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Investigational New Drugs
Published in: Investigational New Drugs 5/2016

01-10-2016 | SHORT REPORT

Involvement of AMP-activated protein kinase in mediating pyrrolo-1,5-benzoxazepine–induced apoptosis in neuroblastoma cells

Authors: Jennifer C. Lennon, Stefania Butini, Giuseppe Campiani, Anne O’Meara, D. Clive Williams, Daniela M. Zisterer

Published in: Investigational New Drugs | Issue 5/2016

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Summary

Neuroblastoma, a paediatric malignancy of the sympathetic nervous system, accounts for 15 % of childhood cancer deaths. Despite advances in understanding the biology, it remains one of the most difficult paediatric cancers to treat partly due to the development of multidrug resistance. There is thus a compelling demand for new treatment strategies that can bypass resistance mechanisms. The pyrrolo-1,5-benzoxazepine (PBOX) compounds are a series of novel microtubule-targeting agents that potently induce apoptosis in various tumour models. We have previously reported that PBOX compounds induce apoptosis in drug sensitive and multidrug resistant neuroblastoma cells and synergistically enhance apoptosis induced by chemotherapeutics such as carboplatin. In this study we present further data concerning the molecular basis of PBOX-induced apoptosis in neuroblastoma. We demonstrate that PBOX-6 induced AMP-activated protein kinase (AMPK) activation and downstream acetyl-CoA carboxylase phosphorylation. Increased reactive oxygen species (ROS) appeared to serve as the upstream signal for AMPK activation as pretreatment of cells with the antioxidant N-acetylcysteine inhibited both AMPK activation and PBOX-induced apoptosis. Furthermore, activation of AMPK by PBOX-6 was found to inhibit mTOR complex 1 (mTORC1) signalling. Finally, we demonstrate the efficacy of PBOX-6 in an in vivo xenograft model of neuroblastoma. This study provides new insights into understanding the molecular and cellular mechanisms involved in PBOX-induced cell death in neuroblastoma and further supports their future use as novel anti-cancer agents for the treatment of neuroblastoma.
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Metadata
Title
Involvement of AMP-activated protein kinase in mediating pyrrolo-1,5-benzoxazepine–induced apoptosis in neuroblastoma cells
Authors
Jennifer C. Lennon
Stefania Butini
Giuseppe Campiani
Anne O’Meara
D. Clive Williams
Daniela M. Zisterer
Publication date
01-10-2016
Publisher
Springer US
Published in
Investigational New Drugs / Issue 5/2016
Print ISSN: 0167-6997
Electronic ISSN: 1573-0646
DOI
https://doi.org/10.1007/s10637-016-0366-3

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