Thailandepsin-A Decreases Notch1 and Cell Proliferation in Neuroblastoma
Abstract
Introduction: Neuroblastoma is an aggressive childhood tumor that is derived from neural crest progenitor cells. Notch signaling determines cell fate during differentiation of ectodermal cells in the sympathetic nervous... [ view full abstract ]
Introduction:
Neuroblastoma is an aggressive childhood tumor that is derived from neural crest progenitor cells. Notch signaling determines cell fate during differentiation of ectodermal cells in the sympathetic nervous system. It is associated with low differentiation, activation of proliferation and motility of cancer cells. Histone deacetylase inhibitors (HDACi) are well-known for their anti-tumor activity as well as their ability to regulate Notch signaling. We tested a novel HDACi Thailandepsin-A (TDP-A) as a treatment option for neuroblastoma.
Methods:
Methylthiazolyldiphenyl-tetrazolium bromide (MTT) rapid colorimetric assay was used to determine the IC50 of TDP-A on LA-N-5, NGP and SK-N-SH cell lines. The effect of TDP-A on Notch1 and apoptotic markers p21 and p27 were assessed after treatment of neuroblastoma cells with DMSO and TDP-A. Additionally N-myc-amplified NGP cell lysates were assessed for N-myc protein levels. Neurite outgrowth was measured as a sign of differentiation.
Results:
IC50 was determined to be around 4nM. Notch1 decreased in all cell lines. Treatment increased p27 levels in LA-N-5 cells, increase of p21 and decrease of N-myc levels in NGP. Increase of neurite outgrowth was observed with the treatment in LA-N-5 cells (12.5um vs 47.8um, p=0.464).
Conclusion:
TDPA has potent anti-proliferating effect on neuroblastoma cell lines in low nanomolar concentrations. It decreased Notch1 in all cell lines together with decrease of N-myc in NGP that is known to have amplified N-myc gene, which is observed in one-third of neuroblastomas and correlated with advanced disease. These results show that TDPA is a promising drug for treatment of neuroblastoma.
Authors
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Zviadi Aburjania
(University of Alabama - Birmingham)
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Andrew Janssen
(University of Alabama - Birmingham)
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Samuel Jang
(University of Alabama - Birmingham)
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Herb Chen
(University of Alabama - Birmingham)
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Renata Jaskula-sztul
(University of Alabama - Birmingham)
Topic Areas
Pediatric Surgery , Surgical Oncology
Session
QS-Peds » Quick-Shot Presentations: Pediatric Surgery (15:00 - Thursday, 21st September, Dearth Tower Conf 1)