Effects of polyamines on the DNA-reactive properties of dimeric mithramycin complexed with cobalt(II): implications for anticancer therapy.
Few studies have examined the effects of polyamines on the action of DNA-binding anticancer drugs. Here, a Co(II)-mediated dimeric mithramycin (Mith) complex, (Mith)(2)-Co(II), was shown to be resistant to polyamine competition toward the divalent metal ion when compared to the Fe(II)-mediated drug complexes. Surface plasmon resonance experiments demonstrated that polyamines interfered with the binding capacity and association rates of (Mith)(2)-Co(II) binding to DNA duplexes, while the dissociation rates were not affected. Although (Mith)(2)-Co(II) exhibited the highest oxidative activity under physiological conditions (pH 7.3 and 37 degrees C), polyamines (spermine in particular) inhibited the DNA cleavage activity of the (Mith)(2)-Co(II) in a concentration-dependent manner. Depletion of intracellular polyamines by methylglyoxal bis(guanylhydrazone) (MGBG) enhanced the sensitivity of A549 lung cancer cells to (Mith)(2)-Co(II), most likely due to the decreased intracellular effect of polyamines on the action of (Mith)(2)-Co(II). Our study suggests a novel method for enhancing the anticancer activity of DNA-binding metalloantibiotics through polyamine depletion.
Hou
Ming-Hon
MH
Biotechnology Center, National Chung Hsing University, Taichung, 402 Taiwan. mhho@dragon.nchu.edu.tw
Lu
Wen-Je
WJ
Huang
Chun-Yu
CY
Fan
Ruey-Jane
RJ
Yuann
Jeu-Ming P
JM
D000903:Antibiotics, Antineoplastic / Q000378:metabolism / Q000627:therapeutic use / Q000633:toxicity*; D001667:Binding, Competitive; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects*; D002942:Circular Dichroism; D003035:Cobalt / Q000378:metabolism / Q000627:therapeutic use / Q000633:toxicity*; D004269:DNA, Bacterial / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004278:DNA, Superhelical / Q000037:antagonists & inhibitors / Q000378:metabolism; D019281:Dimerization; D006801:Humans; D008935:Mitoguazone / Q000633:toxicity; D008926:Plicamycin / Q000037:antagonists & inhibitors / Q000627:therapeutic use / Q000633:toxicity*; D013095:Spermidine / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D013096:Spermine / Q000037:antagonists & inhibitors / Q000494:pharmacology*
D000903:Antibiotics, Antineoplastic; D004269:DNA, Bacterial; D004278:DNA, Superhelical; D013096:Spermine; D003035:Cobalt; D008926:Plicamycin; D008935:Mitoguazone; D013095:Spermidine