COX-2 targeting Ru-arene complexes from metal-ligand synergistic enhancement strategy for breast cancer therapy

Triple-negative breast cancer (TNBC) has been a significant therapeutic challenge, due to its aggressive and metastatic characteristics. Cyclooxygenase-2 (COX-2), which is frequently overexpressed in TNBC and implicated in tumor progression, is considered as a potent therapeutic target. In this study, we reported a novel Ru-arene complex, Ru-tol, utilizing a metal-ligand synergistic enhancement (MLSE) strategy. Toxic Ru-tol was synthesized from the non-toxic precursors aryl ruthenium azide and tolfenamic acid. Complex Ru-tol not only owned the enhanced antiproliferative performance, but also preserved the COX-2 inhibitory activity of tolfenamic acid. Ru-tol could induce the generation of intracellular reactive oxygen species (ROS), leading to the mitochondrial and nuclear damages, which ultimately results in the apoptotic and autophagic cell death. Moreover, Ru-tol significantly downregulated the expression of COX-2, matrix metalloproteinases (MMP)-2 and MMP-9, and effectively suppressed the cell migration and invasion. Ru-tol demonstrated supeior penetration capacity and antiproliferative efficacy in 3D multicellular tumor spheroids (MCTS), suggesting the potent clinical applications. This work not only demonstrated the efficiency of MLSE strategy for the development of novel anti-cancer metal-based drugs, but also presented a promising target for the TNBC treatment.