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CARAJURIN INDUCES APOPTOSIS IN LEISHMANIA AMAZONENSIS PROMASTIGOTES THROUGH REACTIVE OXYGEN SPECIES PRODUCTION AND MITOCHONDRIAL DYSFUNCTION
Leishmania amazonensis
Mitocôndria
Morte celular
Apoptose
Author
Affilliation
Abstract
Carajurin is the main constituent of Arrabidaea chica species with reported anti-Leishmania
activity. However, its mechanism of action has not been described. This study investigated the
mechanisms of action of carajurin against promastigote forms of Leishmania amazonensis. Carajurin
was effective against promastigotes with IC50 of 7.96 1.23 g.mL1 (26.4 M), and the cytotoxic
concentration for peritoneal macrophages was 258.2 1.20 g.mL1 (856.9 M) after 24 h of treatment.
Ultrastructural evaluation highlighted pronounced swelling of the kinetoplast with loss of
electron-density in L. amazonensis promastigotes induced by carajurin treatment. It was observed
that carajurin leads to a decrease in the mitochondrial membrane potential (p = 0.0286), an increase
in reactive oxygen species production (p = 0.0286), and cell death by late apoptosis (p = 0.0095)
in parasites. Pretreatment with the antioxidant NAC prevented ROS production and significantly
reduced carajurin-induced cell death. The electrochemical and density functional theory (DFT) data
contributed to support the molecular mechanism of action of carajurin associated with the ROS
generation, for which it is possible to observe a correlation between the LUMO energy and the electroactivity
of carajurin in the presence of molecular oxygen. All these results suggest that carajurin
targets the mitochondria in L. amazonensis. In addition, when assessed for its drug-likeness, carajurin
follows Lipinski”s rule of five, and the Ghose, Veber, Egan, and Muegge criteria.
Keywords in Portuguese
Leishmania amazonensisLeishmania amazonensis
Mitocôndria
Morte celular
Apoptose
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