Inhibition of mitochondrial translocase SLC25A5 and histone deacetylation is an effective combination therapy in neuroblastoma
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PROVIDER: PRJNA803444 | ENA |
REPOSITORIES: ENA
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Project description:Mitochondria are gatekeepers of apoptotic processes and mediate drug resistance to several chemotherapy agents used to treat cancer. Neuroblastoma is a common solid cancer in young children with poor clinical outcomes following conventional chemotherapy. We sought druggable mitochondrial protein targets in neuroblastoma cells. Among mitochondria-associated gene targets, we found that high expression of the mitochondrial adenine nucleotide translocase 2 (SLC25A5/ANT2), was a strong predictor of poor neuroblastoma patient prognosis and contributed to a more malignant phenotype in pre-clinical models. Inhibiting this transporter with PENAO reduced cell viability in a panel of neuroblastoma cell lines in a TP53-status-dependent manner. We identified the histone deacetylase inhibitor, suberanilohydroxamic acid (SAHA), as the most effective drug in clinical use against mutant TP53 neuroblastoma cells. SAHA and PENAO synergistically reduced cell viability, and induced apoptosis, in neuroblastoma cells independent of TP53-status. The SAHA and PENAO drug combination significantly delayed tumour progression in pre-clinical neuroblastoma mouse models, suggesting that these clinically advanced inhibitors may be effective in treating the disease.
2022-02-05 | GSE196128 | GEO
Project description:The mitochondrion is a gatekeeper of apoptotic processes, and mediates drug resistance to several chemotherapy agents used to treat cancer. Neuroblastoma is a common solid cancer in young children with poor clinical outcomes following conventional chemotherapy. We sought druggable mitochondrial protein targets in neuroblastoma cells. Among mitochondria-associated gene targets, we found that high expression of the mitochondrial adenine nucleotide translocase 2 (SLC25A5/ANT2), was a strong predictor of poor neuroblastoma patient prognosis and contributed to a more malignant phenotype in pre-clinical models. Inhibiting this transporter with PENAO reduced cell viability in a panel of neuroblastoma cell lines in a TP53-status-dependant manner. We identified the histone deacetylase inhibitor, suberanilohydroxamic acid (SAHA), as the most effective drug in clinical use against mutant TP53 neuroblastoma cells. SAHA and PENAO synergistically reduced cell viability, and induced apoptosis, in neuroblastoma cells independent of TP53-status. The SAHA and PENAO drug combination significantly delayed tumour progression in pre-clinical neuroblastoma mouse models, suggesting that these clinically advanced inhibitors may be effective in treating the disease.
| S-EPMC10953412 | biostudies-literature
Project description:IGFBP3-mediated effects of an effective combination therapy on HCC
| PRJNA1186675 | ENA
Project description:<h4><strong>BACKGROUND: </strong>Neuroblastoma accounts for 7% of paediatric malignancies but is responsible for 15% of all childhood cancer deaths. Despite rigorous treatment involving chemotherapy, surgery, radiotherapy and immunotherapy, the 5-year overall survival rate of high-risk disease remains < 40%, highlighting the need for improved therapy. Since neuroblastoma cells exhibit aberrant metabolism, we determined whether their sensitivity to radiotherapy could be enhanced by drugs affecting cancer cell metabolism.</h4><h4><strong>METHODS:</strong> Using a panel of neuroblastoma and glioma cells, we determined the radiosensitising effects of inhibitors of glycolysis (2-DG) and mitochondrial function (metformin). Mechanisms underlying radiosensitisation were determined by metabolomic and bioenergetic profiling, flow cytometry and live cell imaging and by evaluating different treatment schedules.</h4><h4><strong>RESULTS:</strong> The radiosensitising effects of 2-DG were greatly enhanced by combination with the antidiabetic biguanide, metformin. Metabolomic analysis and cellular bioenergetic profiling revealed this combination to elicit severe disruption of key glycolytic and mitochondrial metabolites, causing significant reductions in ATP generation and enhancing radiosensitivity. Combination treatment induced G<sub>2</sub>/M arrest that persisted for at least 24 h post-irradiation, promoting apoptotic cell death in a large proportion of cells.</h4><h4><strong>CONCLUSION: </strong>Our findings demonstrate that the radiosensitising effect of 2-DG was significantly enhanced by its combination with metformin. This clearly demonstrates that dual metabolic targeting has potential to improve clinical outcomes in children with high-risk neuroblastoma by overcoming radioresistance.</h4>
2022-11-30 | MTBLS858 | MetaboLights
Project description:Neuroblastoma, a prevalent and aggressive childhood cancer, faces a critical lack of effective treatment options.
We systematically analyzed small-molecule perturbation gene expression data from the Library of Integrated Network-Based Cellular Signatures (LINCS), aiming to identify drugs with promising with potential for combination therapy. Following this predictive phase, we proceeded to validate our findings through a series of comprehensive assays.
To achieve this, we employed an array of advanced techniques: quantitative proteomics with tandem mass tag labeling, western blotting, immunocytochemistry, and migration analysis. This multifaceted approach allowed us to gain a more profound understanding of the therapeutic potential and the cellular dynamics involved in treating neuroblastoma.
Our research led us to hypothesize that a synergistic effect could be achieved in neuroblastoma treatment using a combination of two FDA-approved drugs: sirolimus and pyrvinium pamoate. Upon administering this combined therapy, we observed a significant reduction in cell viability, which was also accompanied by decreased mRNA expression. The effectiveness of this combination was further underscored by colony formation assays, which revealed a notably lower survival rate in neuroblastoma cell lines treated with the drug duo, as opposed to those treated with either drug in isolation. Our comprehensive proteomics analysis, encompassing the identification of 20,623 peptides and 3,415 proteins, shed light on the underlying biological processes affected by the therapy.
2025-08-07 | PXD052461 | JPOST Repository
Project description:Neuroblastoma, a prevalent and aggressive childhood cancer, faces a critical lack of effective treatment options.
We systematically analyzed small-molecule perturbation gene expression data from the Library of Integrated Network-Based Cellular Signatures (LINCS), aiming to identify drugs with promising with potential for combination therapy. Following this predictive phase, we proceeded to validate our findings through a series of comprehensive assays.
To achieve this, we employed an array of advanced techniques: quantitative proteomics with tandem mass tag labeling, western blotting, immunocytochemistry, and migration analysis. This multifaceted approach allowed us to gain a more profound understanding of the therapeutic potential and the cellular dynamics involved in treating neuroblastoma.
Our research led us to hypothesize that a synergistic effect could be achieved in neuroblastoma treatment using a combination of two FDA-approved drugs: sirolimus and pyrvinium pamoate. Upon administering this combined therapy, we observed a significant reduction in cell viability, which was also accompanied by decreased mRNA expression. The effectiveness of this combination was further underscored by colony formation assays, which revealed a notably lower survival rate in neuroblastoma cell lines treated with the drug duo, as opposed to those treated with either drug in isolation. Our comprehensive proteomics analysis, encompassing the identification of 20,623 peptides and 3,415 proteins, shed light on the underlying biological processes affected by the therapy.
2025-08-07 | PXD052282 | JPOST Repository
Project description:Neuroblastoma, a prevalent and aggressive childhood cancer, faces a critical lack of effective treatment options.
We systematically analyzed small-molecule perturbation gene expression data from the Library of Integrated Network-Based Cellular Signatures (LINCS), aiming to identify drugs with promising with potential for combination therapy. Following this predictive phase, we proceeded to validate our findings through a series of comprehensive assays.
To achieve this, we employed an array of advanced techniques: quantitative proteomics with tandem mass tag labeling, western blotting, immunocytochemistry, and migration analysis. This multifaceted approach allowed us to gain a more profound understanding of the therapeutic potential and the cellular dynamics involved in treating neuroblastoma.
Our research led us to hypothesize that a synergistic effect could be achieved in neuroblastoma treatment using a combination of two FDA-approved drugs: sirolimus and pyrvinium pamoate. Upon administering this combined therapy, we observed a significant reduction in cell viability, which was also accompanied by decreased mRNA expression. The effectiveness of this combination was further underscored by colony formation assays, which revealed a notably lower survival rate in neuroblastoma cell lines treated with the drug duo, as opposed to those treated with either drug in isolation. Our comprehensive proteomics analysis, encompassing the identification of 20,623 peptides and 3,415 proteins, shed light on the underlying biological processes affected by the therapy.
2025-09-08 | PXD054625 | JPOST Repository
Project description:Combination treatment with BMI1 and MAPK/ERK inhibitors is effective in medulloblastoma
| PRJNA723029 | ENA
Project description:<p>Relapse and treatment resistance are common in children with high-risk neuroblastoma, and novel therapies are needed. Conventional drug discovery is slow, expensive, often fails in practice, and consequently falls short in addressing pediatric and rare conditions. In such instances, drug repurposing is a promising strategy. Here, we used two independent in silico prediction tools including machine learning to identify approved drugs for repurposing against neuroblastoma. The combination of statins and phenothiazines showed strong synergistic effects in human neuroblastoma organoids, decreased tumor growth and prolonged survival in MYCN-amplified neuroblastoma patient-derived xenografts. The drug combination altered cholesterol metabolism through two different mechanisms and induced a phenotypic change towards an adrenergic state in vitro, which was associated with enhanced chemosensitivity. Integration of the drug combination into standard-of-care chemotherapy regressed tumors and prolonged survival in chemoresistant patient-derived xenografts. Thus, a combination of safe and approved medications added to standard-of-care chemotherapy outperforms chemotherapy alone in chemoresistant neuroblastoma.</p>
2025-11-13 | MTBLS13246 | MetaboLights
Project description:RNA-seq upon JQ1 (1 uM), THZ1 (35 nM), UT (untreated) or combination treatment in the neuroblastoma cell line IMR-5/75. Analysis was performed 10h upon treament. Four biological replicates per condition.
2018-08-17 | E-MTAB-7025 | biostudies-arrayexpress