Estratégias terapêuticas para o tratamento do câncer de mama triplo negativo: novos alvos moleculares e design de drogas

Abstract

Triple-negative breast cancers (TNBCs) are more aggressive than other breast cancer (BC) subtypes and lack effective therapeutic options. Unraveling marker events of TNBCs may provide new directions for development of strategies for targeted TNBC therapy. Herein we reported that Cathepsin D (CatD) is higlhly expressed in aggressive TNBC lineages and, specifically in MDA-MB-231, this expression is associated with overexpression of Annexin A1 (AnxA1). This fact favors the cleavage of AnxA1 by CatD, a critical mechanism proposed by the preent work for pro-tumorigenic protease activity. Thus, since we investigate the inhibition mechanism of CatD by its inhibitor PepA, it has been show that such inhibition is due to the occupation of the active site of CatD by PepA and, at atomic level, the OH group from PepA is capable of interactiong with CO from carboxylic acids of the CatD catalytic aspartic dyad, a reaction that favors the deprotonation of Asp33 and, consequently, promotes the inhibition of CatD. In the functional assays, treatment of MDA-MB-231 with PepA was able to induce apoptosis and autophagy and, at the same time, reduce proliferation, migration and invasion. A broad approach of TNBC, it has been shown that the overall survival of patients with high CatD high expression. Is lower when compared to patients whose tumor cells have low protease expression. In addition, analyzing several TNBC lineages, it was noted that CatD high expression. Is associated with expression of mesenchymal markers. Then, we treated cells with PepA and its drug derived with boronic acid, called PepA-BoA, which was shown to be more efficient and capable of modulating EMT markers by passing from the mesenchymal to epitelial phenotype and reducing the aggressiveness of these cells by decreasing cell viability, migration, invasion, proliferation and stem cell population. In conclusion, the presente work presentes the inhibition of CatD as an effective strategy for the treatment of TNBC cells with similar characteristics to MDA-MB-231.