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Journal of Nanobiotechnology May 2024Glioblastoma (GBM) is the most aggressive primary brain tumor with low survival rate. Currently, temozolomide (TMZ) is the first-line drug for GBM treatment of which...
Glioblastoma (GBM) is the most aggressive primary brain tumor with low survival rate. Currently, temozolomide (TMZ) is the first-line drug for GBM treatment of which efficacy is unfortunately hindered by short circulation time and drug resistance associated to hypoxia and redox tumor microenvironment. Herein, a dual-targeted and multi-responsive nanoplatform is developed by loading TMZ in hollow manganese dioxide nanoparticles functionalized by polydopamine and targeting ligands RAP12 for photothermal and receptor-mediated dual-targeted delivery, respectively. After accumulated in GBM tumor site, the nanoplatform could respond to tumor microenvironment and simultaneously release manganese ion (Mn), oxygen (O) and TMZ. The hypoxia alleviation via O production, the redox balance disruption via glutathione consumption and the reactive oxygen species generation, together would down-regulate the expression of O-methylguanine-DNA methyltransferase under TMZ medication, which is considered as the key to drug resistance. These strategies could synergistically alleviate hypoxia microenvironment and overcome TMZ resistance, further enhancing the anti-tumor effect of chemotherapy/chemodynamic therapy against GBM. Additionally, the released Mn could also be utilized as a magnetic resonance imaging contrast agent for monitoring treatment efficiency. Our study demonstrated that this nanoplatform provides an alternative approach to the challenges including low delivery efficiency and drug resistance of chemotherapeutics, which eventually appears to be a potential avenue in GBM treatment.
Topics: Glioblastoma; Temozolomide; Tumor Microenvironment; Drug Resistance, Neoplasm; Humans; Cell Line, Tumor; Animals; Manganese Compounds; Nanoparticles; Brain Neoplasms; Oxides; Mice; Drug Delivery Systems; Indoles; Polymers; Mice, Nude; Mice, Inbred BALB C; Antineoplastic Agents, Alkylating; Reactive Oxygen Species
PubMed: 38760771
DOI: 10.1186/s12951-024-02531-3 -
Cell Communication and Signaling : CCS May 2024Glioblastoma (GBM) is a type of brain cancer categorized as a high-grade glioma. GBM is characterized by limited treatment options, low patient survival rates, and...
Glioblastoma (GBM) is a type of brain cancer categorized as a high-grade glioma. GBM is characterized by limited treatment options, low patient survival rates, and abnormal serotonin metabolism. Previous studies have investigated the tumor suppressor function of aldolase C (ALDOC), a glycolytic enzyme in GBM. However, it is unclear how ALDOC regulates production of serotonin and its associated receptors, HTRs. In this study, we analyzed ALDOC mRNA levels and methylation status using sequencing data and in silico datasets. Furthermore, we investigated pathways, phenotypes, and drug effects using cell and mouse models. Our results suggest that loss of ALDOC function in GBM promotes tumor cell invasion and migration. We observed that hypermethylation, which results in loss of ALDOC expression, is associated with serotonin hypersecretion and the inhibition of PPAR-γ signaling. Using several omics datasets, we present evidence that ALDOC regulates serotonin levels and safeguards PPAR-γ against serotonin metabolism mediated by 5-HT, which leads to a reduction in PPAR-γ expression. PPAR-γ activation inhibits serotonin release by HTR and diminishes GBM tumor growth in our cellular and animal models. Importantly, research has demonstrated that PPAR-γ agonists prolong animal survival rates and increase the efficacy of temozolomide in an orthotopic brain model of GBM. The relationship and function of the ALDOC-PPAR-γ axis could serve as a potential prognostic indicator. Furthermore, PPAR-γ agonists offer a new treatment alternative for glioblastoma multiforme (GBM).
Topics: Temozolomide; Glioblastoma; Humans; Animals; PPAR gamma; Mice; Cell Line, Tumor; Brain Neoplasms; Disease Progression; Serotonin; Signal Transduction; Antineoplastic Agents, Alkylating; Gene Expression Regulation, Neoplastic; PPAR-gamma Agonists
PubMed: 38741139
DOI: 10.1186/s12964-024-01645-3 -
Cell Death & Disease May 2024Glioblastoma stem cells (GSCs) play a key role in glioblastoma (GBM) resistance to temozolomide (TMZ) chemotherapy. With the increase in research on the tumour...
Glioblastoma stem cells (GSCs) play a key role in glioblastoma (GBM) resistance to temozolomide (TMZ) chemotherapy. With the increase in research on the tumour microenvironment, exosomes secreted by GSCs have become a new focus in GBM research. However, the molecular mechanism by which GSCs affect drug resistance in GBM cells via exosomes remains unclear. Using bioinformatics analysis, we identified the specific expression of ABCB4 in GSCs. Subsequently, we established GSC cell lines and used ultracentrifugation to extract secreted exosomes. We conducted in vitro and in vivo investigations to validate the promoting effect of ABCB4 and ABCB4-containing exosomes on TMZ resistance. Finally, to identify the transcription factors regulating the transcription of ABCB4, we performed luciferase assays and chromatin immunoprecipitation-quantitative PCR. Our results indicated that ABCB4 is highly expressed in GSCs. Moreover, high expression of ABCB4 promoted the resistance of GSCs to TMZ. Our study found that GSCs can also transmit their highly expressed ABCB4 to differentiated glioma cells (DGCs) through exosomes, leading to high expression of ABCB4 in these cells and promoting their resistance to TMZ. Mechanistic studies have shown that the overexpression of ABCB4 in GSCs is mediated by the transcription factor ATF3. In conclusion, our results indicate that GSCs can confer resistance to TMZ in GBM by transmitting ABCB4, which is transcribed by ATF3, through exosomes. This mechanism may lead to drug resistance and recurrence of GBM. These findings contribute to a deeper understanding of the mechanisms underlying drug resistance in GBM and provide novel insights into its treatment.
Topics: Temozolomide; Glioblastoma; Humans; Exosomes; Neoplastic Stem Cells; Drug Resistance, Neoplasm; ATP Binding Cassette Transporter, Subfamily B; Activating Transcription Factor 3; Cell Line, Tumor; Brain Neoplasms; Animals; Antineoplastic Agents, Alkylating; Mice; Gene Expression Regulation, Neoplastic; Mice, Nude
PubMed: 38710703
DOI: 10.1038/s41419-024-06695-6 -
Physiological Research Apr 2024Nephrotoxicity as a cause of acute kidney injury (AKI) induced by cisplatin (CP), limits its usefulness as an anticancer agent. Diminazene, an angiotensin converting... (Comparative Study)
Comparative Study
Nephrotoxicity as a cause of acute kidney injury (AKI) induced by cisplatin (CP), limits its usefulness as an anticancer agent. Diminazene, an angiotensin converting enzyme 2 activator, exhibited renoprotective properties on rat models of kidney diseases. This research aims to investigate the salutary effect of diminazene in comparison with lisinopril or valsartan in CP-induced AKI. The first and second groups of rats received oral vehicle (distilled water) for 9 days, and saline injection or intraperitoneal CP (6 mg/kg) on day 6, respectively. Third, fourth, and fifth groups received intraperitoneal injections of CP on day 6 and diminazene (15 mg/kg/day, orally), lisinopril (10 mg/kg/day, orally), or valsartan (30 mg/kg/day, orally), for 9 days, respectively. 24h after the last day of treatment, blood and kidneys were removed under anesthesia for biochemical and histopathological examination. Urine during the last 24 h before sacrificing the rats was also collected. CP significantly increased plasma urea, creatinine, neutrophil gelatinase-associated lipocalin, calcium, phosphorus, and uric acid. It also increased urinary albumin/creatinine ratio, N-Acetyl-beta-D-Glucosaminidase/creatinine ratio, and reduced creatinine clearance, as well the plasma concentrations of inflammatory cytokines [plasma tumor necrosis factor-alpha, and interleukin-1beta], and significantly reduced antioxidant indices [catalase, glutathione reductase , and superoxide dismutase]. Histopathologically, CP treatment caused necrosis of renal tubules, tubular casts, shrunken glomeruli, and increased renal fibrosis. Diminazine, lisinopril, and valsartan ameliorated CP-induced biochemical and histopathological changes to a similar extent. The salutary effect of the three drugs used is, at least partially, due to their anti-inflammatory and antioxidant effects. Keywords: Cisplatin, Diminazene, ACE2 activator, Lisinopril, Valsartan, Acute kidney injury.
Topics: Animals; Acute Kidney Injury; Lisinopril; Cisplatin; Valsartan; Male; Diminazene; Rats; Rats, Wistar; Antineoplastic Agents; Angiotensin-Converting Enzyme Inhibitors; Kidney
PubMed: 38710058
DOI: 10.33549/physiolres.935210 -
Frontiers in Immunology 2024Temozolomide (TMZ) is a key component in the treatment of gliomas. Hypermutation induced by TMZ can be encountered in routine clinical practice, and its significance is...
BACKGROUND
Temozolomide (TMZ) is a key component in the treatment of gliomas. Hypermutation induced by TMZ can be encountered in routine clinical practice, and its significance is progressively gaining recognition. However, the relationship between TMZ-induced hypermutation and the immunologic response remains controversial.
CASE PRESENTATION
We present the case of a 38-year-old male patient who underwent five surgeries for glioma. Initially diagnosed with IDH-mutant astrocytoma (WHO grade 2) during the first two surgeries, the disease progressed to grade 4 in subsequent interventions. Prior to the fourth surgery, the patient received 3 cycles of standard TMZ chemotherapy and 9 cycles of dose-dense TMZ regimens. Genomic and immunologic analyses of the tumor tissue obtained during the fourth surgery revealed a relatively favorable immune microenvironment, as indicated by an immunophenoscore of 5, suggesting potential benefits from immunotherapy. Consequently, the patient underwent low-dose irradiation combined with immunoadjuvant treatment. After completing 4 cycles of immunotherapy, the tumor significantly shrank, resulting in a partial response. However, after a 6-month duration of response, the patient experienced disease progression. Subsequent analysis of the tumor tissue obtained during the fifth surgery revealed the occurrence of hypermutation, with mutation signature analysis attributing TMZ treatment as the primary cause. Unfortunately, the patient succumbed shortly thereafter, with a survival period of 126 months.
CONCLUSION
Patients subjected to a prolonged regimen of TMZ treatment may exhibit heightened vulnerability to hypermutation. This hypermutation induced by TMZ holds the potential to function as an indicator associated with unfavorable response to immunotherapy in gliomas.
Topics: Humans; Temozolomide; Male; Adult; Brain Neoplasms; Glioma; Antineoplastic Agents, Alkylating; Mutation; Immunotherapy; Fatal Outcome; Tumor Microenvironment
PubMed: 38690285
DOI: 10.3389/fimmu.2024.1369972 -
In Vivo (Athens, Greece) 2024Gliomas are the most common and recalcitrant malignant primary brain tumors. All cancer types are addicted to methionine, which is a fundamental and general hallmark of...
Extensive Shrinkage and Long-term Stable Disease in a Teenage Female Patient With High-grade Glioma Treated With Temozolomide and Radiation in Combination With Oral Recombinant Methioninase and a Low-methionine Diet.
BACKGROUND/AIM
Gliomas are the most common and recalcitrant malignant primary brain tumors. All cancer types are addicted to methionine, which is a fundamental and general hallmark of cancer known as the Hoffman effect. Particularly glioma cells exhibit methionine addiction. Because of methionine addiction, [C]-methionine positron emission tomography (MET-PET) is widely used for glioma imaging in clinical practice, which can monitor the extent of methionine addiction. Methionine restriction including recombinant methioninase (rMETase) and a low-methionine diet, has shown high efficacy in preclinical models of gliomas, especially in combination with chemotherapy. The aim of the present study was to determine the efficacy of methionine restriction with oral rMETase (o-rMETase) and a low-methionine diet, combined with radiation and temozolomide (TMZ), on a teenage female patient with high-grade glioma.
CASE REPORT
A 16-year-old girl was diagnosed with high-grade glioma. Magnetic resonance imaging (MRI) showed a left temporal-lobe tumor with compression to the left lateral ventricle and narrowing of sulci in the left temporal lobe. After the start of methionine restriction with o-rMETase and a low-methionine diet, along with TMZ combined with radiotherapy, the tumor size shrunk at least 60%, with improvement in the left lateral ventricle and sulci. The patient's condition remains stable for 19 months without severe adverse effects.
CONCLUSION
Methionine restriction consisting of o-rMETase and a low-methionine diet, in combination with radiation and TMZ as first-line chemotherapy, were highly effective in a patient with high-grade glioma.
Topics: Humans; Female; Glioma; Carbon-Sulfur Lyases; Temozolomide; Methionine; Adolescent; Magnetic Resonance Imaging; Brain Neoplasms; Treatment Outcome; Neoplasm Grading; Positron-Emission Tomography; Recombinant Proteins; Combined Modality Therapy
PubMed: 38688589
DOI: 10.21873/invivo.13591 -
International Journal of Molecular... Apr 2024Virotherapy is one of the perspective technologies in the treatment of malignant neoplasms. Previously, we have developed oncolytic vaccinia virus VV-GMCSF-Lact and its...
Virotherapy is one of the perspective technologies in the treatment of malignant neoplasms. Previously, we have developed oncolytic vaccinia virus VV-GMCSF-Lact and its high cytotoxic activity and antitumor efficacy against glioma was shown. In this work, using immortalized and patient-derived cells with different sensitivity to VV-GMCSF-Lact, we evaluated the cytotoxic effect of chemotherapy agents. Additionally, we studied the combination of VV-GMCSF-Lact with temozolomide which is the most preferred drug for glioma treatment. Experimental results indicate that first adding temozolomide and then the virus to the cells is inherently more efficient than dosing it in the reverse order. Testing these regimens in the U87 MG xenograft glioblastoma model confirmed this effect, as assessed by tumor growth inhibition index and histological analysis. Moreover, VV-GMCSF-Lact as monotherapy is more effective against U87 MG glioblastoma xenografts comparing temozolomide.
Topics: Humans; Animals; Oncolytic Virotherapy; Oncolytic Viruses; Temozolomide; Xenograft Model Antitumor Assays; Cell Line, Tumor; Mice; Glioma; Vaccinia virus; Granulocyte-Macrophage Colony-Stimulating Factor; Brain Neoplasms; Mice, Nude; Antineoplastic Agents; Glioblastoma; Combined Modality Therapy
PubMed: 38673835
DOI: 10.3390/ijms25084244 -
CNS Neuroscience & Therapeutics Apr 2024Besides the hallmark of H3K27M mutation, aberrant amplifications of receptor tyrosine kinases (RTKs) are commonly observed in diffuse midline glioma (DMG), a highly...
BACKGROUND
Besides the hallmark of H3K27M mutation, aberrant amplifications of receptor tyrosine kinases (RTKs) are commonly observed in diffuse midline glioma (DMG), a highly malignant brain tumor with dismal prognosis. Here, we intended to evaluate the efficacy and safety of a multitarget RTK inhibitor anlotinib in patients with H3K27M-DMG.
METHODS
A total of 40 newly diagnosed H3K27M-DMG patients including 15 with anlotinib and 25 without anlotinib treatment were retrospectively enrolled in this cohort. Progression-free survival (PFS), overall survival (OS), and toxicities were assessed and compared.
RESULTS
The median PFS and OS of all patients in this cohort were 8.5 months (95% CI, 6.5-11.3) and 15.5 months (95% CI, 12.6-17.1), respectively. According to the Response Assessment in Neuro-Oncology (RANO) criteria, the disease control rate in the anlotinib group [93.3%, 95% confidence interval (CI), 70.2-98.8] was significantly higher than those without anlotinib (64%, 95% CI: 40.5-79.8, p = 0.039). The median PFS of patients with and without anlotinib was 11.6 months (95% CI, 7.8-14.3) and 6.4 months (95% CI, 4.3-10.3), respectively. Both the median PFS and OS of DMG patients treated with anlotinib were longer than those without anlotinib in the infratentorial patients (PFS: 10.3 vs. 5.4 months, p = 0.006; OS: 16.6 vs. 8.7 months, p = 0.016). Multivariate analysis also indicated anlotinib (HR: 0.243, 95% CI: 0.066-0.896, p = 0.034) was an independent prognosticator for longer OS in the infratentorial subgroup. In addition, the adverse events of anlotinib administration were tolerable in the whole cohort.
CONCLUSIONS
This study first reported that anlotinib combined with Stupp regimen is a safe and feasible regimen for newly diagnosed patients with H3K27M-DMG. Further, anlotinib showed significant efficacy for H3K27M-DMG located in the infratentorial region.
Topics: Humans; Male; Indoles; Quinolines; Female; Retrospective Studies; Middle Aged; Adult; Brain Neoplasms; Glioma; Temozolomide; Mutation; Young Adult; Cohort Studies; Adolescent; Chemoradiotherapy; Aged
PubMed: 38644565
DOI: 10.1111/cns.14730 -
CNS Neuroscience & Therapeutics Apr 2024To elucidate the relationship between USP19 and O(6)-methylguanine-DNA methyltransferase (MGMT) after temozolomide treatment in glioblastoma (GBM) patients with...
OBJECTIVE
To elucidate the relationship between USP19 and O(6)-methylguanine-DNA methyltransferase (MGMT) after temozolomide treatment in glioblastoma (GBM) patients with chemotherapy resistance.
METHODS
Screening the deubiquitinase pannel and identifying the deubiquitinase directly interacts with and deubiquitination MGMT. Deubiquitination assay to confirm USP19 deubiquitinates MGMT. The colony formation and tumor growth study in xenograft assess USP19 affects the GBM sensitive to TMZ was performed by T98G, LN18, U251, and U87 cell lines. Immunohistochemistry staining and survival analysis were performed to explore how USP19 is correlated to MGMT in GBM clinical management.
RESULTS
USP19 removes the ubiquitination of MGMT to facilitate the DNA methylation damage repair. Depletion of USP19 results in the glioblastoma cell sensitivity to temozolomide, which can be rescued by overexpressing MGMT. USP19 is overexpressed in glioblastoma patient samples, which positively correlates with the level of MGMT protein and poor prognosis in these patients.
CONCLUSION
The regulation of MGMT ubiquitination by USP19 plays a critical role in DNA methylation damage repair and GBM patients' temozolomide chemotherapy response.
Topics: Humans; Temozolomide; DNA Repair Enzymes; DNA Modification Methylases; Antineoplastic Agents, Alkylating; Animals; Cell Line, Tumor; Drug Resistance, Neoplasm; Tumor Suppressor Proteins; DNA Methylation; Mice, Nude; Brain Neoplasms; Glioblastoma; Mice; Male; Female; Dacarbazine; DNA Repair; Endopeptidases; Xenograft Model Antitumor Assays; Ubiquitination
PubMed: 38644551
DOI: 10.1111/cns.14711 -
ACS Applied Materials & Interfaces May 2024While temozolomide (TMZ) has been a cornerstone in the treatment of newly diagnosed glioblastoma (GBM), a significant challenge has been the emergence of resistance to...
While temozolomide (TMZ) has been a cornerstone in the treatment of newly diagnosed glioblastoma (GBM), a significant challenge has been the emergence of resistance to TMZ, which compromises its clinical benefits. Additionally, the nonspecificity of TMZ can lead to detrimental side effects. Although TMZ is capable of penetrating the blood-brain barrier (BBB), our research addresses the need for targeted therapy to circumvent resistance mechanisms and reduce off-target effects. This study introduces the use of PEGylated mesoporous silica nanoparticles (MSN) with octyl group modifications (C8-MSN) as a nanocarrier system for the delivery of docetaxel (DTX), providing a novel approach for treating TMZ-resistant GBM. Our findings reveal that C8-MSN is biocompatible in vitro, and DTX@C8-MSN shows no hemolytic activity at therapeutic concentrations, maintaining efficacy against GBM cells. Crucially, in vivo imaging demonstrates preferential accumulation of C8-MSN within the tumor region, suggesting enhanced permeability across the blood-brain tumor barrier (BBTB). When administered to orthotopic glioma mouse models, DTX@C8-MSN notably prolongs survival by over 50%, significantly reduces tumor volume, and decreases side effects compared to free DTX, indicating a targeted and effective approach to treatment. The apoptotic pathways activated by DTX@C8-MSN, evidenced by the increased levels of cleaved caspase-3 and PARP, point to a potent therapeutic mechanism. Collectively, the results advocate DTX@C8-MSN as a promising candidate for targeted therapy in TMZ-resistant GBM, optimizing drug delivery and bioavailability to overcome current therapeutic limitations.
Topics: Temozolomide; Glioblastoma; Docetaxel; Silicon Dioxide; Blood-Brain Barrier; Animals; Nanoparticles; Humans; Mice; Drug Resistance, Neoplasm; Brain Neoplasms; Cell Line, Tumor; Porosity; Drug Carriers; Mice, Nude; Antineoplastic Agents; Apoptosis
PubMed: 38629735
DOI: 10.1021/acsami.4c04289