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Identification of MYCN transcriptional activity inhibitors yields compounds which preferentially inhibit the growth of neuroblastoma cells
Lookup NU author(s)
Dr Xiaohong Lu
Professor Herbie Newell
Professor Andrew Pearson
Professor John Lunec
Lu X, Newell DR, Pearson ADJ, Lunec J
Conference Proceedings (inc. Abstract)
Advanced Neuroblastoma Research
Year of Conference
16-19 June 2004
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Amplification of the MYCN oncogene is associated with rapid tumour progression and poor outcome in human neuroblastoma. We have explored MYCN as a potential cancer therapeutic target by developing a MYCN reporter gene assay, using a luciferase gene construct under control of the ornithine decarboxylase (ODC) gene promoter. To screen for specific inhibitors of MYCN transcriptional function, this luciferase gene construct has been stably transfected into MYCN amplified neuroblastoma cells (NGP, clone19) and MYC-overexpressing neuroepithelioma cells (NB/CHP100, clone11). A pilot screen of 2800 compounds identified two (NUMYCNA1, IC50=7±2µm and NUMYCNA2, IC50=6±1µm) that reduced MYCN-dependent luciferase activity in NGP19, but not NB11, suggesting these compounds preferentially inhibit MYCN function. Western blot analysis showed that MYCN protein levels did not change, whereas its transcriptional target, ODC, was reduced to 50% in NGP19 after 24hrs exposure to these compounds. Electrophoretic mobility shift assays indicated the inhibitory mechanism did not involve direct disruption of MYCN/MAX complex formation and binding to its E-box DNA recognition sequence. Growth inhibition was examined in a panel of eight MYCN amplified and non-amplified neuroblastoma cell lines, and compared with six non-neuroblastoma tumour cell lines, all chosen to be wild-type for p53. There was no clear relationship between MYCN amplification and the sensitivity of neuroblastoma cell lines to these compounds, however the neuroblastoma cell lines were markedly more sensitive (median IC50=6.8µM and 7.0µM respectively for NUMYCNA1 and NUMYCNA2) to the growth inhibitory effects of these compounds compared with the non-neuroblastoma cell lines (median IC50=56.1µM and 58.2µM respectively for NUMYCNA1 and NUMYCNA2), indicating a potential class of neuroblastoma specific agents.
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