Estudo dos mecanismos de morte induzidos pelo complexo de rutênio hmxbato (cis-[RuII((ŋ2-O2CC7H7O2)(dppm)2]PF6) com atividade contra Leishmania (Leishmania) amazonensis e células tumorais de pulmão – A549

Abstract

Ruthenium complexes have gained prominence in recent years due mainly to their favorable properties and different therapeutic applications. In this sense, its application as a metallopharmaceutical against parasitic and tumoral diseases has shown increasing interest in the scientific community. In this work we elucidate the probable mechanisms of cell death involved in the anti-Leishmania and anti-tumor activity of the ruthenium complex – hmxbato (cis-[RuII((ŋ2O2CC7H7O2)(dppm)2]PF6). Firstly, we demonstrated that hmxbate and its precursor were able to induce the formation of ROS in L. (L.) amazonensis promastigotes, causing the depolarization of mitochondrial potential, significant changes in the cell cycle, DNA damage, increased formation of autophagic vacuoles and expressive structural and ultrastructural morphological changes, thus inducing the death of the parasite through apoptosis and autophagy. The activity of hmxbato in tumor and normal lung cells was also verified. In this sense, we demonstrate that hmxbato is able to interact with DNA through a hydrogen bond existing between the hydrogen atom of the -OH group (hmxbato) and the O (phosphate) atom of the guanine DG10 present in the analyzed DNA structure, promoting cellular stress that culminates in the increase in the production of ROS and consequent changes in the potential of the mitochondrial membrane. Then, activation of caspase-9, caspase-3 and PARPB-1 occurs, thus culminating in programmed cell death by apoptosis of A549 tumor cells. We also demonstrated that apoptosis caused by hmxbate in A549 cells promotes changes in mitochondrial potential; drag in the cell cycle; morphological changes; inhibition of cell proliferation and DNA damage. In addition to the death mechanisms involved in hmxbate activity, we demonstrate a predilection for the action of the complex for tumor cells, an unusual property for most existing chemotherapeutic agents. Thus, we conclude the elucidation of the probable mechanisms of death involved in the anti-Leishmania and anti-tumor activity of the ruthenium hmxbate complex which make this molecule an interesting candidate for the design of new drugs against Leishmaniasis and Lung Cancer.