patients IDH1 wild-type and IDH1-mutant GBM.

Green Synthesis of Silver Nanoparticles Derived from Papaver rhoeas L. Leaf Extract: Cytotoxic and Antimicrobial Properties.

In the last few decades, the search for metal nanoparticles as an alternative to cancer treatments and antibiotics has increased. In this article, the spectroscopic (ultraviolet-visible (UV-vis), electron-dispersing X-ray (EDX), and Fourier transform infrared (FT-IR)), microscopic (field emission scanning electron microscope (FE-SEM), transmission electron microscope (TEM), and atomic force microscope (AFM)), structural (X-ray diffractometer (XRD) and zetasizer), and analytic (thermogravimetric/differential thermal analyzer (TGA-DTA)) characterization of the silver nanoparticles (AgNPs) produced from Papaver rhoeas (PR) L. leaf extract are presented. PR-AgNPs are generally spherical and have a maximum surface plasmon resonance of 464.03 nm. The dimensions of the manufactured nanomaterial are in the range of 1.47-7.31 nm. PR-AgNPs have high thermal stability and a zeta potential of -36.1 mV. The minimum inhibitory concentration (MIC) values (mg L-1) of PR-AgNPs on Staphylococcus aureus, Escherichia coli, Bacillus subtilis, Pseudomonas aeruginosa, and Candida albicans are 1.50, 0.75, 3.00, 6.00, and 0.37, respectively. In the study, the cytotoxic and proliferative effects of PR-AgNPs using the MTT (3-(4,5-dimethylthiazol-2-yl)-diphenyltetrazolium bromide) method on various cancer cell lines (CACO-2 (human colon adenocarcinoma cell), MCF-7 (human breast cancer cell), T98-G (glioblastoma multiforme cell), and healthy HUVEC (human umbilical vein endothelial cell)) cell lines are presented. After 24 and 48 h of the application, the half-maximum inhibitory concentration (IC50) values (μg mL-1) of PR-AgNPs on HUVEC, CACO-2, MCF-7, and T98-G lines are 2.365 and 2.380; 2.526 and 2.521; 3.274 and 3.318; 3.472 and 3.526, respectively. Comprehensive in vivo research of PR-AgNPs is proposed to reveal their potential for usage in sectors such as nanomedicine and nanochemistry.

BCL2L13 promotes mitophagy through DNM1L-mediated mitochondrial fission in glioblastoma

There is an urgent need for novel diagnostic and therapeutic strategies for patients with Glioblastoma multiforme (GBM). Previous studies have shown that BCL2 like 13 (BCL2L13) is a member of the BCL2 family regulating cell growth and apoptosis in different types of tumors. However, the clinical significance, biological role, and potential mechanism in GBM remain unexplored. In this study, we showed that BCL2L13 expression is significantly upregulated in GBM cell lines and clinical GBM tissue samples. Mechanistically, BCL2L13 targeted DNM1L at the Ser616 site, leading to mitochondrial fission and high mitophagy flux. Functionally, these alterations significantly promoted the proliferation and invasion of GBM cells both in vitro and in vivo. Overall, our findings demonstrated that BCL2L13 plays a significant role in promoting mitophagy via DNM1L-mediated mitochondrial fission in GBM. Therefore, the regulation and biological function of BCL2L13 render it a candidate molecular target for treating GBM.

FOXO1 promotes the expression of canonical WNT target genes in examined basal-like breast and glioblastoma multiforme cancer cells.

Basal-like breast cancer (BBC) and glioblastoma multiforme (GBM) are aggressive cancers associated with poor prognosis. BBC and GBM have stem cell-like gene expression signatures, which are in part driven by forkhead box O (FOXO) transcription factors. To gain further insight into the impact of FOXO1 in BBC, we treated BT549 cells with AS1842856 and performed RNA sequencing. AS1842856 binds to unphosphorylated FOXO1 and inhibits its ability to directly bind to DNA. Gene Set Enrichment Analysis indicated that a set of WNT pathway target genes, including lymphoid enhancer-binding factor 1 (LEF1) and transcription factor 7 (TCF7), were robustly induced after AS1842856 treatment. These same genes were also induced in GBM cell lines U87MG, LN18, LN229, A172, and DBTRG upon AS1842856 treatment. By contrast, follow-up RNA interference (RNAi) targeting of FOXO1 led to reduced LEF1 and TCF7 gene expression in BT549 and U87MG cells. In agreement with RNAi experiments, CRISPR Cas9-mediated FOXO1 disruption reduced the expression of canonical WNT genes LEF1 and TCF7 in U87MG cells. The loss of TCF7 gene expression in FOXO1 disruption mutants was restored by exogenous expression of the DNA-binding-deficient FOXO1-H215R. Therefore, FOXO1 induces TCF7 in a DNA-binding-independent manner, similar to other published FOXO1-activated genes such as TCF4 and hes family bHLH transcription factor 1. Our work demonstrates that FOXO1 promotes canonical WNT gene expression in examined BBC and GBM cells, similar to results found in Drosophila melanogaster, T-cell development, and murine acute myeloid leukemia models.

Comparative analysis of α-pinene alone and combined with temozolomide in human glioblastoma cells

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.

Overcoming multidrug resistance by reversan and exterminating glioblastoma and glioblastoma stem cells by delivering drug-loaded nanostructure hybrid lipid capsules (nHLCs).

Glioblastoma multiforme (GBM) is regarded as a highly aggressive brain cancer with a poor prognosis. There is an increase in the expression of P-glycoprotein (P-gp), responsible for multidrug resistance (MDR), making it a potential target for improving drug responses. Additionally, glioblastoma stem cells (GSCs) increase resistance to chemo- and radiotherapy and play a major role in cancer relapse. In this study, we targeted P-gp using a small molecule inhibitor, reversan (RV), to inhibit MDR that prolonged the retention of drugs in the cytosolic milieu. To eliminate GBM and GSCs, we have used two well-established anti-cancer drugs, regorafenib (RF) and curcumin (CMN). To improve the pharmacokinetics and decrease systemic delivery of drugs, we developed nanostructure hybrid lipid capsules (nHLCs), where hydrophobic drugs can be loaded in the core, and their physicochemical properties were determined by dynamic light scattering (DLS) and cryo-scanning electron microscopy (SEM). Inhibition of MDR by RV has also shown enhanced retention of nHLC in GBM cells. Co-delivery of drug-loaded nHLCs, pre-treated with RV, exhibited superior cytotoxicity in both GBM and GSCs than their individualdoses and effectively reduced the size and stemness of tumor spheres and accelerated the rate of apoptosis, suggesting a promising treatment for glioblastoma.

Claudin-3 facilitates the progression and mediates the tumorigenic effects of TGF-β in glioblastoma multiforme.

Glioblastoma multiforme (GBM) is a significantly malignant and lethal brain tumor with an average survival time of less than 12months. Several researches had shown that Claudin-3 (CLDN3) is overexpressed in various cancers and might be important in their growth and spread. In this study, we used qRT-PCR, western blotting, immunohistochemistry, and immunofluorescence staining assays to investigate the expression levels of various proteins. To explore the proliferation abilities of GBM cells, we conducted the CCK-8 and EdU-DNA formation assays. Wound healing and transwell assays were used to investigate the capacities of invasion and migration of GBM cells. Additionally, we constructed an intracranial xenograft model of GBM to study the in vivo role of CLDN3. Our study devoted to investigate the function of CLDN3 in the pathogenesis and progression of GBM. Our study revealed that CLDN3 was upregulated in GBM and could stimulate tumor cell growth and epithelial-mesenchymal transition (EMT) in both laboratory and animal models. We also discovered that CLDN3 expression could be triggered by transforming growth factor-β (TGF-β) and reduced by specific inhibitors of the TGF-β signaling pathway, such as ITD-1. Further analysis revealed that increased CLDN3 levels enhanced TGF-β-induced growth and EMT in GBM cells, while reducing CLDN3 levels weakened these effects. Our study demonstrated the function of CLDN3 in facilitating GBM growth and metastasis and indicated its involvement in the tumorigenic effects of TGF-β. Developing specific inhibitors of CLDN3 might, therefore, represent a promising new approach for treating this devastating disease.

Transcriptional induction of NF-κB-inducing kinase by E2F4/5 facilitates collective invasion of GBM cells

The prognosis of high-grade gliomas, such as glioblastoma multiforme (GBM), is extremely poor due to the highly invasive nature of these aggressive cancers. Previous work has demonstrated that TNF-weak like factor (TWEAK) induction of the noncanonical NF-κB pathway promotes the invasiveness of GBM cells in an NF-κB-inducing kinase (NIK)-dependent manner. While NIK activity is predominantly regulated at the posttranslational level, we show here that NIK (MAP3K14) is upregulated at the transcriptional level in invading cell populations, with the highest NIK expression observed in the most invasive cells. GBM cells with high induction of NIK gene expression demonstrate characteristics of collective invasion, facilitating invasion of neighboring cells. Furthermore, we demonstrate that the E2F transcription factors E2F4 and E2F5 directly regulate NIK transcription and are required to promote GBM cell invasion in response to TWEAK. Overall, our findings demonstrate that transcriptional induction of NIK facilitates collective cell migration and invasion, thereby promoting GBM pathogenesis.

Targeted Glioblastoma Treatment via Synthesis and Functionalization of Gold Nanoparticles With De Novo-Engineered Transferrin-Like Peptides: Protocol for a Novel Method.

Glioblastoma multiforme (GBM) is an aggressive brain tumor with limited treatment options due to the blood-brain barrier's (BBB's) impedance and inherent resistance to chemotherapy. Gold nanoparticles (AuNPs) functionalized with transferrin-like peptides show promise in overcoming these challenges, enhancing drug delivery to the brain, and reducing chemotherapy resistance. The primary goal of this study is to establish a detailed protocol for synthesizing and stabilizing AuNPs, functionalizing them with de novo-engineered transferrin-like peptides, and conjugating them with the chemotherapeutic agent temozolomide. This strategy aims to improve drug delivery across the BBB and circumvent chemotherapy resistance. The secondary objective includes an assessment of the safety and potential for in vivo use of the synthesized nanoparticle complex. The proposal involves multiple steps with rigorous quality control of AuNP synthesis, stabilization with surfactants, and polyethylene glycol coating. The engineered transferrin-like peptides will be synthesized and attached to the AuNPs' surface, followed by the attachment of temozolomide and O6-methylguanine-DNA methyltransferase inhibitors. The resulting complex will undergo in vitro testing to assess BBB penetration, efficacy against GBM cells, and potential toxicity. Initial preliminary experiments and simulations suggest successful synthesis and stabilization of AuNPs and effective attachment of transferrin-like peptides. We propose peptide attachment verification using Fourier transform infrared spectroscopy and surface plasmon resonance. Additionally, we will conduct pH stability tests to ensure our functionalized AuNPs retain their properties in acidic brain tumor microenvironments. The proposed functionalization of AuNPs with de novo-engineered transferrin-like peptides represents a novel approach to GBM treatment. Our strategy opens new avenues for drug delivery across the BBB and chemotherapy resistance reduction. While we primarily focus on in vitro studies and computational modeling at this stage, successful completion will lead to further development, including in vivo studies and nanoparticle design optimization. This proposal anticipates inspiring future research and funding in neuro-oncology, presenting a potentially innovative and effective treatment option for GBM. RR1-10.2196/49417.

Establishment of a 3D Model to Characterize the Radioresponse of Patient-Derived Glioblastoma Cells.

Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor in adults. Despite modern, multimodal therapeutic options of surgery, chemotherapy, tumor-treating fields (TTF), and radiotherapy, the 5-year survival is below 10%. In order to develop new therapies, better preclinical models are needed that mimic the complexity of a tumor. In this work, we established a novel three-dimensional (3D) model for patient-derived GBM cell lines. To analyze the volume and growth pattern of primary GBM cells in 3D culture, a CoSeedisTM culture system was used, and radiation sensitivity in comparison to conventional 2D colony formation assay (CFA) was analyzed. Both culture systems revealed a dose-dependent reduction in survival, but the high variance in colony size and shape prevented reliable evaluation of the 2D cultures. In contrast, the size of 3D spheroids could be measured accurately. Immunostaining of spheroids grown in the 3D culture system showed an increase in the DNA double-strand-break marker γH2AX one hour after irradiation. After 24 h, a decrease in DNA damage was observed, indicating active repair mechanisms. In summary, this new translational 3D model may better reflect the tumor complexity and be useful for analyzing the growth, radiosensitivity, and DNA repair of patient-derived GBM cells.

NQO1 drives glioblastoma cell aggressiveness through EMT induction via the PI3K/Akt/mTOR/Snail pathway.

Glioblastoma multiforme (GBM) is the most frequent and lethal cancer derived from the central nervous system, of which the mesenchymal (MES) subtype seriously influences the survival and prognosis of patients. NAD(P)H: quinone acceptor oxidoreductase 1 (NQO1) serves an important role in the carcinogenesis and progression of various types of cancer; however, the specific mechanism underlying the regulatory effects of NQO1 on GBM is unclear. Thus, the present study aimed to explore the role and mechanism of NQO1 in GBM progression. The results of bioinformatics analysis and immunohistochemistry showed that high expression of NQO1 was significantly related to the MES phenotype of GBM and shorter survival. In addition, MTT, colony formation, immunofluorescence and western blot analyses, and lung metastasis model experiments suggested that silencing NQO1 inhibited the proliferation and metastasis of GBM cells invitro and invivo. Furthermore, western blotting showed that the activity of the PI3K/Akt/mTOR signaling pathway was revealed to be inhibited by downregulation of NQO1 expression, whereas it was enhanced by overexpression of NQO1. Notably, co‑immunoprecipitation and ubiquitination experiments suggested that Snail was considered an important downstream target of NQO1 in GBM cells. Snail knockdown could eliminate the promoting effect of ectopic NQO1 on the proliferation and invasion of GBM cells, and reduce its effects on the activity of PI3K/Akt/mTOR signaling pathway. These results indicated that NQO1 could promote GBM aggressiveness by activating the PI3K/Akt/mTOR signaling pathway in a Snail‑dependent manner, and NQO1 and its relevant pathways may be considered novel targets for GBM therapy.

Identifying the personalized driver gene sets maximally contributing to abnormality of transcriptome phenotype in glioblastoma multiforme individuals.

High heterogeneity in genome and phenotype of cancer populations made it difficult to apply population-based common driver genes to the diagnosis and treatment of cancer individuals. Characterizing and identifying the personalized driver mechanism for glioblastoma multiforme (GBM) individuals were pivotal for the realization of precision medicine. We proposed an integrative method to identify the personalized driver gene sets by integrating the profiles of gene expression and genetic alterations in cancer individuals. This method coupled genetic algorithm and random walk to identify the optimal gene sets that could explain abnormality of transcriptome phenotype to the maximum extent. The personalized driver gene sets were identified for 99 GBM individuals using our method. We found that genomic alterations in between one and seven driver genes could maximally and cumulatively explain the dysfunction of cancer hallmarks across GBM individuals. The driver gene sets were distinct even in GBM individuals with significantly similar transcriptomic phenotypes. Our method identified MCM4 with rare genetic alterations as previously unknown oncogenic genes, the high expression of which were significantly associated with poor GBM prognosis. The functional experiments confirmed that knockdown of could significantly inhibit proliferation, invasion, migration and clone formation of the GBM cell lines U251 and U118MG, and overexpression of MCM4 significantly promoted the proliferation, invasion, migration and clone formation of the GBM cell line U87MG. Our method could dissect the personalized driver genetic alteration sets that are pivotal for developing targeted therapy strategies and precision medicine. Our method could be extended to identify key drivers from other levels, and could be applied to more cancer types.

SYST-12 LP-184, A NOVEL ACYLFULVENE-DERIVED TUMOR SITE ACTIVATED SMALL MOLECULE INHIBITS ADULT AND PEDIATRIC CNS TUMOR CELL GROWTH

Abstract Blood-brain barrier (BBB) permeable agents effective against recurrent, chemotherapy-resistant central nervous system (CNS) tumors are urgently needed, particularly in Glioblastoma multiforme (GBM) and atypical teratoid/rhabdoid tumors (ATRT). These represent extremely aggressive and lethal types of CNS malignancies. LP-184 is a next-generation acylfulvene class drug candidate and has received FDA orphan drug designations for the treatment of malignant gliomas and ATRT. LP-184 creates covalent DNA adducts that are selectively repaired via nucleotide excision repair (NER). Repair of LP-184-induced DNA damage is mediated by ERCC complexes. Consistent with this, we observed 3-6X decreased cancer cell viability in U87, M1123 and Mayo39 GBM cells treated with LP-184 in combination with the ERCC3 degrader Spironolactone (SP) relative to LP-184 alone. Mice bearing pre-established subcutaneous U87 xenografts were treated with SP alone, LP-184 alone or their combination. Tumors recurred after initial regression in 5/5 animals treated with LP-184 alone whereas tumors showed durable complete regression without recurrence in 4/5 animals treated with LP-184 + SP. Thus, LP-184 likely functions as a synthetically lethal agent in the presence of DNA repair deficiencies. LP-184 inhibited cell growth in CHLA06 and BT37 ATRT cell lines, with IC50s in the 20-25nM range. LP-184 induced apoptosis 96 hours after treatment in these ATRT cell lines as measured by immunofluorescence for cleaved caspase-3 and Western blot for c-PARP. LP-184 intravenous treatment at 4 mg/kg twice weekly for 2 weeks showed tumor regression in mice implanted with CHLA06 ATRT subcutaneous xenografts, with 112% tumor growth inhibition and 2/10 treated mice being tumor-free at study termination. LP-184 further showed favorable intracranial tumor bioavailability along with in vivo BBB permeability comparable to other CNS cancer drugs. These findings identify LP-184 as a promising new agent and support its further development for treating CNS tumors in adult and pediatric populations.

FOXO1-miR-506 axis promotes chemosensitivity to temozolomide and suppresses invasiveness in glioblastoma through a feedback loop of FOXO1/miR-506/ETS1/FOXO1.

To explore the role of forkhead box protein O1 (FOXO1) in the progression of glioblastoma multiforme (GBM) and related drug resistance, we deciphered the roles of FOXO1 and miR-506 in proliferation, apoptosis, migration, invasion, autophagy, and temozolomide (TMZ) sensitivity in the U251 cell line using in vitro and in vivo experiments. Cell viability was tested by a cell counting kit-8 (CCK8) kit; migration and invasion were checked by the scratching assay; apoptosis was evaluated by terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining and flow cytometry. The construction of plasmids and dual-luciferase reporter experiment were carried out to find the interaction site between FOXO1 and miR-506. Immunohistochemistry was done to check the protein level in tumors after the in vivo experiment. We found that the FOXO1-miR-506 axis suppresses GBM cell invasion and migration and promotes GBM chemosensitivity to TMZ, which was mediated by autophagy. FOXO1 upregulates miR-506 by binding to its promoter to enhance transcriptional activation. MiR-506 could downregulate E26 transformation-specific 1 (ETS1) expression by targeting its 3'-untranslated region (UTR). Interestingly, ETS1 promoted FOXO1 translocation from the nucleus to the cytosol and further suppressed the FOXO1-miR-506 axis in GBM cells. Consistently, both miR-506 inhibition and ETS1 overexpression could rescue FOXO1 overactivation-mediated TMZ chemosensitivity in mouse models. Our study demonstrated a negative feedback loop of FOXO1/miR-506/ETS1/FOXO1 in GBM in regulating invasiveness and chemosensitivity. Thus, the above axis might be a promising therapeutic target for GBM.

Recent and future applications of ultrasound-activated piezoelectric nanoparticles for anticancer treatment: mini-review

Piezoelectric nanomaterials have the ability to control cancer cells from a distance. Chronic stimulation using ultrasound-driven piezoelectric nanoparticles can reduce cancer cell growth by inducing cell cycle arrest. This method presents a promising solution to minimize undesirable effects. Numerous in vitro studies with various types of piezoelectric nanomaterials have shown that chronic stimulation interferes with multiple oncogenes, tumor suppressor gene, modifying the balance of cancer cell proliferation and calcium homeostasis, leading to the upregulation of K+ channel gene expression, and resulting in the arrest of the cancer cell cycle in the G0/G1 phase. Additionally, the stimulation affects the organization of mitotic spindles during mitosis and modifies the cytoskeleton capable of disrupting the normal function of cancer cells, leading to their destruction. Evidence of anticancer effects has been demonstrated in cells of osteosarcoma, colorectal cancer, breast cancer, and glioblastoma multiforme, showing a potential wide antitumor effect of piezoelectric nanomaterials.

Chemotherapeutic Effects of Boswellic Acid Against Human Glioblastoma Multiform: A Comprehensive Review

Background: Glioblastoma multiform (GBM) is a malignant subgroup of gliomas. Due to the natural resistance of GBM cells to radio-and chemotherapy usually, recurrence occurs 6-9 months after diagnosis. Objective: This paper reviewed the beneficial effects of Boswellic acid (BA) in adjacent therapy for GBM, based on its possible molecular mechanisms. Methods: In this review paper, all papers indexed in scientific databases, including PubMed, Scopus, Embase, Google Scholar, and Elsevier were searched during 2000 - 2021 using apoptosis, Boswellic acid, cancer, glioblastoma multiform, inflammation, oxidative stress as keywords. Results: The most important compounds of BAs are alpha-boswellic acid, beta- boswellic acid, acetylbeta- boswellic acid, acetyl-alpha- boswellic acid, and 11-keto-beta- boswellic acid (KBA). Antiinflammation, reduction of skin irritation, anti-tumor, anti-cancer, anxiolytic, and anti-phlogistic are the main properties of BAs. Boswellic acid is recognized as a chemopreventive agent. Boswellic acid exerts its effects mainly via various mechanisms such as induction of apoptosis and cytotoxic effects on malignant cells, activation of caspases, up-regulation of genes expression with potential antiapoptotic and pro-survival properties, inhibition the signaling and activity pathway of nuclear factorkappa B (NF-κB) and enhancing poly (ADP)-ribose polymerase (PARP) cleavage. Boswellic acid inhibits the signaling pathway of 5 and 12-lipoxygenase (5, 12 LOX), and cyclooxygenase-2 (COX-2), which are considered triggers in the production of inflammatory cytokines such as tumor necrosis factor (TNF-α), and interleukin-1β (IL-1β). Conclusion: Future clinical trials are needed to identify the interaction between Boswellic acid and the severity of GBM and to define the safe dose and effective duration of supplementation.