Abstract
Aberrant activation/expression of pathways/molecules including NF-kB, mTOR, hedgehog and polo-like-kinase-1 (PLK1) are correlated with poor-prognosis neuroblastoma. Therefore, to identify a most efficacious treatment for neuroblastoma, we investigated the efficacy of NF-kB/mTOR dual-inhibitor 13-197, hedgehog inhibitor vismodegib and PLK1 inhibitor BI2536 alone or combined with topotecan against high-risk neuroblastoma. The in vitro efficacy of the inhibitors alone or combined with topotecan on cell growth/apoptosis and molecular mechanism(s) were investigated. Results showed that as single agents 13-197, BI2536 and vismodegib significantly decreased neuroblastoma cell growth and induced apoptosis by targeting associated pathways/molecules. In combination with topotecan, 13-197 did not show significant additive/synergistic effects against neuroblastoma. However, BI2536 or vismodegib further significantly decreased neuroblastoma cell growth/survival. These results clearly showed that vismodegib combination with topotecan was synergistic and more efficacious compared with BI2536 in combination. Together, in vitro data demonstrated that vismodegib was most efficacious in potentiating topotecan-induced antineuroblastoma effects. Therefore, we tested the combined efficacy of vismodegib and topotecan against neuroblastoma in vivo using NSG mice. This resulted in significantly (p<0.001) reduced tumor growth and increased survival of mice. Together, the combination of vismodegib and topotecan showed a significant enhanced antineuroblastoma efficacy by targeting associated pathways/molecules which warrants further preclinical evaluation for translation to the clinic.
Highlights
Neuroblastoma, the most common pediatric malignancy of neural crest origin, accounts for 8-10% of childhood cancers and 15% of pediatric cancer deaths
In order to examine the efficacy of the small molecule inhibitors 13-197 (NF-kB/mTOR dual inhibitor), BI2536 (PLK1 inhibitor) and vismodegib on the proliferation and survival of neuroblastoma cells in vitro, three non-MYCN amplified (SH-SY-5Y, SK-N-SH and SK-N-AS) and three MYCN amplified (IMR-32, SK-N-BE(2) and SK-N-DZ) neuroblastoma cell lines were used
We investigated the ability of these inhibitors to induce apoptosis in neuroblastoma cells following treatment at optimum concentrations for 72 hours
Summary
Neuroblastoma, the most common pediatric malignancy of neural crest origin, accounts for 8-10% of childhood cancers and 15% of pediatric cancer deaths. The clinical outcomes of patients with neuroblastoma are highly variable, ranging from spontaneous regression to fatal progression of the disease [1, 2]. Approximately 60% of patients are diagnosed as high risk with metastases and these patients have remained as a therapeutic challenge for pediatric oncologists. Despite intensive multimodal therapy including radiation, surgery, and chemotherapy, the overall survival of high risk patients has remained at less than 40% [3]. Amplification of the MYCN gene, which occurs in 40-50% of the high risk neuroblastoma cases, remains the major key predictor of poor outcomes. Patients with high risk neuroblastoma and those with MYCN amplification typically show emergence of treatment resistance [3,4,5]. Novel effective therapies are urgently needed to improve clinical outcomes of high risk neuroblastoma patients
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