Novos mecanismos mediados por complexos metálicos de cobre em células tumorais mamárias

Abstract

Breast cancer (BC) is the malignant neoplasm that most affects women worldwide. It is a disease whose etiology is multifactorial in nature, with varied clinical and morphological manifestations, distinct molecular signatures and different response profiles to therapy. Currently, BC is the leading cause of death associated with cancer and it is estimated that between the years 2020 to 2040, about 3 million new diagnoses will occur. Due to their molecular complexity, breast tumors are classified into different subtypes. Among these, triple negative CM (TNCM) corresponds to about 15% of cases, with worse prognosis and lower free and overall survival. The clinical management of CMTN is restricted. These are tumors that do not express estrogen, progesterone and epidermal growth factor receptor type 2 receptors. Thus, they are mostly treated systemically by chemotherapy. Indeed, the benefits of chemotherapy for CMTN have been reported. Data from different studies have demonstrated its efficacy in neoadjuvant, adjuvant and metastatic scenarios. However, the side effects caused by drugs, due to their non-specificity for tumor cells and cytotoxicity in normal cells, added to the high aggressiveness and high potential for dissemination and recurrence of TN breast tumors, require new approaches. The inclusion of metal complexes in cancer treatment began with the discovery of the antineoplastic properties of cisplatin. However, due to serious side effects, such as hepatotoxicity, and limited therapeutic efficacy, the synthesis of new metal complexes with antitumor properties has become necessary. In this context, the synthesis of copper-based complexes has stood out. Copper is an essential micronutrient for the body acting as a catalytic cofactor and structural component of different enzymes. Its unique electronic structure and its endogenous nature make it a promising metal for the chemical synthesis of drugs based on potentially less toxic and more selective metals. The benefits of administering copper complexes in the treatment of BC have been described, however the antiproliferative mechanism associated with these compounds is mostly restricted to the 2 apoptosis and generation of reactive oxygen species. Interestingly, the scenario described drives the development of new copper-based complexes with antitumor potential in the treatment of CMNT, as well as the investigation of novel signaling pathways that can be modulated by these compounds. In the present study, we evaluated the antiproliferative potential of new copper complexes in different breast tumor cell lines. Since the complexes showed significant cytotoxicity against tumor cells and remarkable selectivity, we selected the one that exhibited the best results and performed additional assays seeking to identify its mechanism of action. We raised the hypothesis that the assessed complex also exerts its action via modulation of purinergic signaling. Our study, therefore, sheds light on novel targets modulated by copper metal complexes and opens new avenues in determining therapeutic regimens for CMTN.