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

Abstract

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)Cl3 (1), [Ru(bbp)2 ]Cl2 (2 a) (in which bbp=2,6-bis(benzimidazol-1-yl)pyridine), and [Ru(bbp)2]Cl2 (2 b) (where bbp=2,6-bis-(6-nitrobenzimidazol-2-yl)pyridine). We evaluated their radiosensitization capacities in vitro and mechanisms of action. Complex 2 b 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 2 b exhibited a high degree of selectivity between human cancer and normal cells. Mechanistic studies revealed that 2 b 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.

Radiosensitisation of human colorectal cancer cells by ruthenium(II) arene anticancer complexes

“…This observation is also consistent with the radiosensitisation observed in p53-mutant DLD1 cells treated with large fractions of RT. These results in p53-wildtype cells are consistent with a previous study of a ruthenium complex containing a bis-benzimidazole derivative, which showed radiosensitising ability and G2/M cell cycle arrest in p53-wildtype A375 melanoma cells 39 40 . Our results, particularly in view of the chiral stability that we have demonstrated, identify AH54 and AH63 as promising radiosensitisers, particularly in cancer cells with wildtype p53 status.…”

A highly X-ray sensitive iridium prodrug for visualized tumor radiochemotherapy

“…3d, the SER of the designed prodrug Ir-NB was much higher than that of cisplatin (SER: 4.36) and other metalbased RSs reported in the literature. [30][31][32][33][34] These results indicated that the cancer-targeting delivery system facilitates the sensitization efficiency of the RS in curing malignant cells. The synergistic effect was further conrmed by the clonogenic survival assay ( Fig.…”

The development of ruthenium(ii) polypyridyl complexes and conjugates forin vitrocellular andin vivoapplications

“…306,307 In recent years, researchers have begun to evaluate the potential of Ru(II) polypyridyl complexes in such treatment regimes and have demonstrated that upon exposure to ionising radiation, a synergistic decrease in survival can be achieved in cancer cells pre-treated with Ru(II) polypyridyl complexes. 64,220,308,309 For example, Gill et al demonstrated that when HeLa cells were pre-treated with complex 71 (40 µM) for 20 hrs and exposed to 137 Cs-γ-rays with a dose of 6 Gy, a 7-fold decrease in cancer cell survival was achieved relative to radiation alone, as shown in Fig. 32b.…”