Efeitos de complexos metálicos de cobre no câncer de mama triplo negativo

Abstract

Breast cancer is the second most common type in the world and can be considered a disease with good prognosis if diagnosed early and treated timely. The treatment of breast cancer aims to increase survival and improve the quality of life of women. Chemotherapy drugs cause DNA damage to both tumor and normal cells. Cisplatin is considered one of the best drugs in the treatment of various cancers in the world, but it has several side effects. Research into replacing platinum with another metal center, such as copper and ruthenium, shows advantages mainly in its ability to lessen side effects. In this sense, the objective of the present study was to evaluate the effect of copper complexes in in vitro experimental models on different tumor and non-tumoral breast cell lines. For this, different in vitro experiments were performed using the non-tumor human breast cell lines MCF-10A, the human tumoral cell lines MDA-MB-231, MCF-7, SK-BR3, mouse fibroblast L929 and mouse tumor 4t1.The results demonstrated that the copper [Cu(sdmx-)2(phen)].H2O complex was the most effective in inducing toxicity in triple negative subtype breast tumor cells (MDA-MB-231) compared to non-tumoral breast cell line MCF-10A, which was slightly more resistant to the same complex. Furthermore, it was able to decrease the number and size of colonies, modify the structure of the cytoskeleton, and inhibit cell migration. The importance of copper transporter protein 1, CTR1, was also verified by cell transfection, in which after this process, gene expression was increased approximately ten-fold in transfected MDA-MB-231 cells, and that the complex [CuCl2(-impy)] was more cytotoxic in these cells compared to non-transfected cells. This can be attributed to the presence of vacant points in copper through the loss of chloride ions, which allows their interaction with CTR1 and greater uptake through it. In summary, the results show that the [Cu(sdmx-)2(phen)].H2O and [CuCl2(-impy)] complexes were cytotoxic to tumor cell line MDA-MB-231 and that increased expression of CTR1 caused sensitization in transfected cells upon treatment with the [CuCl2(-impy)] complex. Further studies should be performed with the [Cu(sdmx-)2(phen)].H2O and [CuCl2(-impy)] complexes for understanding of the mechanisms of action and the influence of CTR1 in this process. In addition, considering CTR1 as a target in tumor cells supports the development of strategies that use rational drug design to improve therapeutic efficacy through greater specificity and consecutive reduction of side effects.