Rational Design of Ruthenium Complexes Containing 2,6-Bis(benzimidazolyl)pyridine Derivatives with Radiosensitization Activity by Enhancing p53 Activation

The rational design of metal-based complexes is an effective strategy for the discovery of potent sensitizers for use in cancer radiotherapy. In this study, we synthesized three ruthenium complexes containing bis-benzimidazole derivatives: Ru(bbp)Cl-3 (1), [Ru(bbp)(2)]Cl-2 (2a) (in which bbp=2,6-bis(benzimidazol-1-yl)pyridine), and [Ru(bnbp)(2)]Cl-2 (2b) (where bnbp=2,6-bis-(6-nitrobenzimidazol-2-yl)pyridine). We evaluated their radiosensitization capacities in vitro and mechanisms of action. Complex 2b was found to be particularly effective in sensitizing human melanoma A375 cells toward radiation, with a sensitivity enhancement ratio of 2.4. Along with this potency, complex 2b exhibited a high degree of selectivity between human cancer and normal cells. Mechanistic studies revealed that 2b promotes radiation-induced accumulation of intracellular reactive oxygen species (ROS) by reacting with cellular glutathione (GSH) and then causing DNA stand breaks. The subsequent DNA damage induces phosphorylation of p53 (p-p53) and upregulates the expression levels of p21, which inhibits the expression of cyclin-B, leading to G2M arrest. Moreover, p-p53 activates caspases-3 and -8, triggers cleavage of poly(ADP-ribose) polymerase (PARP), finally resulting in apoptosis. Taken together, the results of this study provide a strategy for the design of ruthenium-based radiosensitizers for use in cancer therapy.