Repositioning an Old Anti-Alcoholism Drug: Disulfiram as a Selective, Effective and Economical Anticancer Agent

Soave, Claire; Viola-Rhenals, Maricela; Elghoul, Yasmine; Peng, Tao; Dou, Q. Ping

doi:10.4172/2329-6631.1000e147

Cited by 1 publication

(1 citation statement)

References 29 publications

(27 reference statements)

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“…The drug combination using DSF offers important advantages, which may be both economical (Cvek, 2012;Soave et al, 2016) and pharmacological, since this compound protects normal cells (Jia and Huang, 2021), can diminish the toxicity of different drugs such as cis-diamminedichloroplatinum (Wysor et al, 1982), including myocardial protection (Sonawane et al, 2018) and circa 30% of the CD patients develop heart disease, characterized by arrhythmias among other cardiac manifestations (Saraiva et al, 2021). It is worth mentioning that DSF can suppress cardiac arrhythmogenesis (Sander et al, 2021).…”

Section: •-mentioning

confidence: 99%

The repositioned drugs disulfiram/diethyldithiocarbamate combined to benznidazole: Searching for Chagas disease selective therapy, preventing toxicity and drug resistance

Almeida-Silva

Menezes

Fernandes

et al. 2022

Front. Cell. Infect. Microbiol.

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Chagas disease (CD) affects at least 6 million people in 21 South American countries besides several thousand in other nations all over the world. It is estimated that at least 14,000 people die every year of CD. Since vaccines are not available, chemotherapy remains of pivotal relevance. About 30% of the treated patients cannot complete the therapy because of severe adverse reactions. Thus, the search for novel drugs is required. Here we tested the benznidazole (BZ) combination with the repositioned drug disulfiram (DSF) and its derivative diethyldithiocarbamate (DETC) upon Trypanosoma cruzi in vitro and in vivo. DETC-BZ combination was synergistic diminishing epimastigote proliferation and enhancing selective indexes up to over 10-fold. DETC was effective upon amastigotes of the BZ- partially resistant Y and the BZ-resistant Colombiana strains. The combination reduced proliferation even using low concentrations (e.g., 2.5 µM). Scanning electron microscopy revealed membrane discontinuities and cell body volume reduction. Transmission electron microscopy revealed remarkable enlargement of endoplasmic reticulum cisternae besides, dilated mitochondria with decreased electron density and disorganized kinetoplast DNA. At advanced stages, the cytoplasm vacuolation apparently impaired compartmentation. The fluorescent probe H2-DCFDA indicates the increased production of reactive oxygen species associated with enhanced lipid peroxidation in parasites incubated with DETC. The biochemical measurement indicates the downmodulation of thiol expression. DETC inhibited superoxide dismutase activity on parasites was more pronounced than in infected mice. In order to approach the DETC effects on intracellular infection, peritoneal macrophages were infected with Colombiana trypomastigotes. DETC addition diminished parasite numbers and the DETC-BZ combination was effective, despite the low concentrations used. In the murine infection, the combination significantly enhanced animal survival, decreasing parasitemia over BZ. Histopathology revealed that low doses of BZ-treated animals presented myocardial amastigote, not observed in combination-treated animals. The picrosirius collagen staining showed reduced myocardial fibrosis. Aminotransferase de aspartate, Aminotransferase de alanine, Creatine kinase, and urea plasma levels demonstrated that the combination was non-toxic. As DSF and DETC can reduce the toxicity of other drugs and resistance phenotypes, such a combination may be safe and effective.

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