Efeitos de complexos de rutênio(II) contendo derivados do ácido cinâmico sobre células derivadas de melanoma humano.

Abstract

Melanoma is a rare aggressive skin cancer and highly lethal with late diagnosis. Metastatic melanoma overall survival is lower than a year. Despite advances in the treatment with immunotherapy or protein kinase inhibitors, the clinical outcome is poor. In this scenario, the search for new drugs is imperative for the improvement of melanoma therapeutic proposes. Studies have shown that cinnamic acid and derivatives present promising antitumor activity. In addition, nowadays numerous metallic complexes based in Ruthenium were obtained from its coordination with organic compounds. Ruthenium complexes have been investigated as potential antineoplastic drugs and represent an alternative for platinum compounds that has known toxicity. Previous studies developed by our group showed that Ruthenium complex (II) with piperonilic acid inhibited proliferation and induced apoptosis in lung adenocarcinoma cells. In this way, the objective of the present study was to evaluate the effect of three different ruthenium complexes containing cinnamic acid derivatives on melanoma cell lines (HT-144, CHL-1, SK-MEL-147 and WM1366). The complexes named CINAM, TRANSCINAM and

CLOROCINAM were obtained by the coordination of ruthenium with 3,4-methlenedioxy- cinnamic, trans-4-trifluoromethyl-cinnamic and trans-4-chloro-cinnamic acids, respectively.

All complexes reduced cell viability in tested cell lines in a concentration-dependent manner. The IC50 values varied from 2.83 to 13.83 μM. TRANSCINAM was selected for future investigation based on its cytotoxicity and selectivity profiles. CHL-1 cell line was more responsive to TRANSCINAM when compared SKM-MEL-147 and WM1366, considering cell cycle and clonogenic capacity analyses. Therefore, the mechanisms associated to the capacity of TRANSCINAM to inhibit the cell cycle progression at G1/S transition in CHL-1 cells were further investigated. The results showed that TRANSCINAM reduced and increased the expression CCNE2 (cyclin E2) and CDKN1A (p21), respectively, which are critical regulators of G1/S transition. Moreover, TRANSCINAM induced apoptosis on CHL-1 cells and inhibited migration of these cells. Pro-apoptotic effect was associated to increase BAX/Bcl-2 ratio. Taken together, the data show that TRANSCINAM is a promising antitumor prototype, however further studies should be carried out to evaluate its effective contributing for melanoma treatment.