Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2005, 149(2):449-453 | DOI: 10.5507/bp.2005.078

OXIDATION OF AN ANTITUMOR DRUG ELLIPTICINE BY PEROXIDASES

Jitka Poljaková^a, Kristina Forsterová^a, Miroslav Šulc^a, Eva Frei^b, Marie Stiborová^a

^a Department of Biochemistry, Faculty of Science, Charles University, Albertov 2030, 12840 Prague 2, Czech Republic

^b Division of Molecular Toxicology, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg,

Germany

Ellipticine is a potent antineoplastic agent, whose mode of action is considered to be based mainly on DNA intercalation and/or inhibition of topoisomerase II. Since we found that ellipticine also forms the cytochrome P450 (CYP)-mediated covalent DNA adducts, this anticancer drug is considered to function as a pro-drug, whose pharmacological efficiency and/or genotoxic side effects are dependent on its enzymatic activation in target tissues. Here, we demonstrate that ellipticine is also oxidized by peroxidases, which are abundantly expressed in several target tumor tissues. Lactoperoxidase, myeloperoxidase and horseradish peroxidase were used as models. Peroxidases in the presence of hydrogen peroxide oxidize ellipticine to an ellipticine dimer and N²-oxide of ellipticine as the major and minor metabolite, respectively. Inhibition of the peroxidase-mediated ellipticine oxidation by radical scavengers ascorbate, glutathione and NADH suggests a one-electron mechanism of the oxidation. The implication of the oxidation of ellipticine by peroxidases in its mechanism of action is discussed.

Keywords: Ellipticine, Anticancer drug, Peroxidase, Cytochrome P450, Oxidation

Received: June 10, 2005; Accepted: September 25, 2005; Published: December 1, 2005  Show citation