Complexos de Pd (II) - tipo Melofen com duplo efeito: anticancerígeno e antiangiogênico.

Abstract

Cancer is considered one of the most common causes of mortality in the world and designates a set of diseases characterized by the presence of cells in uncontrolled growth, capable of dividing rapidly and migrating, causing metastasis. Among the therapeutic approaches used in its treatment, chemotherapy is the method of greatest accessibility and clinical use. However, adverse side effects and multidrug resistance remain a huge challenge with chemotherapeutic agents. A promising strategy to address this issue has been related to the prospecting of new pharmacological agents with specificity for cancer cells. Thus, a favorable branch towards which new therapies have been turned to concerns compounds with dual effect, i.e., that present the ability to compromise tumor angiogenesis and induce cancer cell death in a specific and selective way. Such characteristics can be found in metal complexes, especially those structurally related to Schiff's bases. Thus, the present study aimed to investigate the toxicity and the potential anticancer and antiangiogenic effect of four palladium metal complexes structurally related to Schiff's bases. To this end, experimental protocols for toxicity in cancer and non-cancer models were performed, in addition to a protocol for investigating angiogenesis. Initially, to determine the safety in the use of the molecules, the acute toxicity bioassay with Artemia salina larvae and the hemolytic test in human erythrocytes were performed. Treatment with the structural precursor pd1 induced a high percentage of hemolysis (103.1 ± 10.2%) and provided toxicity to the microcrustaceans with CL50 of 58.1 ± 1.1 μM. However, the pd2-5 complexes did not induce damage to the erythrocyte membrane (CI50 >200 μM), as well as were not toxic to microcrustaceans (CL50 >200 μM) at the tested concentrations, and were selected for elucidation of their respective biological properties. Subsequently, cell viability (MTT) assessment assay was performed on human breast cancer tumor cell lines isolated from triple negative metastatic tumor (MDA-MB-231) and glioma (U-373MG). The four distinct pd2-5 complexes demonstrated cytotoxic effect, most prominently pd5 with CI50 of 162.5 ± 1.2 μM and 56.6 ± 1.1 μM, respectively, for MDA-MB-231 and U-373MG lineage. Additionally, the antiangiogenic properties of the molecules were investigated using the chicken embryonated egg chorioallantoic membrane (HET-CAM) assay. All pd2-5 metal complexes promoted reduction of the evaluated vascular parameters, including diameter, length and number of branching of blood vessels. In conclusion, the results obtained so far demonstrate that all pd2-5 metal complexes evaluated showed anticancer activity and were able to impair the formation of new blood vessels, with such effects observed in sub-toxic concentrations, making them, therefore, promising for the prospection of new drugs to strengthen an alternative line for the treatment of cancer, mainly because they act in two distinct therapeutic targets of the tumor microenvironment.