Disulfiram inhibits activating transcription factor/cyclic AMP-responsive element binding protein and human melanoma growth in a

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Mol Cancer Ther.
2004 Sep;3(9):1049-60.
Disulfiram inhibits
activating transcription factor/cyclic AMP-responsive element binding
protein and human melanoma growth in a metal-dependent manner in vitro,
in mice and in a patient with metastatic disease.
Brar
SS
, Grigg
C
, Wilson
KS
, Holder
WD Jr
, Dreau
D
, Austin
C
, Foster
M
, Ghio
AJ
, Whorton
AR
, Stowell
GW
, Whittall
LB
, Whittle
RR
, White
DP
, Kennedy
TP
.
Cannon Research Center, Carolinas Medical
Center, Charlotte, North Carolina, USA.

The
thiocarbamate alcoholism drug disulfiram blocks the P-glycoprotein
extrusion pump, inhibits the transcription factor nuclear factor-kappaB,
sensitizes tumors to chemotherapy, reduces angiogenesis, and inhibits
tumor growth in mice. Thiocarbamates react with critical thiols and also
complex metal ions. Using melanoma as the paradigm, we tested whether
disulfiram might inhibit growth by forming mixed disulfides with
critical thiols in a mechanism facilitated by metal ions. Disulfiram
given to melanoma cells in combination with Cu2+ or Zn2+ decreased
expression of cyclin A and reduced proliferation in vitro at lower
concentrations than disulfiram alone. In electrophoretic mobility shift
assays, disulfiram decreased transcription factor binding to the cyclic
AMP-responsive element in a manner potentiated by Cu2+ ions and by the
presence of glutathione, suggesting that thiocarbamates might disrupt
transcription factor binding by inducing S-glutathionylation of the
transcription factor DNA binding region. Disulfiram inhibited growth and
angiogenesis in melanomas transplanted in severe combined
immunodeficient mice, and these effects were potentiated by Zn2+
supplementation. The combination of oral zinc gluconate and disulfiram
at currently approved doses for alcoholism also induced >50%
reduction in hepatic metastases and produced clinical remission in a
patient with stage IV metastatic ocular melanoma, who has continued on
oral zinc gluconate and disulfiram therapy for 53 continuous months with
negligible side effects. These findings present a novel strategy for
treating metastatic melanoma by employing an old drug toward a new
therapeutic use.