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Combined Effect of Conventional Chemotherapy with Epigenetic Modulators on Glioblastoma
Adrian Albulescu1,2, Anca Botezatu1, Alina Fudulu1
1Molecular Virology Department, Stefan S. Nicolau Institute of Virology, Romanian Academy, 030304 Bucharest, Romania.
Background/Objectives:
Glioblastoma is the most common malignant primary brain tumor, characterized by necrosis, uncontrolled proliferation, infiltration, angiogenesis, apoptosis resistance, and genomic instability. Epigenetic modifiers hold promise as adjuvant therapies for gliomas, with synergistic combinations being explored to enhance efficacy and reduce toxicity. This study aimed to evaluate the effects of single or combined treatments with various anticancer drugs (Carboplatin, Paclitaxel, Avastin), natural compounds (Quercetin), and epigenetic modulators (suberoylanilide hydroxamic acid and 5-Azacytidine) on the expression of some long noncoding RNAs and methylation drivers or some functional features in the U87-MG cell line.
Methods:
Treated and untreated U87-MG cells were used for the evaluation of drug-induced cytotoxicity, apoptotic events, and distribution in cell cycle phases, detection of cytokine release, and assessment of gene expression and global methylation.
Results:
Cytotoxicity assays led to the selection of drug concentrations to be used in further experiments. Expression analysis revealed distinct downregulation of nearly all investigated genes and long noncoding RNAs following treatments. All treatments resulted in a higher percentage of global methylation compared to untreated controls. All treatments effectively increased levels of apoptosis, while the epigenetic modulators exhibited a lower proliferation profile, with combined treatments showing elevated values of cell lysis.
Conclusions:
The results indicate a link between Carboplatin and Avastin treatments and DNA methylation mechanisms involving EZH2, DNMT3A, and DNMT3B, with Avastin's direct impact on these enzymes warranting further study. This research underscores the promise of platinum-based therapies combined with epigenetic drugs to reactivate silenced tumor suppressor genes and optimize methylation profiles.
Insights
This study shows that combining platinum-based chemotherapy with epigenetic drugs can increase global methylation and apoptosis in glioblastoma cells. These combinations may help reactivate silenced tumor suppressor genes for better treatment outcomes.
Area of Science:
- Oncology
- Molecular Biology
- Epigenetics
Background:
- Glioblastoma is an aggressive brain tumor with complex genetic and epigenetic alterations.
- Epigenetic modifiers are being explored as adjuvant therapies to improve glioma treatment efficacy.
- Synergistic drug combinations are crucial for enhancing therapeutic effects and reducing toxicity.
Purpose of the Study:
- To evaluate the effects of single and combined treatments on U87-MG glioblastoma cells.
- To assess the impact of anticancer drugs, natural compounds, and epigenetic modulators on gene expression and methylation.
- To investigate functional changes including cytotoxicity, apoptosis, and cell cycle distribution.
Main Methods:
- U87-MG cells were treated with various agents including Carboplatin, Paclitaxel, Avastin, Quercetin, suberoylanilide hydroxamic acid, and 5-Azacytidine.
- Assays included cytotoxicity, apoptosis detection, cell cycle analysis, cytokine release measurement, gene expression, and global methylation analysis.
- Drug concentrations were optimized based on initial cytotoxicity assays.
Main Results:
- Treatments led to downregulation of most investigated genes and long noncoding RNAs.
- All treatment groups exhibited increased global methylation compared to controls.
- Apoptosis levels were elevated across all treatments, with epigenetic modulators showing reduced proliferation and combined treatments enhancing cell lysis.
Conclusions:
- Carboplatin and Avastin treatments are linked to DNA methylation mechanisms involving EZH2, DNMT3A, and DNMT3B.
- Avastin's direct impact on these methylation enzymes requires further investigation.
- Combined platinum-based and epigenetic therapies show promise for reactivating tumor suppressor genes and optimizing methylation profiles in glioblastoma.
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