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EJNMMI Research
Published in: EJNMMI Research 1/2013

Open Access 01-12-2013 | Original research

Radiosensitization of noradrenaline transporter-expressing tumour cells by proteasome inhibitors and the role of reactive oxygen species

Authors: Colin Rae, Mathias Tesson, John W Babich, Marie Boyd, Robert J Mairs

Published in: EJNMMI Research | Issue 1/2013

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Abstract

Background

The radiopharmaceutical 131I-metaiodobenzylguanidine (131I-MIBG) is used for the targeted radiotherapy of noradrenaline transporter (NAT)-expressing neuroblastoma. Enhancement of 131I-MIBG's efficacy is achieved by combination with the topoisomerase I inhibitor topotecan - currently being evaluated clinically. Proteasome activity affords resistance of tumour cells to radiation and topoisomerase inhibitors. Therefore, the proteasome inhibitor bortezomib was evaluated with respect to its cytotoxic potency as a single agent and in combination with 131I-MIBG and topotecan. Since elevated levels of reactive oxygen species (ROS) are induced by bortezomib, the role of ROS in tumour cell kill was determined following treatment with bortezomib or the alternative proteasome inhibitor, MG132.

Methods

Clonogenic assay and growth of tumour xenografts were used to investigate the effects of proteasome inhibitors alone or in combination with radiation treatment. Synergistic interactions in vitro were evaluated by combination index analysis. The dependency of proteasome inhibitor-induced clonogenic kill on ROS generation was assessed using antioxidants.

Results

Bortezomib, in the dose range 1 to 30 nM, decreased clonogenic survival of both SK-N-BE(2c) and UVW/NAT cells, and this was prevented by antioxidants. It also acted as a sensitizer in vitro when administered with X-radiation, with 131I-MIBG, or with 131I-MIBG and topotecan. Moreover, bortezomib enhanced the delay of the growth of human tumour xenografts in athymic mice when administered in combination with 131I-MIBG and topotecan. MG132 and bortezomib had similar radiosensitizing potency, but only bortezomib-induced cytotoxicity was ROS-dependent.

Conclusions

Proteasome inhibition shows promise for the treatment of neuroblastoma in combination with 131I-MIBG and topotecan. Since the cytotoxicity of MG132, unlike that of bortezomib, was not ROS-dependent, the latter proteasome inhibitor may have a favourable toxicity profile in normal tissues.
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Metadata
Title
Radiosensitization of noradrenaline transporter-expressing tumour cells by proteasome inhibitors and the role of reactive oxygen species
Authors
Colin Rae
Mathias Tesson
John W Babich
Marie Boyd
Robert J Mairs
Publication date
01-12-2013
Publisher
Springer Berlin Heidelberg
Published in
EJNMMI Research / Issue 1/2013
Electronic ISSN: 2191-219X
DOI
https://doi.org/10.1186/2191-219X-3-73

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