The Cytotoxicity of the Anticancer Drug Elesclomol Is Due to Oxidative Stress Indirectly Mediated Through Its Complex With Cu(II)

J Inorg Biochem. 2014 Aug;137:22-30. doi: 10.1016/j.jinorgbio.2014.04.004. Epub 2014 Apr 16.

Abstract

Elesclomol is an anticancer drug that is currently undergoing clinical trials. Elesclomol forms a strong 1:1 complex with Cu(II) and may exert its anticancer activity through the induction of oxidative stress and/or its ability to transport copper into the cell. A UV-vis spectrophotometric titration showed that Cu(I) also formed a 1:1 complex with elesclomol. Ascorbic acid, but not glutathione or NADH, potently reduced the Cu(II)-elesclomol complex to produce hydrogen peroxide. Even though hydrogen peroxide mediated reoxidation of the copper(I) produced by ascorbic acid reduction has the potential to lead to hydroxyl radical formation, electron paramagnetic resonance spin trapping experiments, either with or without added hydrogen peroxide, showed that the ascorbic acid-reduced Cu(II)-elesclomol complex could not directly generate damaging hydroxyl radicals. Both Cu(II)-elesclomol and elesclomol potently oxidized dichlorofluorescin in K562 cells. The highly specific copper chelators tetrathiomolybdate and triethylenetetramine were found to greatly reduce the cytotoxicity of both elesclomol and Cu(II)-elesclomol complex towards erythroleukemic K562 cells, consistent with a role for copper in the cytotoxicity of elesclomol. The superoxide dismutating activity of Cu(II)-elesclomol was much lower than that of Cu(II). Depletion of glutathione levels in K562 cells by treatment with buthionine sulfoximine sensitized cells to both elesclomol and Cu(II)-elesclomol. In conclusion, these results showed that elesclomol indirectly inhibited cancer cell growth through Cu(II)-mediated oxidative stress.

Keywords: Ascorbic acid; Copper; Dichlorofluorescin; Electron paramagnetic resonance; Elesclomol; Oxidative stress.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / chemistry
  • Coordination Complexes / administration & dosage
  • Coordination Complexes / chemistry*
  • Copper / chemistry
  • Copper / metabolism*
  • DNA Damage / drug effects
  • Free Radical Scavengers / metabolism
  • Humans
  • Hydrazines / administration & dosage
  • Hydrazines / chemistry*
  • Hydrogen Peroxide / metabolism
  • K562 Cells
  • Oxidation-Reduction
  • Oxidative Stress / drug effects*
  • Reactive Oxygen Species / metabolism

Substances

  • Antineoplastic Agents
  • Coordination Complexes
  • Free Radical Scavengers
  • Hydrazines
  • Reactive Oxygen Species
  • elesclomol
  • Copper
  • Hydrogen Peroxide