Aquation Is a Crucial Activation Step for Anticancer Action of Ruthenium(II) Polypyridyl Complexes to Trigger Cancer Cell Apoptosis

Abstract

Aquation has been proposed as crucial chemical action step for ruthenium (Ru) complexes, but its effects on the action mechanisms remain elusive. Herein, we have demonstrated the aquation process of a potent Ru polypyridyl complex (RuBmp=[Ru(II) (bmbp)(phen)Cl]ClO4 , bmbp=2,6-bis(6-methylbenzimidazol-2-yl) pyridine, phen=phenanthroline) with a chloride ligand, and revealed that aquation of RuBmp effectively enhanced its hydrophilicity and cellular uptake, thus significantly increasing its anticancer efficacy. The aquation products (H-RuBmp=[Ru(II) (bmbp)(phen)Cl]ClO4 , [Ru(II) (bmbp)(phen)(H2 O)]ClO4 , bmbp) exhibited a much higher apoptosis-inducing ability than the intact complex, with involvement of caspase activation, mitochondria dysfunction, and interaction with cell membrane death receptors. H-RuBmp demonstrated a higher interaction potency with the cell membrane and induced higher levels of ROS overproduction in cancer cells to regulate the AKT, MAPK, and p53 signaling pathways. Taken together, this study could provide useful information for fine-tuning the rational design of next-generation metal medicines.

Investigation of inducing apoptosis in human lung cancer A549 cells and related mechanism of a ruthenium(II) polypyridyl complex

“…4A, phosphorylation of MAPKs was activated in Ru2-induced apoptotic pathways, and there was no significant change in phosphorylation of AKT. Notably, Ru2 treatment up-regulated the phosphorylation level of ERK (p-ERK) dramatically, which was not in accordance with previous reported of ruthenium complexes [8][9][10]. Moreover, the level of p-ERK increased in a time-dependent manner (Fig.…”

“…Although many studies on the abilities of Ru(II) polypyridyl complexes to modulate the ERK signaling pathways have been reported [8][9][10], data on the effect of these complexes on ERK activation and subsequent cellular responses remain limited. Hence, in this study, two compounds containing 2,2-bipyridine (bpy) ligands with 3-(pyrazin-2-yl)- [1,2,4] triazino [5,6-f] [1,10]phenanthroline (pztp) or 3-(pyridin-2-yl)- [1,2,4] triazino [5,6-f] [1,10]phenanthroline (pytp) as main ligands; Ru1 and Ru2 (Fig.…”

Synthesis, characterization, DNA binding/cleavage, cytotoxic, apoptotic, and antibacterial activities of V(IV), Mo(VI), and Ru(II) complexes containing a bioactive ONS‐donor chelating agent

“…Several studies supported our results of the apoptotic activation of ruthenium compounds on different cell lines. [ 101,102 ] However, the ruthenium compounds may have another way to destroy cancer cell besides apoptosis but needs more analysis to be confirmed which will be discussed in our future in vivo study.…”

Bufadienolides induce p53-mediated apoptosis in esophageal squamous cell carcinoma cells in�vitro and in�vivo

“…3 ). The activation of caspase-9 suggested the induction of the mitochondria-mediated apoptotic pathway, while the activation of caspase-8 indicated the induction of death receptor-mediated apoptosis ( 29 ). These results revealed that bufotalin induces ESCC cell apoptosis through the activation of caspase-mediated apoptosis, with the involvement of mitochondria and death receptors.…”