Ellipticine is a potent
antineoplastic agent exhibiting multiple mechanisms of action. This
anticancer agent should be considered a
pro-drug, whose pharmacological efficiency and/or genotoxic side effects are dependent on its
cytochrome P450 (CYP)- and/or
peroxidase-mediated activation to species forming covalent
DNA adducts.
Ellipticine can also act as an inhibitor or inducer of biotransformation
enzymes, thereby modulating its own metabolism leading to its genotoxic and pharmacological effects. Here, a comparison of the toxicity of
ellipticine to human breast
adenocarcinoma MCF-7 cells,
leukemia HL-60 and CCRF-CEM cells,
neuroblastoma IMR-32, UKF-NB-3 and UKF-NB-4 cells and U87MG
glioblastoma cells and mechanisms of its action to these cells were evaluated. Treatment of all cells tested with
ellipticine resulted in inhibition of cell growth and proliferation. This effect was associated with formation of two covalent
ellipticine-derived
DNA adducts, identical to those formed by 13-hydroxy- and
12-hydroxyellipticine, the
ellipticine metabolites generated by CYP and
peroxidase enzymes, in MCF-7, HL-60, CCRF-CEM, UKF-NB-3, UKF-NB-4 and U87MG cells, but not in
neuroblastoma UKF-NB-3 cells. Therefore,
DNA adduct formation in most
cancer cell lines tested in this comparative study might be the predominant cause of their sensitivity to
ellipticine treatment, whereas other mechanisms of
ellipticine action also contribute to its cytotoxicity to
neuroblastoma UKF-NB-3 cells.