Abstract
Over the past several decades, much attention has been focused on ruthenium complexes in antitumor therapy. Ruthenium is a transition metal that possesses several advantages for rational antitumor drug design and biological applications. In the present study, five ruthenium complexes containing amino acids were studied in vitro to determine their biological activity against sarcoma-180 tumor cells. The cytotoxicity of the complexes was evaluated by an MTT assay, and their mechanism of action was investigated. The results demonstrated that the five complexes inhibited the growth of the S180 tumor cell line, with IC50 values ranging from 22.53 µM to 50.18 µM, and showed low cytotoxicity against normal L929 fibroblast cells. Flow cytometric analysis revealed that the [Ru(gly)(bipy)(dppb)]PF6 complex (2) inhibited the growth of the tumor cells by inducing apoptosis, as evidenced by an increased number of Annexin V-positive cells and G0/G1 phase cell cycle arrest. Further investigation showed that complex 2 caused a loss of mitochondrial membrane potential; activated caspases 3, caspase-8, and caspase-9 and caused a change in the mRNA expression levels of caspase 3, caspase-9 as well as the bax genes. The levels of the pro-apoptotic Bcl-2 family protein Bak were increased. Thus, we demonstrated that ruthenium amino acid complexes are promising drugs against S180 tumor cells, and we recommend further investigations of their role as chemotherapeutic agents for sarcomas.
Highlights
Sarcomas constitute a heterogeneous group of rare solid tumors of mesenchymal cell origin with distinct clinical and pathological features, and they are usually divided into 2 broad categories: sarcomas of soft tissues and sarcomas of the bone
Synthesis of the Ru(II) amino acid complexes All the synthesized complexes are of orange color, and their elemental analyses data suggest the formation of [Ru(AA)(dppb)(bipy)]PF6 species for the amino acids glycine, L-alanine, Lmethionine and L-leucine and [Ru(AA)(dppb)(bipy)](PF6)2 for the L-aspartic acid
The complexes were characterized by elemental analyses (Table 1), and their purity, which were of .97% were determined by 31P{1H} NMR, and by Thin layer chromatography (TLC) analysis [16]
Summary
Sarcomas constitute a heterogeneous group of rare solid tumors of mesenchymal cell origin with distinct clinical and pathological features, and they are usually divided into 2 broad categories: sarcomas of soft tissues (including fat, muscle, nerve, nerve sheath, blood vessels, and other connective tissues) and sarcomas of the bone. After failure of these drugs, patients with advanced soft tissue sarcomas have few treatment options, and the limitation of current therapeutic options for these tumors has prompted the development and evaluation of a very large number of new chemotherapeutic and biological agents for their treatment [2]. Ruthenium complexes represent a new family of promising metal-based anticancer drugs that offer the potential for reduced toxicity compared to the antitumor platinum(II) complexes currently used in the clinical setting. These complexes have a novel mechanism of action, are less likely to exhibit crossresistance, and have a different spectrum of activity compared to the platinum drugs [3,4,5,6]
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