Ruthenium(II) salicylate complexes inducing ROS-mediated apoptosis by targeting thioredoxin reductase

J Inorg Biochem. 2019 Apr:193:112-123. doi: 10.1016/j.jinorgbio.2019.01.011. Epub 2019 Jan 25.

Abstract

Thioredoxin reductase (TrxR), a major component of the thioredoxin system, makes a critical role in regulating cellular redox signaling and is found to be overexpressed in many human cancer cells. TrxR has become an attractive target for anticancer agents. In this work, three Ru(II) complexes with salicylate as ligand, [Ru(phen)2(SA)] (phen = 1,10-phenanthroline, SA = salicylate, 1), [Ru(dmb)2(SA)] (dmb = 4,4'-dimethyl-2,2'-bipyridine, 2) and [Ru(bpy)2(SA)] (bpy = 2,2'-bipyridine, 3), were synthesized and characterized. The anticancer effect exerted by them was evaluated. Complex 1 was found to exhibit obvious anticancer activity, in comparison with cisplatin, against cancer cell lines, while displaying low toxicity to the normal cell line BEAS-2B. The mechanism of complex 1 cancer cell growth suppress was investigated in A549 cells. Complex 1 exerted its anticancer through inducing apoptosis and triggering cell cycle arrest at the G0/G1 phase. Complex 1 can selectively inhibit TrxR activity and thus promote the generation and accumulation of reactive oxygen species (ROS), which subsequently trigger mitochondrial dysfunction and DNA damage, activate oxidative stress-sensitive mitogen activated protein kinase (MAPK), and suppress the protein kinase B (PKB or AKT) signal pathway, resulting in apoptosis in A549 cells.

Keywords: Apoptosis; ROS; Ru (II) complexes; Salicylate; Thioredoxin reductase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / toxicity
  • Apoptosis / drug effects*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Coordination Complexes / chemical synthesis
  • Coordination Complexes / pharmacology*
  • Coordination Complexes / toxicity
  • DNA Damage / drug effects
  • Drug Screening Assays, Antitumor
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / pharmacology
  • Enzyme Inhibitors / toxicity
  • G1 Phase Cell Cycle Checkpoints / drug effects
  • Humans
  • Mitochondria / metabolism
  • Reactive Oxygen Species / metabolism*
  • Ruthenium / chemistry
  • Salicylates / chemical synthesis
  • Salicylates / pharmacology*
  • Salicylates / toxicity
  • Signal Transduction / drug effects
  • Thioredoxin-Disulfide Reductase / antagonists & inhibitors*

Substances

  • Antineoplastic Agents
  • Coordination Complexes
  • Enzyme Inhibitors
  • Reactive Oxygen Species
  • Salicylates
  • Ruthenium
  • Thioredoxin-Disulfide Reductase