Interações moleculares e efeitos celulares de novos complexos metálicos de cobre sobre células tumorais prostáticas

Abstract

Prostate Cancer (PCa) is the second leading cause of cancer death in men worldwide and in Brazil. The treatment of advanced cases is based on the use of chemotherapic drugs, which lack specificity, as they cause undesirable side effects, and efficacy, due to resistance mechanisms developed by tumor cells. Copper complexes are promising antitumor therapeutic agents, since their pharmacological properties can be optimized by changing the nature of the ligand and donor atoms. They exhibit antitumor activity by intercalating into DNA, promoting oxidative stress, and inducing apoptosis. In this study, we aimed to evaluate the cellular effects of two copper metal complexes on the prostatic lineages PNT-2 (non-tumorigenic), LNCaP (hormone-responsive PCa) and PC-3 (castration-resistant PCa - CRPC). Cell viability was assessed by MTT method and the ability to interact with DNA was predicted in silico by molecular docking. The plasmid DNA degradation assay was used to verify the ability of the complexes to interact and cleave the genetic material. Then, the expression levels of cell proliferation markers Ki-67 and Cyclin D1 were analyzed by flow cytometry in the LNCaP lineage, after treatment with Complexes 1 and 2 within 48h. The results indicated that the complexes showed cytotoxic activity against the tumor cell lines and were selective for LNCaP cells. The in silico analysis revealed the possibility that the complexes present affinity with DNA. Binding preference was found for the minor groove and the ascending order of the best scoring anchored compounds was 1>2. The complexes cleaved the plasmid DNA inducing form II (circular) on the gel. However, in the presence of H2O2, only Complex 1 promoted cleavage in both strands of plasmid DNA (form III or linear). Furthermore, the results obtained demonstrated that Complex 1 significantly reduced the expression levels of Ki-67 and Cyclin D1, inhibiting cell proliferation in the hormone-responsive tumor lineage. On the other hand, Complex 2 was able to reduce only the expression of Cyclin D1. Therefore, our results suggest that Complexes 1 and 2 have chemotherapeutic potential, which makes them promising for the development of new antitumor drugs for the treatment of PCa.