Avaliação da atividade in silico e in vitro de compostos metálicos em diferentes linhagens de câncer de mama

Abstract

The mortality associated with Breast Cancer (BC) is alarming, especially in view of the restricted therapeutic strategies for cases of resistance to routinely used drugs. Among the resistance mechanisms presented by breast tumors, some are strongly related to the expression of estrogen receptors. In this context, the search for new compounds is urgent so that there is, in fact, an increase in the overall survival of patients. Metal complexes have stood out due to their versatility, effectiveness and selectivity and the present study aimed to evaluate the biological activities of five new metallic prototypes of copper (Cu) and nickel (Ni) in CM cell lines. Initially, affinity for DNA was predicted, highlighting Complex III. Subsequently, the cytotoxicity of the five complexes to MCF10A (non-tumorigenic), MCF7 (luminal CM) and MDA-MB231 (triple-negative CM) strains was evaluated. Complex III was selective for the MCF7 lineage after 48 hours and, for this reason, it was also used in the treatment of these cells resistant to the hormone therapy Tamoxifen (MCF7/TAM). Interestingly, Complex III was active in this strain, with IC50 = 0.66μM. When evaluating the modulated mechanisms, we observed that the compound decreased ESR1 and AR transcripts and increased ESR2 transcripts in the MCF7 cell line, with the opposite effect in MCF7/TAM cells. At the protein level, an increase in the expression of cleaved Caspase 3 and a decrease in Bcl2 was observed in the resistant strain. Finally, Complex III also increased Reactive Oxygen Species levels in MCF7/TAM cells. Therefore, Complex III is a potential candidate in the control of luminal BC cells, and can be used as a complementary tool to treatment with Tamoxifen and, in case of therapeutic resistance, it induces apoptosis of tumor cells, which makes it potentially promising. Additional studies are needed to deepen the understanding of its mechanisms of action, especially in animal models.