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)
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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 |
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| 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 > School 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 |
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