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

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

Research output: Contribution to journalArticle

Abstract

Abstract
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 -irradiation and 131I-metaiodobenzylguanidine (131I-MIBG), a radiopharmaceutical used for the therapy of neuroendocrine tumors. 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. 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 M was copper-dependent, whereas cytotoxicity at concentrations greater than 10 M 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. 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.
LanguageEnglish
Number of pages8
JournalThe Journal of Nuclear Medicine
DOIs
Publication statusAccepted/In press - 2013

Fingerprint

Disulfiram
Copper
Neoplasms
Heterografts
Oxidative Stress
Radiotherapy
Therapeutics
Cellular Spheroids
Norepinephrine Plasma Membrane Transport Proteins
Neuroendocrine Tumors
Radiopharmaceuticals
Proteasome Endopeptidase Complex
Neuroblastoma
Nude Mice
Glioma
Radioisotopes

Keywords

  • disulfiram
  • radiosensitiser
  • neuroblastoma
  • 131I-MIBG
  • copper

Cite this

@article{28d812d503c747139a3036bad4addfd7,
title = "The role of copper in disulfiram-induced toxicity and radiosensitisation of cancer cells.",
abstract = "Abstract 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 -irradiation and 131I-metaiodobenzylguanidine (131I-MIBG), a radiopharmaceutical used for the therapy of neuroendocrine tumors. 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. 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 M was copper-dependent, whereas cytotoxicity at concentrations greater than 10 M 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. 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.",
keywords = "disulfiram, radiosensitiser, neuroblastoma, 131I-MIBG, copper",
author = "Colin Rae and M. Tesson and Babich, {John W} and Marie Boyd and Annette Sorensen and Mairs, {Robert J.}",
year = "2013",
doi = "10.2967/jnucmed.112.113324",
language = "English",
journal = "The Journal of Nuclear Medicine",
issn = "0161-5505",

}

The role of copper in disulfiram-induced toxicity and radiosensitisation of cancer cells. / Rae, Colin; Tesson, M.; Babich, John W; Boyd, Marie; Sorensen, Annette; Mairs, Robert J.

In: The Journal of Nuclear Medicine, 2013.

Research output: Contribution to journalArticle

TY - JOUR

T1 - The role of copper in disulfiram-induced toxicity and radiosensitisation of cancer cells.

AU - Rae, Colin

AU - Tesson, M.

AU - Babich, John W

AU - Boyd, Marie

AU - Sorensen, Annette

AU - Mairs, Robert J.

PY - 2013

Y1 - 2013

N2 - Abstract 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 -irradiation and 131I-metaiodobenzylguanidine (131I-MIBG), a radiopharmaceutical used for the therapy of neuroendocrine tumors. 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. 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 M was copper-dependent, whereas cytotoxicity at concentrations greater than 10 M 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. 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.

AB - Abstract 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 -irradiation and 131I-metaiodobenzylguanidine (131I-MIBG), a radiopharmaceutical used for the therapy of neuroendocrine tumors. 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. 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 M was copper-dependent, whereas cytotoxicity at concentrations greater than 10 M 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. 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.

KW - disulfiram

KW - radiosensitiser

KW - neuroblastoma

KW - 131I-MIBG

KW - copper

U2 - 10.2967/jnucmed.112.113324

DO - 10.2967/jnucmed.112.113324

M3 - Article

JO - The Journal of Nuclear Medicine

T2 - The Journal of Nuclear Medicine

JF - The Journal of Nuclear Medicine

SN - 0161-5505

ER -