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)

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 Jackson, Dr Mark and Chalmers, Professor Anthony
• 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 > School 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