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Nucleic Acids Research 2005 33(4):1352-1361; doi:10.1093/nar/gki276
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Published online 1 March 2005

© The Author 2005. Published by Oxford University Press. All rights reserved
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Article

Mithramycin forms a stable dimeric complex by chelating with Fe(II): DNA-interacting characteristics, cellular permeation and cytotoxicity

Ming-Hon Hou1,2,3 and Andrew H.-J. Wang1,2,*

1Institute of Biological Chemistry, Academia Sinica Taipei, 115 Taiwan 2Institute of Biochemical Sciences, National Taiwan University Taipei, 106 Taiwan 3Department of Food Science, Nutrition and Nutraceutical Biotechnology, Shih Chien University Taipei, 104 Taiwan

*To whom correspondence should be addressed. Tel: +886 2 27881981; Fax: +886 2 27882043; Email: ahjwang{at}gate.sinica.edu.tw

Received December 28, 2004. Revised February 10, 2005. Accepted February 10, 2005.

Mith (mithramycin) forms a 2:1 stoichiometry drug–metal complex through the chelation with Fe(II) ion as studied using circular dichroism spectroscopy. The binding affinity between Mith and Fe(II) is much greater than other divalent metal ions, including Mg(II), Zn(II), Co(II), Ni(II) and Mn(II). The [(Mith)2–Fe(II)] complex binds to DNA and induces a conformational change of DNA. Kinetic analysis of surface plasmon resonance studies revealed that the [(Mith)2–Fe(II)] complex binds to DNA duplex with higher affinity compared with the [(Mith)2–Mg(II)] complex. A molecular model of the Mith-DNA–Metal(II) complex is presented. DNA-break assay showed that the [(Mith)2–Fe(II)] complex was capable of promoting the one-strand cleavage of plasmid DNA in the presence of hydrogen peroxide. Intracellular Fe(II) assays and fluorescence microscopy studies using K562 indicated that this dimer complex maintains its structural integrity and permeates into the inside of K562 cells, respectively. The [(Mith)2–Fe(II)] complex exhibited higher cytotoxicity than the drug alone in some cancer cell lines, probably related to its higher DNA-binding and cleavage activity. Evidences obtained in this study suggest that the biological effects caused by the [(Mith)2–Fe(II)] complex may be further explored in the future.


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