Inhibition of mitochondrial translocase SLC25A5 and histone deacetylation is an effective combination therapy in neuroblastoma
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ABSTRACT:
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: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:The child cancer, neuroblastoma (NB), is characterised by a low incidence of mutations and strong oncogenic embryonal driver signals. Many new targeted epigenetic modifier drugs have failed in human trials as monotherapy. We performed a high‐throughput, combination chromatin‐modifier drug screen against NB cells. We screened 13 drug candidates in 78 unique combinations. We found that the combination of two histone methyltransferase (HMT) inhibitors: GSK343, targeting EZH2, and SGC0946, targeting DOT1L, demonstrated the strongest synergy across 8 NB cell lines, with low normal fibroblast toxicity. High mRNA expression of both EZH2 and DOT1L in NB tumour samples correlated with the poorest patient survival. Combination HMT inhibitor treatment caused activation of ATF4‐mediated endoplasmic reticulum (ER) stress responses. In addition, glutathione and several amino acids were depleted by HMT inhibitor combination on mass spectrometry analysis. The combination of SGC0946 and GSK343 reduced tumour growth in comparison to single agents. Our results support further investigation of HMT inhibitor combinations as a therapeutic approach in NB.
2024-11-13 | GSE281811 | GEO
Project description:The CDK7 inhibitor THZ1 has been shown to suppress MYCN gene transcription but not cause significant cell death as a single agent. The tyrosine kinase inhibitors (TKIs) ponatinib and lapatinib were found to exert synergistic anti-cancer effects in combination with the CDK7 inhibitor THZ1, on MYCN amplified neuroblastoma cell lines.
2020-03-20 | GSE128649 | GEO
Project description:Combined inhibition of histone methyltransferases EZH2 and DOT1L is an effective therapy for neuroblastoma
| PRJNA1185740 | ENA
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:As all known, hepatocellular carcinoma (HCC) accounts for the majority of cases of liver cancer, which is the third leading cause of cancer mortality globally. Moreover, HCC is always accompanied with HBV infection. Here, we used CMAP, a systematic approach for the discovery of functional connections among diseases and drug actions, to identify quercetin as an effective compound to potentially treat HCC. Furthermore, we proved the inhibitory effects of quercetin on HCC cells, shown as decreased cell viability in HCCLM3 and HepG2 cells. In addition, quercetin disturbed the migration of HCC cells in a dose-dependent manner. Furthermore, quercetin treatments effectively elevated the activities of caspase-3 as well as caspase-9 and increased the Bax expression in HCC cells accompanied with decreased levels of p53 and BCL-2, indicating an enhancement of apoptosis induced by quercetin. Notably, quercetin depressed the activities of antioxidant enzymes, including SOD, GST, GPx and CAT, leading to an increase of ROS accumulation. Additionally, quercetin also exhibited an obvious inhibition of tumor growth of HCC in vivo. Through RNA-seq, results showed that genes related to regulation of cell proliferations were enriched, in which IGFBP3 played a critical role in mediating the effects of quercetin on HCC cells by reducing PI3K-mTOR activation. After silencing IGFBP3 in HCCLM3 cells, quercetin exhibited weaken effects on cell proliferation and apoptosis. Notably, IGFBP3 promotor strengthened the suppressed effects induced by single quercetin administration, indicating a potential drug combination for treatments of HCC. Collectively, this study clarified a novel mechanism underlying the inhibitory effects of quercetin on HCC, providing a potential approach for HCC treatment in clinic.
2025-08-27 | GSE282022 | GEO