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

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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 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.

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Abbreviations

Mith:

Mithramycin

CD:

Circular dichroism

UV:

Ultraviolet

SPR:

Surface plasmon resonance

K a :

Association equilibrium constant

K d :

Dissociation equilibrium constant

k a :

Association rate constant

k d :

Dissociation rate constant

SC:

Supercoiled

OC:

Open circular

L:

Linear

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Acknowledgments

This work was supported by the NSC Grant 100-2113-M-005-004-MY3 to M.-H. H. We thank Dr. Andrew H.J. Wang and Lou-Sing Kan for help in making this research possible.

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Authors and Affiliations

  1. Institute of Genomics and Bioinformatics, National Chung Hsing University, Taichung, 402, Taiwan

    Chun-Wei Hsu & Ming-Hon Hou

  2. Department of Food Science, Nutrition, and Nutraceutical Biotechnology, Shih Chien University, Taipei, Taiwan

    Chia-Feng Kuo

  3. Institute of Biomedical Sciences, National Chung Hsing University, Taichung, 402, Taiwan

    Show-Mei Chuang

  4. Biotechnology Center, National Chung Hsing University, Taichung, 402, Taiwan

    Ming-Hon Hou

  5. Department of Life Science, National Chung Hsing University, Taichung, 402, Taiwan

    Ming-Hon Hou

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  1. Chun-Wei Hsu
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  2. Chia-Feng Kuo
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  3. Show-Mei Chuang
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  4. Ming-Hon Hou
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Corresponding author

Correspondence to Ming-Hon Hou.

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Hsu and Kuo contributed equally to this work.

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Hsu, CW., Kuo, CF., Chuang, SM. et al. Elucidation of the DNA-interacting properties and anticancer activity of a Ni(II)-coordinated mithramycin dimer complex. Biometals 26, 1–12 (2013). https://doi.org/10.1007/s10534-012-9589-8

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  • DOI: https://doi.org/10.1007/s10534-012-9589-8

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