TY - JOUR
T1 - Mithramycin forms a stable dimeric complex by chelating with Fe(II)
T2 - DNA-interacting characteristics, cellular permeation and cytotoxicity
AU - Hou, Ming Hon
AU - Wang, Andrew H.J.
PY - 2005
Y1 - 2005
N2 - 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.
AB - 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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U2 - 10.1093/nar/gki276
DO - 10.1093/nar/gki276
M3 - Article
C2 - 15741187
AN - SCOPUS:14844361385
SN - 0305-1048
VL - 33
SP - 1352
EP - 1361
JO - Nucleic Acids Research
JF - Nucleic Acids Research
IS - 4
ER -
