Estudo in silico, in vitro e in vivo de compostos derivados do selênio em células leucêmicas e de câncer de mama

Abstract

The cancer appears as a major public health problem, especially for developing countries. Therefore, they are increasing around the world, research aimed at the development of new and more efficient drugs against this disease. In this perspective, compounds derived from selenium gain significant importance due to the various studies that highlight their antitumor potential, as well as low cytotoxicity for non-tumor cells. Therefore, our objective was to evaluate the antitumor potential of a selenium-based compound, as well as to establish the pathway of death activated by organoselenium. We performed a ligand-based virtual screening analysis (in silico) to identify selenoglycolicamides with potential antitumor activity, as well as in vitro analyzes using HL-60 (human promyelocytic leukemia) and MCF-7 (breast adenocarcinoma) cell lines. Results and Conclusion: Compounds 3, 6, 7 and 8 were selected for in vitro cytotoxicity tests, because, according to the spectrophotometry results, they were active for both cell lines tested (HL-60 and MCF-7). We evaluated the cytotoxicity of the selected selenium derivatives and it was found that compound 3 showed the best results against the HL-60 cell line (IC50 = 9.41μM), evidenced by the decrease in cell viability in a dose-dependent manner, the compound also was able to induce cell death at a frequency similar to that observed for doxorubicin, a drug widely used in the treatment of several cancers, however it presented low toxicity to non-tumor cells (PBMC). Among the essential parameters that must be observed when developing new cancer drugs, the balance between therapeutic and toxicological effects is an important consideration. Many drugs have cytotoxic activity, but are not selective against tumor cells and can also affect non-tumor cells. Depolarization of the mitochondrial membrane at rates higher than the negative control (p <0.05) and similar or higher than the positive control (p <0.001), confirms that the compound promotes apoptosis through the intrinsic mitochondrial pathway. Compound 3 induced the expression of caspases 3 and 7 in a dose-dependent manner at concentrations of 17.0 and 34.0 μM the activation levels were similar and higher than doxorubicin, respectively, thus confirming the etivation of the mechanism death by apoptotic route. The induction of the apoptosis process causes the dying cell of the plasma membrane to remain intact, which prevents the release of pro-inflammatory cytokines in the circulating tissue. In addition, a docking study showed that compound 3 has good interaction energies with caspases 3, 7 and 8, which participate in the path of apoptotic cell death. These results suggest that selenium has significant pharmacological potential for the selective targeting of tumor cells, inducing molecular and cellular events that culminate in the death of tumor cells.