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Biomedicine & Pharmacotherapy =... Oct 2023Glioblastoma is a type of intracranial malignancy. Shikonin, a Chinese traditional medicine, has been shown to have anti-tumor efficacy toward human glioblastoma cells...
BACKGROUND
Glioblastoma is a type of intracranial malignancy. Shikonin, a Chinese traditional medicine, has been shown to have anti-tumor efficacy toward human glioblastoma cells in vitro. However, shikonin cannot easily cross the blood-brain barrier. To address this issue, we evaluated the anti-tumor effects of direct intracranial infusion of shikonin in in vivo orthotopic syngeneic murine glioblastoma models using C57BL/6 mice.
MATERIALS AND METHODS
The cytotoxic effects of shikonin against murine glioblastoma cells, SB28 and CT-2A, were reported resistance to temozolomide, were evaluated using an allophycocyanin-conjugated annexin V and propidium iodide assay with flow cytometry. Impedance-based real-time cell analysis (RTCA) was used to analyze the inhibitory effects of shikonin on growth and proliferation. To evaluate the anti-tumor activity of shikonin in vivo, we used orthotopic syngeneic murine glioblastoma models with SB28 and CT-2A cells.
RESULTS
In flow cytometry-based cytotoxic assays, shikonin induced apoptosis. RTCA indicated that shikonin decreased the cell index of murine glioblastoma cells, SB28 and CT-2A, in a dose-dependent manner (p < 0.0001 for both cell lines), while temozolomide did not (p = 0.91 and 0.82, respectively). In murine glioblastoma models, SB28 and CT-2A, direct intracranial infusion of shikonin, as a local chemotherapy, improved the overall survival of mice in a dose-dependent manner compared with control groups (p < 0.0001 and p = 0.02, respectively). While temozolomide did not (p = 0.48 and 0.52, respectively).
CONCLUSIONS
The direct intracranial infusion of shikonin has potential as a local therapy for patients with glioblastoma.
Topics: Humans; Mice; Animals; Temozolomide; Glioblastoma; Mice, Inbred C57BL; Naphthoquinones; Antineoplastic Agents; Brain Neoplasms; Cell Line, Tumor
PubMed: 37557011
DOI: 10.1016/j.biopha.2023.115296 -
CNS Neuroscience & Therapeutics Aug 2023Temozolomide is extensively applied in chemotherapy for glioblastoma with unclear exact action mechanisms. This article seeks to address the potential molecular...
OBJECTIVE
Temozolomide is extensively applied in chemotherapy for glioblastoma with unclear exact action mechanisms. This article seeks to address the potential molecular mechanisms in temozolomide therapy for glioblastoma involving LINC00470.
METHODS
Bioinformatics analysis was conducted to predict the potential mechanism of LINC00470 in glioblastoma, which was validated by dual-luciferase reporter, RIP, ChIP, and RNA pull-down assays. LINC00470 expression and the predicted downstream transcription factor early growth response 2 (EGR2) were detected in the collected brain tissues from glioblastoma patients. Following temozolomide treatment and/or gain- and loss-of-function approaches in glioblastoma cells, cell viability, invasion, migration, cycle distribution, angiogenesis, autophagy, and apoptosis were measured. In addition, the expression of mesenchymal surface marker proteins was assessed by western blot. Tumor xenograft in nude mice was conducted for in vivo validation.
RESULTS
Mechanistic analysis and bioinformatics analysis revealed that LINC00470 transcriptionally activated SRY-related high-mobility-group box 4 (SOX4) through the transcription factor EGR2. LINC00470 and EGR2 were highly expressed in brain tissues of glioblastoma patients. LINC00470 and EGR2 mRNA expression gradually decreased with increasing concentrations of temozolomide in glioblastoma cells, and SOX4 expression was reduced in cells by temozolomide and LINC00470 knockdown. Temozolomide treatment induced cell cycle arrest, diminished cell viability, migration, invasion, and angiogenesis, and increased apoptosis and autophagy in glioblastoma, which was counteracted by overexpressing LINC00470 or SOX4 but was further promoted by LINC00470 knockdown. Temozolomide restrained glioblastoma growth and angiogenesis in vivo, while LINC00470 or SOX4 overexpression nullified but LINC00470 knockdown further facilitated these trends.
CONCLUSION
Conclusively, temozolomide repressed glioblastoma progression by repressing the LINC00470/EGR2/SOX4 axis.
Topics: Animals; Humans; Mice; Apoptosis; Cell Line, Tumor; Cell Proliferation; Down-Regulation; Early Growth Response Protein 2; Gene Expression Regulation, Neoplastic; Glioblastoma; Mice, Nude; SOXC Transcription Factors; Temozolomide; Transcription Factors; RNA, Long Noncoding
PubMed: 36987665
DOI: 10.1111/cns.14181 -
Frontiers in Immunology 2024Glioblastoma is a highly aggressive and invasive tumor that affects the central nervous system (CNS). With a five-year survival rate of only 6.9% and a median survival... (Review)
Review
Glioblastoma is a highly aggressive and invasive tumor that affects the central nervous system (CNS). With a five-year survival rate of only 6.9% and a median survival time of eight months, it has the lowest survival rate among CNS tumors. Its treatment consists of surgical resection, subsequent fractionated radiotherapy and concomitant and adjuvant chemotherapy with temozolomide. Despite the implementation of clinical interventions, recurrence is a common occurrence, with over 80% of cases arising at the edge of the resection cavity a few months after treatment. The high recurrence rate and location of glioblastoma indicate the need for a better understanding of the peritumor brain zone (PBZ). In this review, we first describe the main radiological, cellular, molecular and biomechanical tissue features of PBZ; and subsequently, we discuss its current clinical management, potential local therapeutic approaches and future prospects.
Topics: Humans; Glioblastoma; Brain Neoplasms; Brain; Temozolomide; Central Nervous System Neoplasms
PubMed: 38487525
DOI: 10.3389/fimmu.2024.1347877 -
Cancer Letters Jun 2024Branched-chain amino acid transferase 1 (BCAT1) is highly expressed in multiple cancers and is associated with poor prognosis, particularly in glioblastoma (GBM)....
Branched-chain amino acid transferase 1 (BCAT1) is highly expressed in multiple cancers and is associated with poor prognosis, particularly in glioblastoma (GBM). However, the post-translational modification (PTM) mechanism of BCAT1 is unknown. Here, we investigated the cross-talk mechanisms between phosphorylation and ubiquitination modifications in regulating BCAT1 activity and stability. We found that BCAT1 is phosphorylated by branched chain ketoacid dehydrogenase kinase (BCKDK) at S5, S9, and T312, which increases its catalytic and antioxidant activity and stability. STUB1 (STIP1 homology U-box-containing protein 1), the first we found and reported E3 ubiquitin ligase of BCAT1, can also be phosphorylated by BCKDK at the S19 site, which disrupts the interaction with BCAT1 and inhibits its degradation. In addition, we demonstrate through in vivo and in vitro experiments that BCAT1 phosphorylation inhibiting its ubiquitination at multiple sites is associated with GBM proliferation and that inhibition of the BCKDK-BCAT1 axis enhances the sensitivity to temozolomide (TMZ). Overall, we identified novel mechanisms for the regulation of BCAT1 modification and elucidated the importance of the BCKDK-STUB1-BCAT1 axis in GBM progression.
Topics: Glioblastoma; Humans; Ubiquitination; Phosphorylation; Ubiquitin-Protein Ligases; Animals; Cell Line, Tumor; Cell Proliferation; Brain Neoplasms; Disease Progression; Mice; Mice, Nude; Proteolysis; Temozolomide; HEK293 Cells
PubMed: 38621458
DOI: 10.1016/j.canlet.2024.216849 -
British Journal of Cancer Dec 2023The optimal treatment for metastatic high-grade gastroenteropancreatic (GEP) neuroendocrine neoplasms when Ki-67 ≤55% is unknown. A prospective multi-centre phase 2...
BACKGROUND
The optimal treatment for metastatic high-grade gastroenteropancreatic (GEP) neuroendocrine neoplasms when Ki-67 ≤55% is unknown. A prospective multi-centre phase 2 study was performed to evaluate the efficacy and safety of everolimus and temozolomide as first-line treatment for these patients.
METHODS
Patients received everolimus 10 mg daily continuously and temozolomide 150 mg/m for 7 days every 2 weeks. Endpoints included response, survival, safety and quality of life (QoL). Histopathological re-evaluation according to the 2019 WHO classification was performed.
RESULTS
For 37 eligible patients, the primary endpoint with 65% disease control rate (DCR) at 6 months (m) was reached. The response rate was 30%, the median progression-free survival (PFS) 10.2 months and the median overall survival (OS) 26.4 months. Considering 26 NET G3 patients, 6 months DCR was 77% vs. 22% among nine NEC patients (p = 0.006). PFS was superior for NET G3 vs. NEC (12.6 months vs. 3.4 months, Log-rank-test: p = 0.133, Breslow-test: p < 0.001). OS was significantly better for NET G3 (31.4 months vs. 7.8 months, p = 0.003). Grade 3 and 4 toxicities were reported in 43% and 38%. QoL remained stable during treatment.
CONCLUSION
Everolimus and temozolomide may be a treatment option for selected GEP-NET G3 patients including careful monitoring. Toxicity did not compromise QoL.
CLINICAL TRIAL REGISTRATION
ClinicalTrials.gov (NTC02248012).
Topics: Humans; Everolimus; Temozolomide; Quality of Life; Prospective Studies; Neuroendocrine Tumors; Pancreatic Neoplasms
PubMed: 37872405
DOI: 10.1038/s41416-023-02462-0 -
International Journal of Molecular... Mar 2024A glioblastoma (GBM) is one of the most aggressive, infiltrative, and treatment-resistant malignancies of the central nervous system (CNS). The current standard of care... (Review)
Review
A glioblastoma (GBM) is one of the most aggressive, infiltrative, and treatment-resistant malignancies of the central nervous system (CNS). The current standard of care for GBMs include maximally safe tumor resection, followed by concurrent adjuvant radiation treatment and chemotherapy with the DNA alkylating agent temozolomide (TMZ), which was approved by the FDA in 2005 based on a marginal increase (~2 months) in overall survival (OS) levels. This treatment approach, while initially successful in containing and treating GBM, almost invariably fails to prevent tumor recurrence. In addition to the limited therapeutic benefit, TMZ also causes debilitating adverse events (AEs) that significantly impact the quality of life of GBM patients. Some of the most common AEs include hematologic (e.g., thrombocytopenia, neutropenia, anemia) and non-hematologic (e.g., nausea, vomiting, constipation, dizziness) toxicities. Recurrent GBMs are often resistant to TMZ and other DNA-damaging agents. Thus, there is an urgent need to devise strategies to potentiate TMZ activity, to overcome drug resistance, and to reduce dose-dependent AEs. Here, we analyze major mechanisms of the TMZ resistance-mediated intracellular signaling activation of DNA repair pathways and the overexpression of drug transporters. We review some of the approaches investigated to counteract these mechanisms of resistance to TMZ, including the use of chemosensitizers and drug delivery strategies to enhance tumoral drug exposure.
Topics: Humans; Temozolomide; Glioblastoma; Antineoplastic Agents, Alkylating; Quality of Life; Brain Neoplasms; Neoplasm Recurrence, Local; DNA; Drug Resistance, Neoplasm; Cell Line, Tumor
PubMed: 38542190
DOI: 10.3390/ijms25063217 -
Cells Oct 2023Temozolomide (TMZ) is standard treatment for glioblastoma (GBM); nonetheless, resistance and tumor recurrence are still major problems. In addition to its association...
Temozolomide (TMZ) is standard treatment for glioblastoma (GBM); nonetheless, resistance and tumor recurrence are still major problems. In addition to its association with recurrent GBM and TMZ resistance, ALDH1A3 has a role in autophagy-dependent ferroptosis activation. In this study, we treated TMZ-resistant LN229 human GBM cells with the ferroptosis inducer RSL3. Remarkably, TMZ-resistant LN229 clones were also resistant to ferroptosis induction, although lipid peroxidation was induced by RSL3. By using Western blotting, we were able to determine that ALDH1A3 was down-regulated in TMZ-resistant LN229 cells. Most intriguingly, the cell viability results showed that only those clones that up-regulated ALDH1A3 after TMZ withdrawal became re-sensitized to ferroptosis induction. The recovery of ALDH1A3 expression appeared to be regulated by EGFR-dependent PI3K pathway activation since Akt was activated only in ALDH1A3 high clones. Blocking the EGFR signaling pathway with the EGFR inhibitor AG1498 decreased the expression of ALDH1A3. These findings shed light on the potential application of RSL3 in the treatment of glioblastoma relapse.
Topics: Humans; Cell Line, Tumor; Drug Resistance, Neoplasm; ErbB Receptors; Ferroptosis; Glioblastoma; Neoplasm Recurrence, Local; Phosphatidylinositol 3-Kinases; Temozolomide
PubMed: 37947601
DOI: 10.3390/cells12212522 -
Neuro-oncology Feb 2024Recurrent brain tumors are the leading cause of cancer death in children. Indoleamine 2,3-dioxygenase (IDO) is a targetable metabolic checkpoint that, in preclinical...
BACKGROUND
Recurrent brain tumors are the leading cause of cancer death in children. Indoleamine 2,3-dioxygenase (IDO) is a targetable metabolic checkpoint that, in preclinical models, inhibits anti-tumor immunity following chemotherapy.
METHODS
We conducted a phase I trial (NCT02502708) of the oral IDO-pathway inhibitor indoximod in children with recurrent brain tumors or newly diagnosed diffuse intrinsic pontine glioma (DIPG). Separate dose-finding arms were performed for indoximod in combination with oral temozolomide (200 mg/m2/day x 5 days in 28-day cycles), or with palliative conformal radiation. Blood samples were collected at baseline and monthly for single-cell RNA-sequencing with paired single-cell T cell receptor sequencing.
RESULTS
Eighty-one patients were treated with indoximod-based combination therapy. Median follow-up was 52 months (range 39-77 months). Maximum tolerated dose was not reached, and the pediatric dose of indoximod was determined as 19.2 mg/kg/dose, twice daily. Median overall survival was 13.3 months (n = 68, range 0.2-62.7) for all patients with recurrent disease and 14.4 months (n = 13, range 4.7-29.7) for DIPG. The subset of n = 26 patients who showed evidence of objective response (even a partial or mixed response) had over 3-fold longer median OS (25.2 months, range 5.4-61.9, p = 0.006) compared to n = 37 nonresponders (7.3 months, range 0.2-62.7). Four patients remain free of active disease longer than 36 months. Single-cell sequencing confirmed emergence of new circulating CD8 T cell clonotypes with late effector phenotype.
CONCLUSIONS
Indoximod was well tolerated and could be safely combined with chemotherapy and radiation. Encouraging preliminary evidence of efficacy supports advancing to Phase II/III trials for pediatric brain tumors.
Topics: Humans; Child; Brain Neoplasms; Temozolomide; Tryptophan; Immunologic Factors; Immunotherapy; Brain Stem Neoplasms
PubMed: 37715730
DOI: 10.1093/neuonc/noad174 -
Medicine Dec 2023Recurrent Glioblastoma presents a formidable challenge in oncology due to its aggressive nature and limited treatment options. Tumour-Treating Fields (TTFields) Therapy,... (Review)
Review
Recurrent Glioblastoma presents a formidable challenge in oncology due to its aggressive nature and limited treatment options. Tumour-Treating Fields (TTFields) Therapy, a novel therapeutic modality, has emerged as a promising approach to address this clinical conundrum. This review synthesizes the current evidence surrounding the efficacy of TTFields Therapy in the context of recurrent Glioblastoma. Diverse academic databases were explored to identify relevant studies published within the last decade. Strategic keyword selection facilitated the inclusion of studies focusing on TTFields Therapy's efficacy, treatment outcomes, and patient-specific factors. The review reveals a growing body of evidence suggesting the potential clinical benefits of TTFields Therapy for patients with recurrent Glioblastoma. Studies consistently demonstrate its positive impact on overall survival (OS) and progression-free survival (PFS). The therapy's safety profile remains favorable, with mild to moderate skin reactions being the most commonly reported adverse events. Our analysis highlights the importance of patient selection criteria, with emerging biomarkers such as PTEN mutation status influencing therapy response. Additionally, investigations into combining TTFields Therapy with other treatments, including surgical interventions and novel approaches, offer promising avenues for enhancing therapeutic outcomes. The synthesis of diverse studies underscores the potential of TTFields Therapy as a valuable addition to the armamentarium against recurrent Glioblastoma. The narrative review comprehensively explains the therapy's mechanisms, clinical benefits, adverse events, and future directions. The insights gathered herein serve as a foundation for clinicians and researchers striving to optimize treatment strategies for patients facing the challenging landscape of recurrent Glioblastoma.
Topics: Humans; Glioblastoma; Temozolomide; Electric Stimulation Therapy; Brain Neoplasms; Combined Modality Therapy
PubMed: 38050252
DOI: 10.1097/MD.0000000000036421 -
ACS Nano Sep 2023Glioblastoma multiforme (GBM) is a devastating tumor of the central nervous system, currently missing an effective treatment. The therapeutic gold standard consists of...
Glioblastoma multiforme (GBM) is a devastating tumor of the central nervous system, currently missing an effective treatment. The therapeutic gold standard consists of surgical resection followed by chemotherapy (usually with temozolomide, TMZ) and/or radiotherapy. TMZ does not, however, provide significant survival benefit after completion of treatment because of development of chemoresistance and of heavy side effects of systemic administration. Improvement of conventional treatments and complementary therapies are urgently needed to increase patient survival and quality of life. Stimuli-responsive lipid-based drug delivery systems offer promising prospects to overcome the limitations of the current treatments. In this work, multifunctional lipid-based magnetic nanovectors functionalized with the peptide angiopep-2 and loaded with TMZ (Ang-TMZ-LMNVs) were tested to enhance specific GBM therapy on an model. Exposure to alternating magnetic fields (AMFs) enabled magnetic hyperthermia to be performed, that works in synergy with the chemotherapeutic agent. Studies on orthotopic human U-87 MG-Luc2 tumors in nude mice have shown that Ang-TMZ-LMNVs can accumulate and remain in the tumor after local administration without crossing over into healthy tissue, effectively suppressing tumor invasion and proliferation and significantly prolonging the median survival time when combined with the AMF stimulation. This powerful synergistic approach has proven to be a robust and versatile nanoplatform for an effective GBM treatment.
Topics: Animals; Mice; Humans; Glioblastoma; Magnetite Nanoparticles; Mice, Nude; Quality of Life; Hyperthermia, Induced; Temozolomide; Lipids
PubMed: 37698887
DOI: 10.1021/acsnano.3c06085