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

Abstract

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 (~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 4.1×10(-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.