Prospecção de novas moléculas sintéticas e determinação do efeito antitumoral de uma nova chalcona-sulfonamida sintética (css185)

Abstract

Cancer is a complex diseases characterized by the uncontrolled growth of abnormal cells with high invasive potential and is considered a global public health problem. The incidence of cancer has increased every year, showing the relevance in conducting research on cancer treatment in its various modalities. New chalcones have been developed from the insertion of organic groups, among them sulfonamides. The cytotoxic, antiinvasive and antimigratory effect of some chalcone-sulfonamides have been described, however, few studies have described the cytotoxic mechanism of action of these molecules. With this, the aim of this study was to determine the cytotoxic potential of new synthetic chalcone-sulfonamides and the mechanisms involved in the antiproliferative activity of synthetic chalcone-sulfonamide 185 (CSS185). Four synthetic chalcone-sulfonamides with similar molecular structure were tested against tumor cell lines to evaluate the cytotoxic potential of these molecules using MTT assay. Among them, chalcone-sulfonamide 185 (CSS185) showed a selective cytotoxic effect against colorectal cancer cell lines, with an IC50 value four times lower when compared to the other cell lines tested. Therefore, the cytotoxic effect of CSS185 against the metastatic lymph node-derived colorectal cancer cell line (SW-620) was carried out. For the determination of the antitumor effect of this molecule, we used techniques of optical microscopy and fluorescence, flow cytometry and Western blot. The molecule induced a cytostatic and cytotoxic effect against this cell line in a time and concentration dependent manner, interfering with cell cycle progression with increasing G2/M cell number, inducing DNA damage and consequent cell death with the appearance of cell morphology alterations associated with apoptosis and necrosis characteristics, loss of membrane integrity and mitochondrial depolarization. Cell death was associated with activation and cleavage of PARP, with reduced expression of pro-apoptotic Bax protein and caspases 3 and 8 depending of the concentration tested, as well as reduction of the expression of proteins related to the activation of the necroptosis death pathway, RIP and MLKL, that may be associated with the activation of the phosphorylated form of these proteins and induction of death by necroptosis. In addition, due to the antimigratory effect of chalcones-sulfonamides previously described in the literature, a preliminary cellular migration assay was performed using the B16F10 murine melanoma cell line. CSS185 presented an antimigratory effect in non-cytotoxic concentrations, opening up prospects for a more study of this effect. With this, it is suggested that the mechanism involved in the in vitro cytotoxic effect of CSS185 may be related to induction of cell cycle arrest in the G2/M phase and consequent DNA damage and cell death by necroptosis, and antimigratory effect is also observed in non-tumor concentrations cytotoxic, being a promising molecule against cancer.