Increased ROS generation causes apoptosis-like death: Mechanistic insights into the anti-Leishmania activity of a potent ruthenium(II) complex

Some metallodrugs that exhibit interesting biological activity contain transition metals such as ruthenium, and have been extensively exploited because of their antiparasitic potential. In previous study, we reported the remarkable anti-Leishmania activity of precursor cis-[RuIICl2(dppm)2], where dppm = bis(diphenylphosphino)methane, and new ruthenium(II) complexes, cis-[RuII(η2-O2CC10H13)(dppm)2]PF6 (bbato), cis-[RuII(η2-O2CC7H7S)(dppm)2]PF6 (mtbato) and cis-[RuII(η2-O2CC7H7O2)(dppm)2]PF6 (hmxbato) against some Leishmania species. In view of the promising activity of the hmxbato complex against Leishmania (Leishmania) amazonensis promastigotes, the present work investigated the possible parasite death mechanism involved in the action of this hmxbato and its precursor. We report, for the first time, that hmxbato and precursor promoted an increase in reactive oxygen species production, depolarization of the mitochondrial membrane, DNA fragmentation, formation of a pre-apoptotic peak, alterations in parasite morphology and formation of autophagic vacuoles. Taken together, our results suggest that these ruthenium complexes cause parasite death by apoptosis. Thus, this work provides relevant knowledge on the activity of ruthenium(II) complexes against L. (L.) amazonensis. Such information will be essential for the exploitation of these complexes as future candidates for cutaneous leishmaniasis treatment. Low concentrations (0.52 μM) of the cis-[RuII(η2-O2CC7H7O2)(dppm)2]PF6 (hmxbato) induced to increased ROS generation, depolarization in mitochondrial membrane potential, DNA cleavage, alterations in the parasite morphology and formation of autophagic vacuoles. Taken together, these findings indicate that this complex induces apoptosis-like death. [Display omitted] •Cell death mechanism in Leishmania triggered by ruthenium(II) complexes.•cis-{RuII[η2-O2CC7H7O2][bis(diphenylphosphino)methane]2}PF6 is abbreviated as hmxbato.•Hmxbato induces apoptosis-like cell death in Leishmania promastigotes.•Hmxbato and its precursor have similar mechanisms of death against promastigotes.•Low concentrations of hmxbato are required to cause death in Leishmania amazonensis.