Effects of polyamines on the DNA-reactive properties of dimeric mithramycin complexed with cobalt (II): Implications for anticancer therapy. Biochemistry [Biochemistry] Journal article

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 inverted exclamation markVCo(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 inverted exclamation markVCo(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 37oC), 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 inverted exclamation markVCo(II). Our study suggests a novel method for enhancing the anticancer activity of DNA-binding metalloantibiotics through polyamine depletion.

Biochemistry [Biochemistry]