Journal
CHEMMEDCHEM
Volume 10, Issue 6, Pages 991-998Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cmdc.201500127
Keywords
antitumor agents; apoptosis; bioinorganic chemistry; p53; radiosensitizers; ruthenium
Categories
Funding
- National High Technology Research and Development Program of China (863 Program) [SS2014AA020538]
- Science Foundation for Distinguished Young Scholars of Guangdong Province [S2013050014667]
- Foundation for High-level Talents in Higher Education of Guangdong
- Natural Science Foundation of China
- Research Fund for the Doctoral Program of Higher Education of China [20114401110004]
- Shenzhen Basic Research Grant [JCYJ20130401152508660]
- YangFan Innovative & Entrepreneurial Research Team Project [201312H05]
Ask authors/readers for more resources
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available