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

Abstract

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.

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