期刊
FRONTIERS IN MICROBIOLOGY
卷 8, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fmicb.2017.00255
关键词
Leishmania amazonensis; drug combination; apoptosis; autophagy; synergism; miltefosine; thiosemicarbazone
类别
资金
- Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq)
- Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (Capes)
- Financiadora de Estudos e Projetos (FINEP)
- Complexo de Centrais de Apoio a Pesquisa (COMCAP-UEM)
- Programa de Nucleos de Excelencia (PRONEX/Fundacao Araucaria)
Drug combination therapy is a current trend to treat complex diseases. Many benefits are expected from this strategy, such as cytotoxicity decrease, retardation of resistant strains development, and activity increment. This study evaluated in vitro combination between an innovative thiosemicarbazone molecule - BZTS with miltefosine, a drug already consolidated in the leishmaniasis treatment, against Leishmania amazonensis. Cytotoxicity effects were also evaluated on macrophages and erythrocytes. Synergistic antileishmania effect and antagonist cytotoxicity were revealed from this combination therapy. Mechanisms of action assays were performed in order to investigate the main cell pathways induced by this treatment. Mitochondrial dysfunction generated a significant increase of reactive oxygen and nitrogen species production, causing severe cell injuries and promoting intense autophagy process and consequent apoptosis cell death. However, this phenomenon was not strong enough to promote dead in mammalian cell, providing the potential selective effect of the tested combination for the protozoa. Thus, the results confirmed that drugs involved in distinct metabolic routes are promising agents for drug combination therapy, promoting a synergistic effect.
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