An
antineoplastic alkaloid ellipticine is a
prodrug, whose pharmacological efficiency is dependent on its
cytochrome P450 (CYP)- and/or
peroxidase-mediated activation in target tissues. The aim of this review was to summarize our knowledge on the molecular mechanisms of
ellipticine action in the
cancer cells. The CYP-mediated
ellipticine metabolites 9-hydroxy- and
7-hydroxyellipticine and the product of
ellipticine oxidation by
peroxidases, the
ellipticine dimer, are the detoxication metabolites of this compound. In contrast, two carbenium
ions, ellipticine-13-ylium and ellipticine-12-ylium, derived from two activation
ellipticine metabolites,
13-hydroxyellipticine and
12-hydroxyellipticine, generate two major
deoxyguanosine adducts in
DNA found in the 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
glioblastoma U87MG cells in vitro and in rat
breast carcinoma in vivo. Formation of these covalent
DNA adducts by
ellipticine is the predominant mechanism of its cytotoxicity and anti-
tumor activity to these
cancer cell lines.
Ellipticine is also an inducer of CYP1A, 1B1, and 3A4
enzymes in the
cancer cells and/or in vivo in rats exposed to this compound, thus modulating its own pharmacological efficiencies. The study forms the basis to further predict the susceptibility of human
cancers to
ellipticine and suggests that this
alkaloid for treatment in combination with CYP and/or
peroxidase gene transfer increasing the anticancer potential of this
prodrug. It also suggests
ellipticine reactive metabolites
13-hydroxyellipticine and
12-hydroxyellipticine to be good candidates for targeting to
tumors absent from the CYP and
peroxidase activation
enzymes.