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.