Ru(II)-Based Amino Acid Complexes Show Promise for Leukemia Treatment: Cytotoxicity and Some Light on their Mechanism of Action.

Abstract

Ruthenium is attracting considerable interest as the basis for new compounds to treat diseases, and studies have shown that complexes with different structures have significant antineoplastic and antimetastatic potential against several types of tumors, including tumors resistant to cisplatin drugs. We examined the cytotoxic, genotoxic, and pro-apoptotic activities of six ruthenium complexes containing amino acid with general formulation [Ru(AA)(bipy)(dppb)]PF6, where AA = amino acid (alanine, glycine, leucine, lysine, methionine, or tryptophan); bipy = 2,2´-bipyridine; and dppb = [1,4-bis(diphenylphosphine)butane], against A549 (lung carcinoma) and K562 (chronic myelogenous leukemia) cancer cells. The results show that the ruthenium complexes tested were able to induce cytotoxicity in A549 and K562 cancer cells. Complex 1 containing alanine inhibited the cell viability of A549 and K562 tumor cells by inducing apoptosis, as evidenced by an increased number of Annexin V-positive cells and the induction of DNA damage and cell cycle arrest. Complex 1 was able to induce caspase-mediated apoptosis in K562 cells through the mitochondrial dysfunction, the upregulation of apoptotic genes, and the downregulation of Bcl2 anti-apoptotic gene. Besides being cytotoxic to K562 and A549 cells, ruthenium complex containing alanine shows low cytotoxicity and genotoxicity against non-tumor cells. These results suggest that the ruthenium (II) complex is a potential safe and efficient antineoplastic candidate for leukemia treatment.