Anticancer activity of ruthenium(II) plumbagin complexes with polypyridyl as ancillary ligands via inhibiting energy metabolism and GADD45A-mediated cell cycle arrest

Abstract

To study the antitumor activity and action mechanism of Ru(II) polypyridyl plumbagin (PLN) complexes, four complexes [Ru(PLN)(DMSO)₂]Cl (Ru1), [Ru(bpy)₂(PLN)](PF₆) (bpy is bipyridine) (Ru2), [Ru(phen)₂(PLN)](PF₆) (phen is 1,10-phenanthroline) (Ru3), and [Ru(DIP)₂(PLN)](PF₆) (DIP is 4,7-diphenyl-1,10-phenanthroline) (Ru4) were obtained and fully characterized. Lipophilicity, cellular uptake and cytotoxicity of these Ru(II) complexes are in the order of: Ru1<Ru2<Ru3<Ru4. The ancillary polypyridyl ligands affected the bioactivity and action mechanisms of these Ru(II) complexes. Ru3 and Ru4 inhibited energy metabolism by severely impairing mitochondrial respiration and glycolysis processes. Moreover, Ru3 and Ru4 induced DNA damage and the increased expression of GADD45A, which led to cell cycle arrest in G0/G1 phase in MGC-803 cells, while the inactivation of GADD45A attenuated these effects; however, Ru3 or Ru4-induced GADD45A did not affect cell apoptosis. Further studies revealed that Ru3 and Ru4 induced ROS-dependent and caspase-dependent apoptotic cell death by mitochondrial dysfunction, and Ru4 displayed higher potency than Ru3. The in vivo results in MGC-803 xenograft nude mice model also confirmed that Ru4 obviously inhibited tumor growth. Ru4 is a promising candidate to be developed as a chemotherapeutic agent.

Keywords: Anticancer activity; Apoptosis; DNA damage; Plumbagin; Ruthenium(II) polypyridyl complexes.