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

Colin Rae, Mathias Tesson, John W Babich, Marie Boyd, Annette Sorensen, Robert J Mairs

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Disulfiram has been used for several decades in the treatment of alcoholism. It now shows promise as an anticancer 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 antitumor efficacy of external-beam γ-irradiation and (131)I-metaiodobenzylguanidine ((131)I-MIBG), a radiopharmaceutical used for the therapy of neuroendocrine tumors. The role of copper in disulfiram-induced toxicity was investigated by clonogenic assay after treatment of human SK-N-BE(2c) neuroblastoma and UVW/noradrenaline transporter (NAT) glioma cells. The 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. Escalating the 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 radiosensitization of tumor cells was copper-dependent. Furthermore, disulfiram treatment enhanced the toxicity of (131)I-MIBG to spheroids and xenografts expressing the noradrenaline transporter. The results demonstrate that the cytotoxicity of disulfiram was copper-dependent, the molar excess of disulfiram relative to copper resulted in attenuation of disulfiram-mediated cytotoxicity, copper was required for the radiosensitizing activity of disulfiram, and copper-complexed disulfiram enhanced the efficacy not only of external-beam radiation but also of targeted radionuclide therapy in the form of (131)I-MIBG. Therefore, disulfiram may have anticancer potential in combination with radiotherapy.
LanguageEnglish
Pages953-960
Number of pages8
JournalThe Journal of Nuclear Medicine
Volume54
Issue number6
Early online date24 Apr 2013
DOIs
Publication statusPublished - 1 Jun 2013

Fingerprint

Disulfiram
Copper
Neoplasms
Norepinephrine Plasma Membrane Transport Proteins
3-Iodobenzylguanidine
Heterografts
Oxidative Stress
Radiotherapy
Therapeutics
Cellular Spheroids
Neuroendocrine Tumors
Radiopharmaceuticals
Proteasome Endopeptidase Complex
Neuroblastoma

Keywords

  • cancer cells
  • disulfiram
  • copper
  • neuroblastoma radiosensitizer

Cite this

Rae, Colin ; Tesson, Mathias ; Babich, John W ; Boyd, Marie ; Sorensen, Annette ; Mairs, Robert J. / The role of copper in disulfiram-induced toxicity and radiosensitization of cancer cells. In: The Journal of Nuclear Medicine. 2013 ; Vol. 54, No. 6. pp. 953-960 .
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The role of copper in disulfiram-induced toxicity and radiosensitization of cancer cells. / Rae, Colin; Tesson, Mathias; Babich, John W; Boyd, Marie; Sorensen, Annette; Mairs, Robert J.

In: The Journal of Nuclear Medicine, Vol. 54, No. 6, 01.06.2013, p. 953-960 .

Research output: Contribution to journalArticle

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AB - Disulfiram has been used for several decades in the treatment of alcoholism. It now shows promise as an anticancer 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 antitumor efficacy of external-beam γ-irradiation and (131)I-metaiodobenzylguanidine ((131)I-MIBG), a radiopharmaceutical used for the therapy of neuroendocrine tumors. The role of copper in disulfiram-induced toxicity was investigated by clonogenic assay after treatment of human SK-N-BE(2c) neuroblastoma and UVW/noradrenaline transporter (NAT) glioma cells. The 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. Escalating the 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 radiosensitization of tumor cells was copper-dependent. Furthermore, disulfiram treatment enhanced the toxicity of (131)I-MIBG to spheroids and xenografts expressing the noradrenaline transporter. The results demonstrate that the cytotoxicity of disulfiram was copper-dependent, the molar excess of disulfiram relative to copper resulted in attenuation of disulfiram-mediated cytotoxicity, copper was required for the radiosensitizing activity of disulfiram, and copper-complexed disulfiram enhanced the efficacy not only of external-beam radiation but also of targeted radionuclide therapy in the form of (131)I-MIBG. Therefore, disulfiram may have anticancer potential in combination with radiotherapy.

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