Disulfiram induces copper-dependent stimulation of reactive oxygen species and activation of the extrinsic apoptotic pathway in

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Melanoma Res. 2010
Feb;20(1):11-20.
Disulfiram
induces copper-dependent stimulation of reactive oxygen species and
activation of the extrinsic apoptotic pathway in melanoma.

Morrison
BW
, Doudican
NA
, Patel
KR
, Orlow
SJ
.
The Ronald O. Perelman Department of
Dermatology, New York University School of Medicine, New York 10016,
USA.

Melanoma is the most aggressive
and deadly form of skin cancer. The current standard of care produces
response rates of less than 20%, underscoring the critical need for
identification of new effective, nontoxic therapies. Disulfiram (DSF)
was identified using a drug screen as one of the several compounds that
preferentially decreased proliferation in multiple melanoma subtypes
compared with benign melanocytes. DSF, a member of the dithiocarbamate
family, is a copper (Cu) chelator, and Cu has been shown previously to
enhance DSF-mediated growth inhibition and apoptosis in cancer cells.
Here, we report that in the presence of free Cu, DSF inhibits cellular
proliferation and induces apoptosis in a panel of cell lines
representing primary and metastatic nodular and superficial spreading
melanoma. Both decreased cellular proliferation and increased apoptosis
were seen at 50-500 nmol/l DSF concentrations that are achievable
through oral dosing of the medication. In the presence of Cu, DSF caused
activation of the extrinsic pathway of apoptosis as measured by
caspase-8 cleavage. The addition of Z-IETD-FMK, a selective caspase-8
inhibitor, was protective against DSF-Cu-induced apoptosis. Production
of reactive oxygen species (ROS) in response to DSF-Cu treatment
preceded the induction of apoptosis. Both ROS production and apoptosis
were prevented by coincubation of N-acetyl cysteine, a free radical
scavenger. Our study shows that DSF might be used to target both nodular
and superficial spreading melanoma through ROS production and
activation of the extrinsic pathway of apoptosis.