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Abrogation of radioresistance in in glioblastoma stem-like cells by inhibition of ATM kinase

Carruthers, R, Ahmed, Shafiq, Strathdee, Karen, Gomez-Roman, N, Amoah-Buahin, E, Watts, C and Chalmers, A (2014) Abrogation of radioresistance in in glioblastoma stem-like cells by inhibition of ATM kinase. Molecular Oncology, 9 (1). pp. 192-203. ISSN 1878-0261

Item Type: Article

Abstract

Resistance to radiotherapy in glioblastoma (GBM) is an important clinical problem and several authors have attributed this to a subpopulation of GBM cancer stem cells (CSCs) which may be responsible for tumour recurrence following treatment. It is hypothesised that GBM CSCs exhibit upregulated DNA damage responses and are resistant to radiation but the current literature is conflicting. We investigated radioresistance of primary GBM cells grown in stem cell conditions (CSC) compared to paired differentiated tumour cell populations and explored the radiosensitising effects of the ATM inhibitor KU-55933. We report that GBM CSCs are radioresistant compared to paired differentiated tumour cells as measured by clonogenic assay. GBM CSC's display upregulated phosphorylated DNA damage response proteins and enhanced activation of the G2/M checkpoint following irradiation and repair DNA double strand breaks (DSBs) more efficiently than their differentiated tumour cell counterparts following radiation. Inhibition of ATM kinase by KU-55933 produced potent radiosensitisation of GBM CSCs (sensitiser enhancement ratios 2.6-3.5) and effectively abrogated the enhanced DSB repair proficiency observed in GBM CSCs at 24 h post irradiation. G2/M checkpoint activation was reduced but not abolished by KU-55933 in GBM CSCs. ATM kinase inhibition overcomes radioresistance of GBM CSCs and, in combination with conventional therapy, has potential to improve outcomes for patients with GBM.

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Depositing User: Paula Normington

Identifiers

Item ID: 6007
Identification Number: https://doi.org/10.1016/j.molonc.2014.08.003
ISSN: 1878-0261
URI: http://sure.sunderland.ac.uk/id/eprint/6007
Official URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC55286...

Users with ORCIDS

ORCID for Shafiq Ahmed: ORCID iD orcid.org/0000-0001-8701-6889

Catalogue record

Date Deposited: 16 Feb 2016 12:17
Last Modified: 30 Sep 2020 10:49

Contributors

Author: Shafiq Ahmed ORCID iD
Author: R Carruthers
Author: Karen Strathdee
Author: N Gomez-Roman
Author: E Amoah-Buahin
Author: C Watts
Author: A Chalmers

University Divisions

Faculty of Health Sciences and Wellbeing
Faculty of Health Sciences and Wellbeing > School of Pharmacy and Pharmaceutical Sciences

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Sciences

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