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

• Published in: Biometals 2013-02, Vol.26 (1), p.1-12
• Main Authors: Hsu, Chun-Wei, Kuo, Chia-Feng, Chuang, Show-Mei, Hou, Ming-Hon
• Format: Article
• Language: English
• Subjects: Antibiotics, Antineoplastic - chemistry; Antibiotics, Antineoplastic - pharmacology; Biochemistry; Biological effects; Biomedical and Life Sciences; Cancer therapies; Cell Biology; Chelating Agents - chemistry; Chelating Agents - pharmacology; Chelation; Coordination Complexes - chemistry; Coordination Complexes - pharmacology; Cytotoxicity; Deoxyribonucleic acid; DNA; DNA polymerase; Drug Screening Assays, Antitumor; Gene expression; Gene Expression - drug effects; HeLa Cells; Hep G2 Cells; Humans; Hydrogen peroxide; Inhibitory Concentration 50; Inverted Repeat Sequences; Iron - chemistry; Life Sciences; Medicine/Public Health; Metals; Microbiology; Nickel; Nickel - chemistry; Pharmacology/Toxicology; Plant Physiology; Plasmids - chemistry; Plicamycin - chemistry; Plicamycin - pharmacology; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - metabolism; Surface Plasmon Resonance; Thiazolidinediones - chemistry; Transition Temperature
• ISSN: 0966-0844; 1572-8773
• DOI: 10.1007/s10534-012-9589-8

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.