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標題: Elucidation of the DNA-interacting properties and anticancer activity of a Ni(II)-coordinated mithramycin dimer complex
作者: Hsu, Chun-Wei
Kuo, Chia-Feng
Chuang, Show-Mei
Hou, Ming-Hon
關鍵字: Mithramycin
Divalent metal
DNA cleavage
c-Myc expression
Cell viability
摘要: 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 DNAbreak assay indicated that NiII(Mith)2 is capable of promoting one-strand cleavage of plasmid DNA in thepresenceofhydrogenperoxide; theDNAcleavage rate of NiII(Mith)2 was calculated to be 4.1 9 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 DNAbinding and cleavage activity. The evidence obtained in this study suggests that the biological effects of NiII(Mith)2 require further investigation in the future.
ISSN: 0966-0844
Appears in Collections:基因體暨生物資訊學研究所



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