Romidepsin induces caspase-dependent cell death in human neuroblastoma cells
Hegarty, Shane V.; Togher, Katie L.; O'Leary, Eimear; Solger, Franziska; Sullivan, Aideen M.; O'Keeffe, Gerard W.
Date:
2017-05-12
Copyright:
© 2017, Elsevier Ltd. All rights reserved. This manuscript version is made available under the CC-BY-NC-ND 4.0 license.
Full text restriction information:
Access to this article is restricted until 12 months after publication by request of the publisher.
Restriction lift date:
2018-05-12
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
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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