Cytoxicity and Apoptotic Mechanism of Ruthenium(II) Amino Acid Complexes in Sarcoma-180 Tumor Cells

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.

Antiproliferative effects of ruthenium-based nucleolipidic nanoaggregates in human models of breast cancer in vitro: insights into their mode of action

“…Indeed, not infrequently the killing of tumor cells by anticancer chemotherapeutics has been linked to activation of extrinsic apoptosis pathways46. These outcomes are consistent with former investigations and demonstrate that some ruthenium(II) and (III) complexes can simultaneously trigger intrinsic and extrinsic apoptosis pathways47.…”

Phytol as an anticarcinogenic and antitumoral agent: An in vivo study in swiss mice with DMBA‐Induced breast cancer

“…The observed extent of DNA damage depends on the release of degradative enzymes that are produced during apoptosis and necrosis, such as the proapoptotic proteins caspase 8, 9, 3, and Bcl2 . PHY, similar to CPA, a frequently used antineoplastic, induced apoptosis by mechanisms of fragmentation and/or nuclear dissolution as evaluated by the comet test.…”

In Vivo Enzymes Activities of Some Ru(II) Compounds with N-Alkylphenothiazines

“…Their properties can be altered by the choice of ligands, which means that complexes potentially have multiple applications. Ruthenium complexes show an antimicrobial activity [5,7] but their most interesting activity is on tumor cells [8][9][10] with developed resistance to the usual medicinal treatment, including cisplatin. The advantage of ruthenium complexes is their relatively low toxicity [6,11], lower than cisplatin, which can partly be explained by its reduced reactivity to DNA in intact cells.…”