Skip to main content
eScholarship
Open Access Publications from the University of California

Disulfiram induces apoptosis in human melanoma cells: a redox-related process.

  • Author(s): Cen, Dazhi
  • Gonzalez, Rachel I
  • Buckmeier, Julie A
  • Kahlon, Ravi S
  • Tohidian, Nilou B
  • Meyskens, Frank L, Jr
  • et al.
Abstract

Melanoma is highly resistant to conventional chemotherapy. We have demonstrated that redox regulation in melanoma cells is aberrant, and redox-modulating agents can induce cell apoptosis. We have currently explored the effect of disulfiram (DSF), a member of the dithiocarbamate family, on apoptosis of melanoma cells in vitro. Human metastatic melanoma cells c81-46A, c81-61, and c83-2C were treated with DSF and apoptosis measured. DSF, at a dose of 25-50 ng/ml, consistently caused a 4-6-fold increase in apoptosis. The same dose of DSF did not significantly affect apoptosis in melanocytes. Coincubation of N-acetyl-cysteine reversed the DSF-induced apoptosis. Buthionine sulfoximine (BSO), an inhibitor of gamma-glutamyl-cysteine synthetase, as a single agent caused a approximately 2-fold increase in apoptosis when incubated with melanoma cells for 4 days. BSO slightly enhanced the level of apoptosis induced by DSF (4-10% higher than DSF alone). Intracellular glutathione was remarkably depleted with BSO treatment. DSF did not cause glutathione depletion; however, the ratio of reduced and oxidized glutathione was significantly decreased (14% of control), and N-acetyl-cysteine partially restored the ratio to 30% of control. There was a transient (2-fold) elevation of intracellular superoxide level after 24 h of DSF treatment (before the overt apoptosis). The intracellular H2O2 level progressively decreased with time. DSF decreased the mitochondrial membrane polarization in a time-dependent manner, and there was a significant inverse correlation between apoptosis and mitochondrial membrane polarization. We propose that DSF-induced apoptosis is redox related but involves a different mechanism from BSO-induced apoptosis in tumor cells. Our findings have provided new data for additional understanding of drug-induced apoptosis in melanoma cells and suggests an alternative therapeutic approach to melanoma.

Many UC-authored scholarly publications are freely available on this site because of the UC Academic Senate's Open Access Policy. Let us know how this access is important for you.

Main Content
Current View