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

Autor:	Almeida-Silva J; Innovations in Therapies, Education and Bioproducts Laboratory, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, RJ, Brazil., Menezes DS; Parasite Biology Laboratory, Gonçalo Moniz Institute, Oswaldo Cruz Foundation, Salvador, BA, Brazil., Fernandes JMP; Innovations in Therapies, Education and Bioproducts Laboratory, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, RJ, Brazil., Almeida MC; Parasite Biology Laboratory, Gonçalo Moniz Institute, Oswaldo Cruz Foundation, Salvador, BA, Brazil., Vasco-Dos-Santos DR; Innovations in Therapies, Education and Bioproducts Laboratory, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, RJ, Brazil., Saraiva RM; Laboratory of Clinical Research on Chagas Disease, Evandro Chagas Infectious Disease Institute, Oswaldo Cruz Foundation, Rio de Janeiro, RJ, Brazil., Viçosa AL; Experimental Pharmacotechnics Laboratory, Department of Galenic Innovation, Institute of Drug Technology - Farmanguinhos, Oswaldo Cruz Foundation, Rio de Janeiro, RJ, Brazil., Perez SAC; Project Management Technical Assistance, Institute of Drug Technology - Farmanguinhos, Oswaldo Cruz Foundation, Rio de Janeiro, RJ, Brazil., Andrade SG; Experimental Chagas Disease Laboratory, Gonçalo Moniz Institute, Oswaldo Cruz Foundation, Salvador, BA, Brazil., Suarez-Fontes AM; Innovations in Therapies, Education and Bioproducts Laboratory, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, RJ, Brazil., Vannier-Santos MA; Innovations in Therapies, Education and Bioproducts Laboratory, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, RJ, Brazil.
Jazyk:	angličtina
Zdroj:	Frontiers in cellular and infection microbiology [Front Cell Infect Microbiol] 2022 Jul 29; Vol. 12, pp. 926699. Date of Electronic Publication: 2022 Jul 29 (Print Publication: 2022).
DOI:	10.3389/fcimb.2022.926699
Abstrakt:	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 H 2 -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. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2022 Almeida-Silva, Menezes, Fernandes, Almeida, Vasco-dos-Santos, Saraiva, Viçosa, Perez, Andrade, Suarez-Fontes and Vannier-Santos.)
Databáze:	MEDLINE
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