Mesothelioma cells depend on the anti-apoptotic protein Bcl-xL for survival and are sensitized to ionizing radiation by BH3-mimetics

Jackson, M. R. , Ashton, M., Koessinger, A. L., Dick, C., Verheij, M. and Chalmers, A. J. (2020) Mesothelioma cells depend on the anti-apoptotic protein Bcl-xL for survival and are sensitized to ionizing radiation by BH3-mimetics. International Journal of Radiation Oncology, Biology, Physics, 106(4), pp. 867-877. (doi: 10.1016/j.ijrobp.2019.11.029) (PMID:31786278)

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Abstract

The incidence of mesothelioma continues to rise and prognosis remains dismal due to resistance to conventional therapies and few novel treatment options. Failure to activate apoptotic cell death is a resistance mechanism that may be overcome by inhibition of anti-apoptotic Bcl-2 proteins using BH3-mimetic drugs. We investigated the role of anti-apoptotic proteins in the radioresistance of mesothelioma, identifying clinically-relevant targets for radiosensitization and evaluating the activity of BH3-mimetics alone and in combination with radiotherapy in pre-clinical models. Mesothelioma cell lines 211H, H2052 and H226 exposed to BH3-mimetics demonstrated Bcl-xL dependence that correlated with protein expression and was confirmed by genetic knockdown. The Bcl-xL inhibitor A1331852 exhibited cytotoxic (EC50 0.13-1.42 μmol/L) and radiosensitizing activities (sensitizer enhancement ratios 1.3-1.8). Cytotoxicity was associated with induction of mitochondrial outer membrane permeabilization and caspase-3/7 activation. Efficacy was maintained in a three-dimensional model in which combination therapy completely eradicated mesothelioma spheroids. Clinical applicability was confirmed by immunohistochemical analysis of Bcl-2 proteins in patient samples and radiosensitizing activity of A1331852 in primary patient-derived mesothelioma cells. Mesothelioma cells exhibit addiction to the anti-apoptotic protein Bcl-xL and their intrinsic radioresistance can be overcome by small molecule inhibition of this novel therapeutic target.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Dick, Dr Craig and Koessinger, Dr Anna and Ashton, Dr Miranda and Chalmers, Professor Anthony and Jackson, Dr Mark
Authors: Jackson, M. R., Ashton, M., Koessinger, A. L., Dick, C., Verheij, M., and Chalmers, A. J.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
Journal Name:International Journal of Radiation Oncology, Biology, Physics
Publisher:Elsevier
ISSN:0360-3016
ISSN (Online):1879-355X
Published Online:28 November 2019
Copyright Holders:Copyright © 2019 Elsevier Inc.
First Published:First published in International Journal of Radiation Oncology, Biology, Physics 106(4):867-877
Publisher Policy:Reproduced in accordance with the publisher copyright policy

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