The anti-tumor therapeutic ellipticine and its derivatives act as potent anticancer agents via a combined mechanism involving cell cycle arrest and induction of apoptosis. Cell death induced by ellipticine has been shown to engage a p53-dependent pathway, cell cycle arrest, interaction with several kinases and induction of the mitochondrial pathway of apoptotic cell death. Cell cycle arrest was shown to result from DNA damage caused by a variety of tumor chemotherapeutic agents; this is also the case for ellipticines. The prevalent DNA-mediated mechanisms of anti-tumor, mutagenic and cytotoxic activities of ellipticine are (i) intercalation into DNA, (ii) inhibition of DNA topoisomerase II activity, and (iii) covalent binding to DNA in vitro and in vivo after enzymatic activation by cytochrome P450 and/or peroxidase enzymes The mechanism leading to apoptosis by ellipticine is thought to also be associated with DNA damage, by inhibition of topoisomerase II and the covalent modification of DNA. In addition, the formation of ellipticine-DNA adducts ultimately can mutate cancer cells or initiate cell death. The aim of this review is to summarize our knowledge on the molecular mechanisms with the aim to explain the effectiveness of ellipticines as DNA-targeted chemotherapeutics in cancer cells.

Department of Biochemistry Charles University Prague Czech Republic

References provided by Crossref.org

Application of hepatic cytochrome b5/P450 reductase null (HBRN) mice to study the role of cytochrome b5 in the cytochrome P450-mediated bioactivation of the anticancer drug ellipticine

The impact of chemotherapeutic drugs on the CYP1A1-catalysed metabolism of the environmental carcinogen benzo[a]pyrene: Effects in human colorectal HCT116 TP53(+/+), TP53(+/-) and TP53(-/-) cells

The Histone Deacetylase Inhibitor Valproic Acid Exerts a Synergistic Cytotoxicity with the DNA-Damaging Drug Ellipticine in Neuroblastoma Cells

Cytochrome b5 plays a dual role in the reaction cycle of cytochrome P450 3A4 during oxidation of the anticancer drug ellipticine

Heterologous expression of human cytochrome P450 2S1 in Escherichia coli and investigation of its role in metabolism of benzo[a]pyrene and ellipticine

Induced expression of microsomal cytochrome b5 determined at mRNA and protein levels in rats exposed to ellipticine, benzo[a]pyrene, and 1-phenylazo-2-naphthol (Sudan I)

The anticancer drug ellipticine activated with cytochrome P450 mediates DNA damage determining its pharmacological efficiencies: studies with rats, Hepatic Cytochrome P450 Reductase Null (HRN™) mice and pure enzymes

Formation of DNA adducts by ellipticine and its micellar form in rats - a comparative study