Elucidation of the DNA-interacting properties and anticancer activity of a Ni(II)-coordinated mithramycin dimer complex

Mithramycin (Mith) forms a drug-metal complex with a 2:1 stoichiometry by chelation with a Ni(II) ion, which was determined using circular dichroism spectroscopy. Mith exhibits an increased affinity (similar to 55 fold) for Ni(II) in the presence of DNA compared to the absence of DNA, suggesting that DNA acts as an effective template to facilitate chelation. Also, we characterized the DNA-acting properties of a Ni(II) derivative of Mith. Kinetic analysis using surface plasmon resonance and UV melting studies revealed that Ni-II(Mith)(2) binds to duplex DNA with a higher affinity compared to Mg-II(Mith)(2). The thermodynamic parameters revealed a higher free energy of formation for duplex DNA in the presence of Ni-II(Mith)(2) compared to duplex DNA in the presence of Mg-II(Mith)(2). The results of a DNA-break assay indicated that Ni-II(Mith)(2) is capable of promoting one-strand cleavage of plasmid DNA in the presence of hydrogen peroxide; the DNA cleavage rate of Ni-II(Mith)(2) was calculated to be 4.1 x 10(-4) s(-1). In cell-based experiments, Ni-II(Mith)(2) exhibited a more efficient reduction of c-myc and increased cytotoxicity compared to Mith alone because of its increased DNA-binding and cleavage activity. The evidence obtained in this study suggests that the biological effects of Ni-II(Mith)(2) require further investigation in the future.