Ruthenium complexes containing 2,6-bis(benzimidazolyl)pyridine derivatives induce cancer cell apoptosis by triggering DNA damage-mediated p53 phosphorylation.

Abstract

DNA has been identified as a primary target for anticancer drug design and remains one of the most promising biological receptors for the development of chemotherapeutic agents. We have previously demonstrated that ruthenium complex [Ru(bmbp)(phen)Cl]ClO(4) (RuBmP; bmbp = 2,6-bis(4-methylbenzimidazol-2-yl)pyridine) is a novel apoptosis-inducer by triggering mitochondria-mediated ROS overproduction in cancer cells. In the present work, the underlying mechanisms of the anticancer action of RuBmP were further elucidated by evaluating its DNA interaction properties and the regulating signalling pathways. Our results showed that RuBmP could effectively activate DNA strand breaks in A375 cells in a dose-dependent manner after cellular internalization. Phosphorylation of a DNA damage marker Histone H2A.X (Ser139) was thus up-regulated in treated cells. DNA damage subsequently activated p53 phosphorylation and inhibited the expression of Bcl-xL, resulting in activation of caspase-3, -8 and -9, and cleavage of poly(ADP-ribose) polymerase (PARP). The interactions between the complexes and cancer cell chromosomal and calf thymus DNA were characterized by UV-vis absorption, fluorescence intensity and viscosity measurements, which clearly demonstrated the intercalative binding of the complexes to DNA. Taken together, these results suggest that RuBmP, as a promising anticancer agent, induces cancer cell apoptosis by triggering DNA damage-mediated p53 phosphorylation.

• Authors: Linlin Li, Wenqiang Cao, Wenjie Zheng, Cundong Fan, Tianfeng Chen
• Journal: Dalton transactions (Cambridge, England : 2003) (Dalton Trans) Vol. 41 Issue 41 Pg. 12766-72 (Nov 07 2012) ISSN: 1477-9234 [Electronic] England
• PMID: 22968364 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 2,6-bis(benzimidazol-2-yl)pyridine
• Antineoplastic Agents
• Benzimidazoles
• H2AX protein, human
• Histones
• Proto-Oncogene Proteins c-bcl-2
• Pyridines
• Tumor Suppressor Protein p53
• Ruthenium

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Benzimidazoles (chemistry, pharmacology)
• Cell Line, Tumor
• DNA Damage
• Histones (metabolism)
• Humans
• Neoplasms (drug therapy, metabolism)
• Phosphorylation (drug effects)
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• Pyridines (chemistry, pharmacology)
• Ruthenium (chemistry, pharmacology)
• Tumor Suppressor Protein p53 (metabolism)