From Oxidative to Reductive Stress: Metal-Dependent Mechanisms of Cancer Cell Death in Troxerutin Complexes.

Flavonoid-oxidovanadium(IV) (VO) complexes have been widely investigated as anticancer agents because of their ability to induce oxidative stress in tumor cells. In contrast, Zn complexes with ligands capable of reducing intracellular reactive oxygen species (ROS) may exert antitumor effects through a reductive-stress mechanism. Herein, we report the synthesis and characterization of a Zn-troxerutin complex, its interaction with bovine serum albumin (BSA), and its anticancer activity. This study aims to correlate the chemical and biological properties of the complex after replacing a redox-active metal ion with a redox-inactive one. The Zn-troxerutin complex exhibited the same coordination mode and 1:1 metal-to-ligand stoichiometry as the VO analog. It showed dose-dependent antiproliferative activity at higher concentrations in A549, MDA-MB-231, and HCT-116 cancer cells, while reducing intracellular ROS. In HCT-116 cells, reductive stress was associated with increased glutathione (GSH) levels and mitochondrial membrane depolarization. The complex displayed greater anticancer efficacy than free troxerutin and selectivity toward cancer cells over normal HEK293 cells. BSA binding studies yielded positive ΔH and ΔS values, indicating that hydrophobic interactions drive complex formation, with binding constants within the optimal range for drug transport. These findings highlight Zn-troxerutin as a promising anticancer agent acting through reductive-stress pathways.