Disulfiram

Disulfiram (Tetraethylthiuram disulfide) is a specific inhibitor of aldehyde-dehydrogenase (ALDH1), used for the treatment of chronic alcoholism by producing an acute sensitivity to alcohol. Disulfiram inhibits gasdermin D (GSDMD) pore formation in liposomes and inflammasome-mediated pyroptosis and IL-1β secretion in human and mouse cells. Disulfiram, a copper ion carrier, with Cu²⁺ increases intracellular ROS levels and induces cuproptosis^{[1][2][3][4][5][6]}. In Vitro:Disulfiram-copper complex potently inhibits the proteasomal activity in cultured breast cancer MDA-MB-231 and MCF10DCIS.com cells, but not normal, immortalized MCF-10A cells, before induction of apoptotic cancer cell death^[1]. Disulfiram (DS), a clinically used anti-alcoholism drug, strongly inhibits constitutive and 5-FU-induced NF-kappaB activity in a dose-dependent manner. Disulfiram inhibits both NF-kappaB nuclear translocation and DNA binding activity but has no effect on 5-FU-induced IkappaBalpha degradation. Disulfiram significantly enhances the apoptotic effect of 5-FU on DLD-1 and RKO(WT) cell lines and synergistically potentiated the cytotoxicity of 5-FU to both cell lines. Disulfiram also effectively abolishes 5-FU chemoresistance in a 5-FU resistant cell line H630(5-FU) in vitro^[2]. Oseltamivir decreases the number of viable cells, and the addition of CuCl₂ significantly enhances the DSF-induced cell death to less than 10% of control^[3]. Disulfiram given to melanoma cells in combination with Cu²⁺ or Zn²⁺ decreases expression of cyclin A and reduces proliferation in vitro at lower concentrations than disulfiram alone^[4].
Disulfiram (0.1 nM-10 μM; 72 h) + Cu²⁺ combination enhances the cytotoxicity on ovarian cancer cell lines^[1]. In Vivo:Disulfiram significantly inhibits the tumor growth (by 74%), associated with in vivo proteasome inhibition and apoptosis induction in mice bearing MDA-MB-231 tumor xenografts^[1].
Proteasome inhibition is measured by decreased levels of tumor tissue proteasome activity and accumulation of ubiquitinated proteins and natural proteasome substrates p27 and Bax^[1].
Apoptosis is shown by caspase activation and apoptotic nuclei formation^[1].
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^[4].
Disulfiram inhibits growth and angiogenesis in melanomas transplanted in severe combined immunodeficient mice, and these effects are potentiated by Zn²⁺ supplementation^[4].