The role of copper in disulfiram-induced toxicity and radiosensitization of cancer cells

Rae, C. , Tesson, M., Babich, J.W., Boyd, M., Sorensen, A. and Mairs, R. (2013) The role of copper in disulfiram-induced toxicity and radiosensitization of cancer cells. Journal of Nuclear Medicine, 54(6), pp. 953-960. (doi: 10.2967/jnumed.112.113324)

[img]
Preview
Text
73170.pdf - Accepted Version

831kB

Abstract

<p>Disulfiram has been used for several decades in the treatment of alcoholism. It now shows promise as an anti-cancer drug and radiosensitizer. Proposed mechanisms of action include the induction of oxidative stress and inhibition of proteasome activity. Our purpose was to determine the potential of disulfiram to enhance the anti-tumor efficacy of external beam ϒ-irradiation and 131I-metaiodobenzylguanidine (131I-MIBG), a radiopharmaceutical used for the therapy of neuroendocrine tumors.</p> <p>Methods: The role of copper in disulfiram-induced toxicity was investigated by clonogenic assay after treatment of human SK-N-BE(2c) neuroblastoma and UVW/NAT glioma cells. Synergistic interaction between disulfiram and radiotherapy was evaluated by combination index analysis. Tumor growth delay was determined in vitro using multicellular tumor spheroids and in vivo using human tumor xenografts in athymic mice.</p> <p>Results: Escalating disulfiram dosage caused a biphasic reduction in the surviving fraction of clonogens. Clonogenic cell kill after treatment with disulfiram concentrations less than 4 μM was copper-dependent, whereas cytotoxicity at concentrations greater than 10 μM was caused by oxidative stress. The cytotoxic effect of disulfiram was maximal when administered with equimolar copper. Likewise, disulfiram’s radiosensitization of tumor cells was copper-dependent. Furthermore, disulfiram treatment enhanced the toxicity of 131I-MIBG to spheroids and xenografts expressing the noradrenaline transporter.</p> <p>Conclusions: The results demonstrate that (i) the cytotoxicity of disulfiram was copper-dependent; (ii) molar excess of disulfiram relative to copper resulted in attenuation of disulfiram-mediated cytotoxicity; (iii) copper was required for the radiosensitizing activity of disulfiram and (iv) copper-complexed disulfiram enhanced the efficacy not only of external beam radiation but also of targeted radionuclide therapy in the form of 131I-MIBG. Therefore disulfiram may have anti-cancer potential in combination with radiotherapy.</p>

Item Type:Articles
Additional Information:This research was originally published in JNM. Rae, C., Tesson, M., Babich, J.W., Boyd, M., Sorensen, A., and Mairs, R., The role of copper in disulfiram-induced toxicity and radiosensitization of cancer cells. JNM. 2013; vol:pp–pp. © by the Society of Nuclear Medicine, Inc.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Tesson, Dr Mathias and Mairs, Professor Robert and Sorensen, Dr Annette and Rae, Dr Colin
Authors: Rae, C., Tesson, M., Babich, J.W., Boyd, M., Sorensen, A., and Mairs, R.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Journal of Nuclear Medicine
ISSN:0161-5505
Published Online:24 April 2013
Copyright Holders:Copyright © 2013 Society of Nuclear Medicine
First Published:First published in Journal of Nuclear Medicine
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher

University Staff: Request a correction | Enlighten Editors: Update this record

Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
539171Exploitation of bystander effects to maximise the efficacy of n.c.a.[131I]MIBG used in combination with cytotoxic drugs for the treatment of neuroblastomaRobert MairsThe Neuroblastoma Society (NEURO-BLAS)Yvonne Boyd 15/RI CANCER SCIENCES
505451Assessment of [131I]MIBG targeted radiotherapy in combination with chemotherapy as a treatment for neuroblastomaRobert MairsSport Aiding Medical Research for Kids (SPARKS)08GLW01RI CANCER SCIENCES
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
511521Experimental targeted cancer therapy combining radiopharmaceuitcals & cytotoxic drugs.Robert MairsMolecularinsight Pharmaceuticals (MOLECULARI)UNSPECIFIEDRI CANCER SCIENCES
511522Experimental targeted cancer therapy combining radiopharmaceuitcals & cytotoxic drugs.Robert MairsMolecularinsight Pharmaceuticals (MOLECULARI)UNSPECIFIEDRI CANCER SCIENCES