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.
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.
Brar
Sukhdev S
SS
Cannon Research Center, Carolinas Medical Center, Charlotte, North Carolina, USA.
Grigg
Claude
C
Wilson
Kimberly S
KS
Holder
Walter D
WD
Dreau
Didier
D
Austin
Catherine
C
Foster
Mareva
M
Ghio
Andrew J
AJ
Whorton
A Richard
AR
Stowell
Grayson W
GW
Whittall
Linda B
LB
Whittle
Robert R
RR
White
David P
DP
Kennedy
Thomas P
TP
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003300:Copper / Q000032:analysis / Q000494:pharmacology; D017362:Cyclic AMP Response Element-Binding Protein / Q000037:antagonists & inhibitors; D019925:Cyclin A / Q000378:metabolism; D004221:Disulfiram / Q000494:pharmacology / Q000627:therapeutic use*; D015536:Down-Regulation; D024202:Electrophoretic Mobility Shift Assay; D005134:Eye Neoplasms / Q000188:drug therapy / Q000473:pathology; D005260:Female; D005978:Glutathione / Q000032:analysis / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000556:secondary; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology; D008670:Metals / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D016513:Mice, SCID; D008875:Middle Aged; D009374:Neoplasms, Experimental / Q000188:drug therapy; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D020218:Response Elements; D014157:Transcription Factors / Q000037:antagonists & inhibitors*; D015032:Zinc / Q000494:pharmacology
D000970:Antineoplastic Agents; D017362:Cyclic AMP Response Element-Binding Protein; D019925:Cyclin A; D008670:Metals; D014157:Transcription Factors; D003300:Copper; D005978:Glutathione; D015032:Zinc; D004221:Disulfiram