Avaliação do perfil citotóxico de análogos intermediários do (7-CLOROQUINOLIN-4-IL) Tiossemicarbazida e o perfil de morte celular da linhagem Kasumi-1

Abstract

Cancer is as a set of correlated diseases, where some cells in the body start to grow disorderly and migrate to other tissues, a process called metastasis. Among cancers, leukemia has a high mortality rate and is a comprehensive term that refers to the types of cancer that affect blood cells. In the search for new molecules for the treatment of cancer, the hybridization process has been widely used for the development of new synthetic molecules with antitumor activity. Among the chemical classes with potential for antitumor activity, there are quinolines and thiazolidines, both of which present several biological activities, among them the antitumor activity proven by different studies. For the present study, the cytotoxic profile of intermediate analogs of (7-chloroquinolin-4-yl) thiosemicarbazide and the mechanism of cell death of the KASUMI-1 lineage induced by the most promising molecule: ethyl chloroacetoacetate (168) were evaluated. Among the analyzed analogues, three showed antiproliferative potential in the lines SF-295, HL-60, PC-3 and HCT-116, where the cell line most susceptible to the action of these intermediates was the leukemic line, selectivity for HL-60 lineage with IC50 value of 2.41uM, whereas for non-tumor lineage (L929), the IC50 value was> 25uM. Due to the selectivity of the 168 analog for leukemic lines, it was tested on a panel with 4 leukemic lines for 24 hour incubation time, where KASUMI-1, an acute myeloid leukemia lineage was selected for the mechanism of action of the analog 168. Cells were treated with different concentrations of analog 168 (5uM, 10uM and 20uM) for 24 hours. A cytostatic effect was observed in KASUMI-1 cells, from the concentration of 5uM and cytotoxic effect at concentrations of 10uM and 20uM, when evaluated by flow cytometry. In addition, the phosphatidylserine externalization analysis showed an apoptotic pattern at the two highest concentrations. Moreover, the cell cycle analysis, showed an accumulation of cells in G2 / M phase with a drastic reduction of the population in S, from the concentration of 10uM. The analog 168 also induced an increase in the cell subG1population, and also caused a number of morphological changes, for example nuclear change and the appearance of blebs in the cell membrane with evidence of apoptosis. Thus, the presented results suggest that, analogue 168, could be considered a new prototype with antitumor potential.