Cytoxicity and Apoptotic Mechanism of Ruthenium

• Published in: PloS one Vol. 9; no. 10
• Main Authors: Lima, Aliny Pereira, Pereira, Flávia Castro, Almeida, Marcio Aurelio Pinheiro, Mello, Francyelli Mariana Santos, Pires, Wanessa Carvalho, Pinto, Thallita Monteiro, Delella, Flávia Karina, Felisbino, Sérgio Luis, Moreno, Virtudes, Batista, Alzir Azevedo, de Paula Silveira-Lacerda, Elisângela
• Format: Journal Article
• Language: English
• Published: Public Library of Science 17.10.2014
• Subjects: Apoptosis; Glycine; Platinum group compounds; Ruthenium; Sarcoma
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0105865

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 IC.sub.50 values ranging from 22.53 [micro]M to 50.18 [micro]M, and showed low cytotoxicity against normal L929 fibroblast cells. Flow cytometric analysis revealed that the [Ru(gly)(bipy)(dppb)]PF.sub.6 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.