Repurposing Disulfiram as An Anti-Cancer Agent: Updated Review on Literature and Patents

Abstract

Background: Despite years of success of most anti-cancer drugs, one of the major clinical problems is inherent and acquired resistance to these drugs. Overcoming the drug resistance or developing new drugs would offer promising strategies in cancer treatment. Disulfiram, a drug currently used in the treatment of chronic alcoholism, has been found to have anti-cancer activity. Objective: To summarize the anti-cancer effects of Disulfiram through a thorough patent review. Methods: This article reviews molecular mechanisms and recent patents of Disulfiram in cancer therapy. Results: Several anti-cancer mechanisms of Disulfiram have been proposed, including triggering oxidative stress by the generation of reactive oxygen species, inhibition of the superoxide dismutase activity, suppression of the ubiquitin-proteasome system, and activation of the mitogen-activated protein kinase pathway. In addition, Disulfiram can reverse the resistance to chemotherapeutic drugs by inhibiting the P-glycoprotein multidrug efflux pump and suppressing the activation of NF-kB, both of which play an important role in the development of drug resistance. Furthermore, Disulfiram has been found to reduce angiogenesis because of its metal chelating properties as well as its ability to inactivate Cu/Zn superoxide dismutase and matrix metalloproteinases. Disulfiram has also been shown to inhibit the proteasomes, DNA topoisomerases, DNA methyltransferase, glutathione S-transferase P1, and O6- methylguanine DNA methyltransferase, a DNA repair protein highly expressed in brain tumors. The patents described in this review demonstrate that Disulfiram is useful as an anti-cancer drug. Conclusion: For years the FDA-approved, well-tolerated, inexpensive, orally-administered drug Disulfiram was used in the treatment of chronic alcoholism, but it has recently demonstrated anti-cancer effects in a range of solid and hematological malignancies. Its combination with copper at clinically relevant concentrations might overcome the resistance of many anti-cancer drugs in vitro, in vivo, and in patients.

Overcoming cancer therapeutic bottleneck by drug repurposing

“…174,175 In the past years, disulfiram has attracted increasing attention for its anticancer activity both as monotherapy and combinational therapies. 176 Notably, numerous studies have reported on mechanisms of action of disulfiram that are closely associated with ALDH-related processes of cellular metabolism. For example, Tacconi et al identified disulfirammediated acetaldehyde metabolism as a potential therapeutic target for BRCA1/2-deficient cancer cells, resulting from endogenous acetaldehyde-induced DNA damage.…”

COP9 signalosome is an essential and druggable parasite target that regulates protein degradation

“…DTC-metal complexes have a relatively long half-life and are widely distributed throughout the body, including the gastrointestinal tract. Therefore, in order to achieve adequate levels, ZnDTC is safely given in vivo as oral disulfiram plus zinc gluconate (31,32,(35)(36)(37)(38). Entamoeba histolytica causes an inflammatory diarrhea termed amebic colitis (10).…”

Disulfiram Overcomes Cisplatin Resistance in Human Embryonal Carcinoma Cells

“…Disulfiram, an alcohol-abuse drug, was found to have anti-cancer activity and several mechanisms of its action were described [40]. Disulfiram triggered oxidative stress by the generation of reactive oxygene species and led to apoptosis in different cancer types [41,42,43].…”