Extending Natures Leads: The Anticancer Agent Ellipticine

Abstract

The natural plant product ellipticine was isolated in 1959 from the Australian evergreen tree of the Apocynaceae family. This compound was found to be an extremely promising anticancer drug. The planar polycyclic structure was found to interact with DNA through intercalation, exhibiting a high DNA binding affinity (10(6) M(-1)). The presence of protonatable ring nitrogens distinguished ellipticine from other simple intercalators. Both monocationic and uncharged species were found to be present under physiological conditions. The positive charge stabilized the binding of ellipticine to nucleic acids, while the more lipophilic uncharged compound was shown to readily penetrate membrane barriers. The structural nature of these compounds offers a plausible basis for the implication of multiple modes of action, including DNA binding, interactions with membrane barriers, oxidative bioactivation and modification of enzyme function; most notably that of topoisomerase II and telomerase. Pharmacologically, a number of toxic side effects have been shown to be problematic, but the amenability of ellipticine towards systematic structural modification has permitted the extensive application of rational drug design. A number of successful ellipticine analogs have been designed and synthesized with improved toxicities and anticancer activities. More recently the synthetic focus has broadened to include the design of hybrid compounds, as well as drug delivery conjugates. Considerable research efforts have been directed towards gaining a greater understanding of the mechanism of action of these drugs that will aid further in the optimization of drug design.

Cytochrome b5 shifts oxidation of the anticancer drug ellipticine by cytochromes P450 1A1 and 1A2 from its detoxication to activation, thereby modulating its pharmacological efficacy

“…This work is, to our knowledge, the first study showing that cytochrome b 5 can alter not only the amounts but also the types of metabolites produced from a single substrate by one CYP.…”

“…It was suggested that the major mechanisms of its antitumor, mutagenic and cytotoxic activities are (i) intercalation into DNA [4,5], and (ii) inhibition of DNA topoisomerase II activity [2][3][4][5][6][7].…”

“…The lack of cytochrome b 5 in our reconstituted systems could therefore be a reason for the low activating capacity of isolated CYP1A1/2. We therefore investigated the role of cytochrome b 5 on CYP catalyzed oxidation of ellipticine. A reconstituted system consisting of pure CYP1A1 or 1A2 enzymes with NADPH:CYP reductase in liposomes with or without cytochrome b 5 was used.…”

The mechanism of cytotoxicity and DNA adduct formation by the anticancer drug ellipticine in human neuroblastoma cells

“…The mode of antitumor, cytotoxic and mutagenic action of ellipticine is considered to be based mainly on DNA damage such as intercalation into DNA [4,44], inhibition of topoisomerase II [4,[14][15][16], and formation of covalent DNA adducts mediated by CYPs and peroxidases [3,19,21,24,45]. Intercalation of ellipticine into DNA and inhibition of topoisomerase II occur in all cell types irrespective of their metabolic capacity, because of the general chemical properties of this drug and its affinity to DNA and topoisomerase II protein [4,9,45]. However, the formation of ellipticine-DNA adducts, which is dependent on ellipticine activation by CYPs and peroxidases, has not yet been proven as a general mechanism.…”

“…Ellipticine has been reported to arrest cell cycle progression by regulating the expression of cyclinB1 and Cdc2 as well as phosphorylation of Cdc2 [5,6], to induce apoptotic cell death by the generation of cytotoxic free radicals, the activation of Fas/Fas ligand system, the regulation of Bcl-2 family proteins [5][6][7][8], an increase of wild-type p53, the rescue of mutant p53 activity and the initiation of the mitochondrial apoptosis pathway [5,6,8,9]. Ellipticine also uncouples mitochondrial oxidative phosphorylation [10] and thereby disrupts the energy A c c e p t e d M a n u s c r i p t 5 balance of cells.…”