Eficácia antitumoral de um complexo de rutênio contendo ácido trans-4-trifluorometil-cinâmico em melanoma murino

Abstract

Despite the promising advances in therapy, classic chemotherapy is nonspecific, besides generating adverse effects for patients. In the context of the most aggressive neoplasms, characterized by a high mortality rate, although low incidence, melanoma stands out, a cutaneous tumor originating from melanocytes. In face of such a problem, the identification of new agents that can improve treatment proposals for melanoma is relevant. Therefore, metal complexes with a structural center based on ruthenium II (Ru (II)) have shown promising antitumor activity. Its octahedral geometry characterized by a significant number of coordination sites, allowed us to conjugate Ru (II) with a phenolic compound, trans-4-trifluoromethyl-cinnamic acid, generating a complex known as Transcinam {[Ru(trans-4-trifluoromethyl-cinnamic acid) (dppb)(bipy)]PF6}. In previous studies involving melanoma cell cultures, Transcinam was able to inhibit cell cycle progression in the G1 phase and induce apoptosis. Thus, this study aimed to evaluate the antitumoral activity of Transcinam in murine melanoma syngeneic model. For tumor induction, B16-F10 cells were inoculated into male C57BL/6 mice, which were treated for 5 consecutive days after tumor growth, with three different doses of Transcinam [2.5; 5 and 10 mg/kg body weight (b.w.)], subcutaneously (s.c.) and cisplatin (CDDP 7 mg/kg b.w. s.c.). Genotoxicological and molecular parameters were investigated. The results demonstrated that Transcinam, in the three tested doses (2,5; 5 and 10 mg/kg b.w.), reduced tumor growth without increasing water consumption and reducing food consumption. In the dose of 5 mg/kg b.w., Transcinam did not cause significant weight reduction, and in doses of 5 and 10 mg/kg b.w. it was possible to observe a reduction in serum creatinine, urea, GOT and GPT levels, when compared to CDDP. Treatment with Transcinam did not impact significantly the organs weight, especially at 5 mg/kg b.w. dose, unlike CDDP. In bone marrow and peripheral blood, the EPC/EPC+ENC ratio demonstrated that Transcinam did not exhibit cytotoxic effects, while micronucleus analyses revealed the presence of these biomarkers, although at levels lower than those in the CDDP group. Transcinam showed strong DNA binding through groove interaction and increased damage in the comet assay; however, when compared to the CDDP group, such lesions were significantly reduced. PCNA expression in tumor tissue was decreased after treatment with Transcinam, indicating a reduction in cell proliferation. These findings suggest that Transcinam has promising antitumor effects, capable of reducing cell proliferation without inducing systemic toxicity.