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)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.
Department of Chemistry, Jinan University, Guangzhou 510632, (P.R. China).
Zhiqin
Z
Deng
Department of Chemistry, Jinan University, Guangzhou 510632, (P.R. China).
Lianling
L
Yu
Department of Chemistry, Jinan University, Guangzhou 510632, (P.R. China).
Wenqiang
W
Cao
Department of Chemistry, Jinan University, Guangzhou 510632, (P.R. China).
Wenjie
W
Zheng
Department of Chemistry, Jinan University, Guangzhou 510632, (P.R. China). tchentf@jnu.edu.cn.
Tianfeng
T
Chen
D059447:Cell Cycle Checkpoints / Q000528:radiation effects; D004249:DNA Damage; D015195:Drug Design; D006801:Humans; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D011838:Radiation-Sensitizing Agents / Q000737:chemistry / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D017975:Ruthenium Compounds / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D011725:Pyridines; D011838:Radiation-Sensitizing Agents; D017382:Reactive Oxygen Species; D017975:Ruthenium Compounds; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53
antitumor agents; apoptosis; bioinorganic chemistry; p53; radiosensitizers; ruthenium