Inhibition of cell proliferation of iridium(III) polypyridyl complexes on osteosarcoma U2OS cells through PI3K/AKT/mTOR pathway

Abstract

In this article, three iridium(III) complexes [Ir(bzq)₂(NPIP)](PF₆) (NPIP = 2-nitrophenyl-1H-imidazo[4,5-f][1,10]phenanthroline) (Ir1), [Ir(bzq)₂(MNPIP)](PF₆) (MNPIP = 3-nitrophenyl-1H-imidazo[4,5-f][1,10]phenanthroline) (Ir2) and [Ir(bzq)₂(PNPIP)](PF₆) (PNPIP = 4-nitrophenyl-1H-imidazo[4,5-f][1,10]phenanthroline) (Ir3) were synthesized and characterization. The cytotoxicity in vitro of the complexes Ir1, Ir2 and Ir3 toward human tibial osteosarcoma cell U2OS, human osteosarcoma cell HOS, human osteoblast-like cells MG-63, and non-cancer cell LO2 was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. Complex Ir1 displays high anticancer activity against U2OS cells with a low IC₅₀ value of 7.4 ± 0.04 μM, while Ir2 and Ir3 show no cytotoxic activity toward the above selected cancer cells. The colonies and wound healing show that Ir1 can effectively inhibit the cell proliferation and migration. The apoptosis was performed using Annex V/propidium iodide (PI) double staining and the obtained results show that Ir1 can induce apoptosis. The cell cycle distribution demonstrates that Ir1 prevents the cell growth at the G0/G1 phase. Ir1 locates at the mitochondria, causes an increase of intracellular ROS levels, induces a decrease of mitochondrial membrane potential. Additionally, Ir1 can cause autophagy, regulate the expression of Bcl-2 family proteins, inhibit the expression of PI3K, AKT, mTOR and p-mTOR. Taken together, Ir1 induces cell death through a ROS-mediated mitochondrial dysfunction and inhibition of PI3K/AKT/mTOR signaling pathway.