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

BMC Cancer

Research Article

Donna L. Nile¹  Robert J. Mairs¹  Colin Rae¹  Iain J. Hyndman¹  Mark N. Gaze² 

[1] Radiation Oncology, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK;University College London Hospitals, London, UK;

关键词: Neuroblastoma;    I-MIBG;    Targeted radiotherapy;    PARP-1;    DNA damage;   

DOI  :  10.1186/s12885-016-2656-8

 received in 2016-04-01, accepted in 2016-07-30,  发布年份 2016

来源: Springer

【 摘 要 】

BackgroundThe 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.MethodsRadiosensitisation 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).ResultsBy 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.ConclusionRucaparib 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.

【 授权许可】

CC BY   
© The Author(s). 2016