The impact of spermine competition on the efficacy of DNA-binding Fe(II), Co(II), and Cu(II) complexes of dimeric chromomycin A3

Wen-Je Lu, Hui-Min Wang, Jeu-Ming P. Yuann, Chun-Yu Huang, Ming-Hon Hou, Wen-Je Lu, Hui-Min Wang, Jeu-Ming P. Yuann, Chun-Yu Huang, Ming-Hon Hou, Wen-Je Lu, Hui-Min Wang, Jeu-Ming P. Yuann, Chun-Yu Huang, Ming-Hon Hou

Index: J. Inorg. Biochem. 103(12) , 1626-33, (2009)

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Abstract

Chromomycin (Chro) forms a 2:1 drug/metal complex through the chelation with Fe(II), Co(II), or Cu(II) ion. The effects of spermine on the interaction of Fe(II), Co(II), and Cu(II) complexes of dimeric Chro with DNA were studied. Circular dichroism (CD) measurements revealed that spermine strongly competed for the Fe(II) and Cu(II) cations in dimeric Chro-DNA complexes, and disrupted the structures of these complexes. However, the DNA-Co II(Chro) 2 complex showed extreme resistance to spermine-mediated competition for the Co(II) cation. According to surface plasmon resonance (SPR) experiments, a 6 mM concentration of spermine completely abolished the DNA-binding activity of Fe II(Chro) 2 and Cu II(Chro) 2 and interfered with the associative binding of Co II(Chro) 2 complexes to DNA duplexes, but only slightly affected dissociation. In DNA integrity assays, lower concentrations of spermine (1 and 2 mM) promoted DNA strand cleavage by Cu II(Chro) 2, whereas various concentrations of spermine protected plasmid DNA from damage caused by either Co II(Chro) 2 or Fe II(Chro) 2. Additionally, DNA condensation was observed in the reactions of DNA, spermine, and Fe II(Chro) 2. Despite the fact that Cu II(Chro) 2 and Fe II(Chro) 2 demonstrated lower DNA-binding activity than Co II(Chro) 2 in the absence of spermine, while Cu II(Chro) 2 and Fe II(Chro) 2 exhibited greater cytoxicity against HepG2 cells than Co II(Chro) 2, possibly due to competition of spermine for Fe(II) or Cu(II) in the dimeric Chro complex in the nucleus of the cancer cells. Our results should have significant relevance to future developments in metalloantibiotics for cancer therapy.