The
thiocarbamate drug disulfiram has been used for decades in the treatment of
alcohol abuse.
Disulfiram induces apoptosis in a number of tumor cell lines and was recently by us proposed to act as a
26S proteasome inhibitor. In this work we characterized
disulfiram in vitro with regard to
tumor-type specificity, possible mechanisms of action and drug resistance and cell death in human tumor cell lines and in 78 samples of
tumor cells from patients using the fluorometric microculture cytotoxicity assay and the automated fluorescence-imaging microscope ArrayScan((R)).
Disulfiram induced cytotoxicity in a biphasic pattern in both cell lines and patient
tumor cells.
Disulfiram induced apoptosis as measured by cell membrane permeability, nuclear fragmentation/condensation and
caspase-3/7 activation using high content screening assays. For many of the cell lines tested
disulfiram was active in sub-micromolar concentrations. When comparing the logIC(50) patterns with other
cytotoxic agents,
disulfiram showed low correlation (R<0.5) with all drugs except
lactacystin (R=0.69), a known
proteasome inhibitor, indicating that the two substances may share mechanistic pathways.
Disulfiram was more active in hematological than in solid
tumor samples, but substantial activity was observed in
carcinomas of the ovary and the breast and in
non-small cell lung cancer.
Disulfiram also displayed higher cytotoxic effect in cells from
chronic lymphocytic leukemia than in normal lymphocytes (p<0.05), which may indicate some
tumor selectivity. These results together with large clinical experience and relatively mild side effects encourage clinical studies of
disulfiram as an anti-
cancer agent.