ArticleBMC cancer2012
Synthetic lethal screen identifies NF-κB as a target for combination therapy with topotecan for patients with neuroblastoma.
Article in BMC cancer, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed, 17 citations in OpenAlex.
- Identification and Characterization of Chemotherapy-Resistant High-Risk Neuroblastoma Persister Cells.Cancer discovery · 2024Article
- Update on the Role of NFκB in Promoting Aggressive Phenotypes of Estrogen Receptor-Positive Breast Cancer.Endocrinology · 2020Review
- Andrographolide potentiates the antitumor effect of topotecan in acute myeloid leukemia cells through an intrinsic apoptotic pathway.Cancer management and research · 2018Article
- Article
- 3-(2-Bromoethyl)-indole inhibits the growth of cancer cells and NF-κB activation.Oncology reports · 2015Article
- Molecular profiling of childhood cancer: Biomarkers and novel therapies.BBA clinical · 2014Review
- The small molecule NSC676914A is cytotoxic and differentially affects NFκB signaling in ovarian cancer cells and HEK293 cells.Cancer cell international · 2014Article
- Radiosensitization of noradrenaline transporter-expressing tumour cells by proteasome inhibitors and the role of reactive oxygen species.EJNMMI research · 2013Article
- TAK1 inhibitor 5Z-7-oxozeaenol sensitizes neuroblastoma to chemotherapy.Apoptosis : an international journal on programmed cell death · 2013Article
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
Abstract
backgroundDespite aggressive multimodal treatments the overall survival of patients with high-risk neuroblastoma remains poor. The aim of this study was to identify novel combination chemotherapy to improve survival rate in patients with high-risk neuroblastoma.
methodsWe took a synthetic lethal approach using a siRNA library targeting 418 apoptosis-related genes and identified genes and pathways whose inhibition synergized with topotecan. Microarray analyses of cells treated with topotecan were performed to identify if the same genes or pathways were altered by the drug. An inhibitor of this pathway was used in combination with topotecan to confirm synergism by in vitro and in vivo studies.
resultsWe found that there were nine genes whose suppression synergized with topotecan to enhance cell death, and the NF-κB signaling pathway was significantly enriched. Microarray analysis of cells treated with topotecan revealed a significant enrichment of NF-κB target genes among the differentially altered genes, suggesting that NF-κB pathway was activated in the treated cells. Combination of topotecan and known NF-κB inhibitors (NSC 676914 or bortezomib) significantly reduced cell growth and induced caspase 3 activity in vitro. Furthermore, in a neuroblastoma xenograft mouse model, combined treatment of topotecan and bortezomib significantly delayed tumor formation compared to single-drug treatments.
conclusionsSynthetic lethal screening provides a rational approach for selecting drugs for use in combination therapy and warrants clinical evaluation of the efficacy of the combination of topotecan and bortezomib or other NF-κB inhibitors in patients with high risk neuroblastoma.
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