title: 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.
authors.affiliation: Institute of Genomics and Bioinformatics, National Chung Hsing University, Taichung, 402, Taiwan.
authors.forename: Chun-Wei
authors.initials: CW
authors.lastname: Hsu
authors.forename: Chia-Feng
authors.initials: CF
authors.lastname: Kuo
authors.forename: Show-Mei
authors.initials: SM
authors.lastname: Chuang
authors.forename: Ming-Hon
authors.initials: MH
authors.lastname: Hou
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000737:chemistry* / Q000494:pharmacology; D002614:Chelating Agents / Q000737:chemistry* / Q000494:pharmacology; D056831:Coordination Complexes / Q000737:chemistry* / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D015870:Gene Expression / Q000187:drug effects; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D055029:Inverted Repeat Sequences; D007501:Iron / Q000737:chemistry; D009532:Nickel / Q000737:chemistry*; D010957:Plasmids / Q000737:chemistry; D008926:Plicamycin / Q000737:chemistry* / Q000494:pharmacology; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D020349:Surface Plasmon Resonance; D045162:Thiazolidinediones / Q000737:chemistry*; D044366:Transition Temperature
chemical_list: D000903:Antibiotics, Antineoplastic; D002614:Chelating Agents; D056831:Coordination Complexes; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D045162:Thiazolidinediones; C114240:DN 108; D009532:Nickel; D007501:Iron; D008926:Plicamycin