Estudo in vitro do potencial antitumoral de complexos de rutênio (II) coordenados a ácidos orgânicos sobre carcinoma de pulmão humano

Abstract

According to the last estimative performed in 2012 by GLOBOCAN/IARC, lung cancer is the most incident type of cancer with more than 1.8 million of diagnosed cases. In Brazil, there were more than 17,000 and 10,000 new cases of lung cancer in 2016, respectively, between men and women. Smoking represents the main cause of lung cancer, and available treatments are not very effective considering that the disease is commonly diagnosed in advanced stage. Although improving the therapeutic approach in the last decades, only 14% of the patients diagnosed with lung cancer survive for 5 years. In this framework, it is relevant to identify new therapeutic proposes against lung cancer. Ruthenium metal compounds emerge as a promising alternative to platinum-based compounds, therefore they displayed lower cytotoxic and they are more selectivity for tumor cells. Thus, the present study aimed to evaluate the effects of innovative ruthenium(II) complexes (PIPE and CINAM) on proliferative behavior of A549 cells, which are derived from human lung adenocarcinoma, a subtype of lung cancer more frequently diagnosed in patients with non-small cell lung cancer. Moreover, the possible molecular mechanisms involved with antiproliferative and cytotoxic activities of the ruthenium complexes were investigated. Cell viability was evaluated by colorimetric assay (MTS) and trypan blue exclusion assay. Clonogenic capacity assay and cell cycle analysis were also performed. Mitotic index determination and cytoskeleton analysis were carried out from cytological preparations stained for tubulin and F-actin. Pro-apoptotic potential was investigated through anexina V and membrane depolarization assays. Results demonstrated that both complexes (CINAM and PIPE) were effective in reducing cell viability and inhibiting proliferation of A549 cells, however CINAM was more cytotoxic than PIPE. When PIPE was used at 9 μM there was increase in G0/G1 cell population with concomitant reduction in frequency of cell in S-phase, indicating cell cycle arrest in G1/S transition. This event was, probably, due to reduction of phosphorylation levels of ERK and reduction of cyclin D1 expression. Cytotoxic effect of PIPE (18 μM) and CINAM (2 and 4 μM) is related to pro-apoptotic activity these compounds. Taken together, the data demonstrated that PIPE and CINAM are promising antitumor agents.