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.

• Authors: Zhiqin Deng, Lianling Yu, Wenqiang Cao, Wenjie Zheng, Tianfeng Chen
• Journal: ChemMedChem (ChemMedChem) Vol. 10 Issue 6 Pg. 991-8 (Jun 2015) ISSN: 1860-7187 [Electronic] Germany
• PMID: 25914192 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Chemical References

• Pyridines
• Radiation-Sensitizing Agents
• Reactive Oxygen Species
• Ruthenium Compounds
• TP53 protein, human
• Tumor Suppressor Protein p53

Topics

• Cell Cycle Checkpoints (radiation effects)
• DNA Damage
• Drug Design
• Humans
• Pyridines (chemistry, pharmacology)
• Radiation-Sensitizing Agents (chemistry, pharmacology)
• Reactive Oxygen Species (metabolism)
• Ruthenium Compounds (chemistry, pharmacology)
• Structure-Activity Relationship
• Tumor Suppressor Protein p53 (metabolism)