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Please use this identifier to cite or link to this item: http://bura.brunel.ac.uk/handle/2438/6547

Title: A chemical screen identifies the chemotherapeutic drug topotecan as a specific inhibitor of the B-MYB/MYCN axis in neuroblastoma
Authors: Sottile, F
Gnemmi, I
Cantilena, S
D'Acunto, WC
Sala, A
Keywords: Neuroblastoma
Tumour
Sympathetic nervous system
Paediatric
MycN
Camptothecin
Publication Date: 2012
Publisher: Impact Journals
Citation: Oncotarget, 3(5): 535-545, May 2012
Abstract: The transcription factor MycN is the prototypical neuroblastoma oncogene and a potential therapeutic target. However, its strong expression caused by gene amplification in about 30% of neuroblastoma patients is a considerable obstacle to the development of therapeutic approaches aiming at eliminating its tumourigenic activity. We have previously reported that B-Myb is essentially required for transcription of the MYCN amplicon and have also shown that B-MYB and MYCN are engaged in a feed forward loop promoting the survival/proliferation of neuroblastoma cells. We postulated that pharmacological strategies breaking the B-MYB/MYCN axis should result in clinically desirable effects. Thus, we implemented a high throughput chemical screen, using a curated library of ~1500 compounds from the National Cancer Institute, whose endpoint was the identification of small molecules that inhibited B-Myb. At the end of the screening, we found that the compounds pinafide, ellipticine and camptothecin inhibited B-Myb transcriptional activity in luciferase assays. One of the compounds, the topoisomerase-1 inhibitor camptothecin, is of considerable clinical interest since its derivatives topotecan and irinotecan are currently used as first and second line treatment agents for various types of cancer, including neuroblastoma. We found that neuroblastoma cells with amplification of MYCN are more sensitive than MYCN negative cells to camptothecin and topotecan killing. Campothecin and topotecan caused selective down-regulation of B-Myb and MycN expression in neuroblastoma cells. Notably, forced overexpression of B-Myb could antagonize the killing effect of topotecan and camptothecin, demonstrating that the transcription factor is a key target of the drugs. These results suggest that camptothecin and its analogues should be more effective in patients whose tumours feature amplification of MYCN and/or overexpression of B-MYB.
Description: Copyright: © 2012 Sottile et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. The article was made available through the Brunel Open Access Publishing Fund.
Sponsorship: This study was funded by a grant from the Olivia Hodson Cancer Fund and the Neuroblastoma Society.
URI: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3388183/
http://bura.brunel.ac.uk/handle/2438/6547
ISSN: 1949-2553
Appears in Collections:School of Health Sciences and Social Care Research Papers
Biological Sciences
Publications
Cancer
Brunel OA Publishing Fund

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