An evaluation in vitro of PARP-1 inhibitors, rucaparib and olaparib, as radiosensitisers for the treatment of neuroblastoma

Nile, D. L., Rae, C. , Hyndman, I. J., Gaze, M. N. and Mairs, R. J. (2016) An evaluation in vitro of PARP-1 inhibitors, rucaparib and olaparib, as radiosensitisers for the treatment of neuroblastoma. BMC Cancer, 16, 621. (doi: 10.1186/s12885-016-2656-8) (PMID:27515310) (PMCID:PMC4982014)

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Background: The radiopharmaceutical 131I-meta-iodobenzylguanidine (131I-MIBG) is an effective treatment for neuroblastoma. However, maximal therapeutic benefit from 131I-MIBG is likely to be obtained by its combination with chemotherapy. We previously reported enhanced antitumour efficacy of 131I-MIBG by inhibition of the poly(ADP-ribose) polymerase-1 (PARP-1) DNA repair pathway using the phenanthridinone derivative PJ34. Recently developed alternative PARP-1 inhibitors have greater target specificity and are expected to be associated with reduced toxicity to normal tissue. Therefore, our purpose was to determine whether the more specific PARP-1 inhibitors rucaparib and olaparib enhanced the efficacy of X-radiation or 131I-MIBG. Methods: Radiosensitisation of SK-N-BE(2c) neuroblastoma cells or noradrenaline transporter gene-transfected glioma cells (UVW/NAT) was investigated using clonogenic assay. Propidium iodide staining and flow cytometry was used to analyse cell cycle progression. DNA damage was quantified by the phosphorylation of H2AX (γH2AX). Results: By combining PARP-1 inhibition with radiation treatment, it was possible to reduce the X-radiation dose or 131I-MIBG activity concentration required to achieve 50 % cell kill by approximately 50 %. Rucaparib and olaparib were equally effective inhibitors of PARP-1 activity. X-radiation-induced DNA damage was significantly increased 2 h after irradiation by combination with PARP-1 inhibitors (10-fold greater DNA damage compared to untreated controls; p < 0.01). Moreover, combination treatment (i) prevented the restitution of DNA, exemplified by the persistence of 3-fold greater DNA damage after 24 h, compared to untreated controls (p < 0.01) and (ii) induced greater G2/M arrest (p < 0.05) than either single agent alone. Conclusion: Rucaparib and olaparib sensitise cancer cells to X-radiation or 131I-MIBG treatment. It is likely that the mechanism of radiosensitisation entails the accumulation of unrepaired radiation-induced DNA damage. Our findings suggest that the administration of PARP-1 inhibitors and 131I-MIBG to high risk neuroblastoma patients may be beneficial.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Mairs, Professor Robert and Nile, Dr Donna and Rae, Dr Colin
Authors: Nile, D. L., Rae, C., Hyndman, I. J., Gaze, M. N., and Mairs, R. J.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:BMC Cancer
Publisher:BioMed Central Ltd.
ISSN (Online):1471-2407
Published Online:11 August 2016
Copyright Holders:Copyright © 2016 The Authors
First Published:First published in BMC Cancer 16: 621
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
594601Assessment of [131l] MIBG in combination with cytotoxic drugs for neuroblastoma therapy.Robert MairsGreat Ormond Street Hospital For Children NHS Trust (NHS-GOSH)2012-NAT-04/W10ICS - EPIGENETICS
609641Enhancement of prostate targeted radiotherapy using PSMA-seeking agents in combination with radiosensitizers.Robert MairsThe Prostate Cancer Charity (PROST-CHAR)PG12-12ICS - EPIGENETICS