Molecular mechanisms of the biological activity of the anticancer drug elesclomol and its complexes with Cu(II), Ni(II) and Pt(II)

• The potent anticancer drug (bis)thiohydrazide amide elesclomol strongly binds Cu2 +.
• The Cu2 + complex is much more cytotoxic than the Ni2 + and Pt2 + complexes.
• A log stability constant of 24.2 was determined for the Cu(II)-elesclomol complex.
• Cu(II)-elesclomol efficiently oxidizes ascorbic acid.
• Elesclomol is cytotoxic by generating Cu(II)-mediated oxidative stress.

The bis(thiohydrazide) amide elesclomol has extremely potent antiproliferative activity and is currently in clinical trials as an anticancer agent. Elesclomol strongly binds copper and may be exerting its cell growth inhibitory effects by generating copper-mediated oxidative stress. Nickel(II) and platinum(II) complexes of elesclomol were synthesized and characterized in order to investigate if these biologically redox inactive metal complexes could also inhibit cell growth. The nickel(II)-elesclomol and platinum(II) elesclomol complexes were 34- and 1040-fold less potent than the copper(II)-elesclomol complex towards human leukemia K562 cells. These results support the conclusion that a redox active metal is required for elesclomol to exert its cell growth inhibitory activity. Copper(II)-elesclomol was also shown to efficiently oxidize ascorbic acid at physiological ascorbic acid concentrations. Reoxidation of the copper(I) thus produced would lead to production of damaging reactive oxygen species. An X-ray crystallographic structure determination of copper(II)-elesclomol showed that it formed a 1:1 neutral complex with a distorted square planar structure. The kinetics and equilibria of the competition reaction of the strong copper(II) chelator TRIEN with copper(II)-elesclomol were studied spectrophotometrically under physiological conditions. These results showed elesclomol bound copper(II) with a conditional stability constant 24-fold larger than TRIEN. A log stability constant of 24.2 was thus indirectly determined for the copper(II)-elesclomol complex.

The anticancer drug elesclomol strongly binds Cu2 +. The redox active Cu2 + complex was much more cytotoxic than the redox inactive Ni2 + and Pt2 + complexes. Thus elesclomol may exert its cytotoxicity through the formation of damaging reactive oxygen species mediated through the reduction and redox cycling of Cu2 +.Figure optionsDownload as PowerPoint slide