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-[(RuCl2)-Cl-II(dppm)(2)], where dppm = bis(diphenylphosphino) methane, and new ruthenium(II) complexes, cis-[Ru-II(eta(2)-O2CC10H13)(dppm)(2)]PF6 (bbato), cis-[Ru-II(eta(2)-O2CC7H7S)(dppm)(2)]PF6 (mtbato) and cis-[Ru-II(eta(2)-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 mitochondria] 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.