Romidepsin induces caspase-dependent cell death in human neuroblastoma cells
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Accepted Version
Date
2017-05-12
Authors
Hegarty, Shane V.
Togher, Katie L.
O'Leary, Eimear
Solger, Franziska
Sullivan, Aideen M.
O'Keeffe, Gerard W.
Journal Title
Journal ISSN
Volume Title
Publisher
Elsevier Ltd
Published Version
Abstract
Neuroblastoma is the most common extracranial pediatric solid tumor, arising from the embryonic sympathoadrenal lineage of the neural crest, and is responsible for 15% of childhood cancer deaths. Although survival rates are good for some patients, those children diagnosed with high-risk neuroblastoma have survival rates as low as 35%. Thus, neuroblastoma remains a significant clinical challenge and the development of novel therapeutic strategies is essential. Given that there is widespread epigenetic dysregulation in neuroblastoma, epigenetic pharmacotherapy holds promise as a therapeutic approach. In recent years, histone deacetylase (HDAC) inhibitors, which cause selective activation of gene expression, have been shown to be potent chemotherapeutics for the treatment of a wide range of cancers. Here we examined the ability of the FDA-approved drug Romidepsin, a selective HDAC1/2 inhibitor, to act as a cytotoxic agent in neuroblastoma cells. Treatment with Romidepsin at concentrations in the low nanomolar range induced neuroblastoma cell death through caspase-dependent apoptosis. Romidepsin significantly increased histone acetylation, and significantly enhanced the cytotoxic effects of the cytotoxic agent 6-hydroxydopamine, which has been shown to induce cell death in neuroblastoma cells through increasing reactive oxygen species. Romidepsin was also more potent in MYCN-amplified neuroblastoma cells, which is an important prognostic marker of poor survival. This study has thus demonstrated that the FDA-approved chemotherapeutic drug Romidepsin has a potent caspase-dependent cytotoxic effect on neuroblastoma cells, whose effects enhance cell death induced by other cytotoxins, and suggests that Romidepsin may be a promising chemotherapeutic candidate for the treatment of neuroblastoma.
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Keywords
Romidepsin , Neuroblastoma , Cell death , Epigenetic regulation , Chemotherapeutic drug
Citation
Hegarty, S. V., Togher, K. L., O'Leary, E., Solger, F., Sullivan, A. M. and O'Keeffe, G. W. (2017) 'Romidepsin induces caspase-dependent cell death in human neuroblastoma cells', Neuroscience Letters, 653, pp. 12-18. doi:10.1016/j.neulet.2017.05.025