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

Area of Science:

• Coordination Chemistry
• Chemical Biology
• Cancer Research

Background:

• Thioredoxin reductase (TrxR) is overexpressed in human cancers and crucial for redox signaling.
• TrxR is an attractive therapeutic target for developing novel anticancer agents.
• Ruthenium(II) complexes are explored for their potential anticancer properties.

Purpose of the Study:

• To synthesize and characterize novel Ruthenium(II) complexes with salicylate ligands.
• To evaluate the anticancer activity and toxicity profile of these complexes.
• To elucidate the mechanism of action of the most potent complex in cancer cells.

Main Methods:

• Synthesis and characterization of three Ru(II) complexes: [Ru(phen)2(SA)], [Ru(dmb)2(SA)], and [Ru(bpy)2(SA)].
• In vitro evaluation of anticancer activity against cancer cell lines and normal cell lines.
• Mechanistic studies in A549 cells, including apoptosis induction, cell cycle analysis, TrxR inhibition, ROS generation, mitochondrial dysfunction, DNA damage, and signaling pathway analysis (MAPK, AKT).

Main Results:

• Complex 1, [Ru(phen)2(SA)], demonstrated significant anticancer activity comparable to cisplatin against cancer cell lines.
• Complex 1 exhibited low toxicity towards the normal cell line BEAS-2B, indicating selectivity.
• Complex 1 selectively inhibited TrxR activity, leading to increased reactive oxygen species (ROS), mitochondrial dysfunction, DNA damage, MAPK activation, and AKT suppression, ultimately causing apoptosis in A549 cells.

Conclusions:

• The synthesized Ru(II) complex [Ru(phen)2(SA)] is a potent and selective anticancer agent.
• Its mechanism involves TrxR inhibition, oxidative stress induction, and subsequent apoptosis.
• This complex represents a promising candidate for further development as a targeted cancer therapy.