The impact of spermine competition on the efficacy of DNA-binding Fe(II), Co(II), and Cu(II) complexes of dimeric chromomycin A(3).
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 6mM 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 2mM) 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.
Lu
Wen-Je
WJ
Biotechnology Center, National Chung Hsing University, Taichung 402, Taiwan.
Wang
Hui-Min
HM
Yuann
Jeu-Ming P
JM
Huang
Chun-Yu
CY
Hou
Ming-Hon
MH
D000903:Antibiotics, Antineoplastic / Q000737:chemistry / Q000378:metabolism*; D045744:Cell Line, Tumor; D014128:Chromomycin A3 / Q000737:chemistry / Q000378:metabolism*; D003035:Cobalt / Q000378:metabolism; D056831:Coordination Complexes / Q000737:chemistry / Q000378:metabolism*; D003300:Copper / Q000378:metabolism; D004247:DNA / Q000378:metabolism*; D019281:Dimerization; D006801:Humans; D007501:Iron / Q000378:metabolism; D013096:Spermine / Q000378:metabolism*
D000903:Antibiotics, Antineoplastic; D056831:Coordination Complexes; D013096:Spermine; D003035:Cobalt; D003300:Copper; D004247:DNA; D014128:Chromomycin A3; D007501:Iron