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Elucidation of the DNA-interacting propertiesand anticancer activity of a Ni(II)-coordinatedmithramycin dimer complex

By Chun-Wei Hsu, Chia-Feng Kuo, Show-Mei Chuang and Ming-Hon Hou


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 NiII(Mith)2 binds to duplex DNA with a higher affinity compared to MgII(Mith)2. The thermodynamic parameters revealed a higher free energy of formation for duplex DNA in the presence of NiII(Mith)2 compared to duplex DNA in the presence of MgII(Mith)2. The results of a DNA-break assay indicated that NiII(Mith)2 is capable of promoting one-strand cleavage of plasmid DNA in the presence of hydrogen peroxide; the DNA cleavage rate of NiII(Mith)2 was calculated to be 4.1 × 10−4 s−1. In cell-based experiments, NiII(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 NiII(Mith)2 require further investigation in the future

Topics: Mithramycin, Dimer, Nickel(II), Divalent metal, DNA-binding, DNA cleavage, c-Myc expression, Cell viability
Year: 2014
DOI identifier: 10.1007/s10534-012-9589-8
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