Abstract
| Language | English |
|---|---|
| Pages | 953-960 |
| Number of pages | 8 |
| Journal | The Journal of Nuclear Medicine |
| Volume | 54 |
| Issue number | 6 |
| Early online date | 24 Apr 2013 |
| DOIs | |
| Publication status | Published - 1 Jun 2013 |
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Keywords
- cancer cells
- disulfiram
- copper
- neuroblastoma radiosensitizer
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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 journal › Article
TY - JOUR
T1 - The role of copper in disulfiram-induced toxicity and radiosensitization of cancer cells
AU - Rae, Colin
AU - Tesson, Mathias
AU - Babich, John W
AU - Boyd, Marie
AU - Sorensen, Annette
AU - Mairs, Robert J
PY - 2013/6/1
Y1 - 2013/6/1
N2 - 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.
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.
KW - cancer cells
KW - disulfiram
KW - copper
KW - neuroblastoma radiosensitizer
UR - http://www.scopus.com/inward/record.url?scp=84878660014&partnerID=8YFLogxK
U2 - 10.2967/jnumed.112.113324
DO - 10.2967/jnumed.112.113324
M3 - Article
VL - 54
SP - 953
EP - 960
JO - The Journal of Nuclear Medicine
T2 - The Journal of Nuclear Medicine
JF - The Journal of Nuclear Medicine
SN - 0161-5505
IS - 6
ER -