title: Induction of Early Autophagic Process onLeishmania amazonensisby Synergistic Effect of Miltefosine and Innovative Semi-synthetic Thiosemicarbazone.
abstract: 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 evaluatedin vitrocombination between an innovative thiosemicarbazone molecule - BZTS with miltefosine, a drug already consolidated in the leishmaniasis treatment, againstLeishmania 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.
authors.affiliation: Laboratório de Inovação Tecnológica no Desenvolvimento de Fármacos e Cosméticos, Departamento de Farmácia, Universidade Estadual de Maringá Maringá, Brazil.
authors.forename: Débora B
authors.initials: DB
authors.lastname: Scariot
authors.affiliation: Laboratório de Inovação Tecnológica no Desenvolvimento de Fármacos e Cosméticos, Departamento de Farmácia, Universidade Estadual de Maringá Maringá, Brazil.
authors.forename: Elizandra A
authors.initials: EA
authors.lastname: Britta
authors.affiliation: Laboratório de Inovação Tecnológica no Desenvolvimento de Fármacos e Cosméticos, Departamento de Farmácia, Universidade Estadual de Maringá Maringá, Brazil.
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Moreira
authors.affiliation: Departamento de Química, Universidade Estadual de Maringá Maringá, Brazil.
authors.forename: Hugo
authors.initials: H
authors.lastname: Falzirolli
authors.affiliation: Departamento de Química, Universidade Estadual de Maringá Maringá, Brazil.
authors.forename: Cleuza C
authors.initials: CC
authors.lastname: Silva
authors.affiliation: Laboratório de Inovação Tecnológica no Desenvolvimento de Fármacos e Cosméticos, Departamento de Farmácia, Universidade Estadual de Maringá Maringá, Brazil.
authors.forename: Tânia
authors.initials: T
authors.lastname: Ueda-Nakamura
authors.affiliation: Laboratório de Inovação Tecnológica no Desenvolvimento de Fármacos e Cosméticos, Departamento de Farmácia, Universidade Estadual de Maringá Maringá, Brazil.
authors.forename: Benedito P
authors.initials: BP
authors.lastname: Dias-Filho
authors.affiliation: Laboratório de Inovação Tecnológica no Desenvolvimento de Fármacos e Cosméticos, Departamento de Farmácia, Universidade Estadual de Maringá Maringá, Brazil.
authors.forename: Celso V
authors.initials: CV
authors.lastname: Nakamura
keywords: Leishmania amazonensis; apoptosis; autophagy; drug combination; miltefosine; synergism; thiosemicarbazone