Ellipticine Binds to a Human Telomere Sequence: An
Additional Mode of Action as a Putative Anticancer Agent?
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Abstract
Polyguanine sequences fold into G-quadruplex
structures in the
presence of monovalent cations. It is accepted that the telomeric
DNA region consists of G-quadruplex structure. There are reports that
potential G-quadruplex forming motifs are also present in the promoter
region of some proto-oncogenes such as c-myc, c-kit, KRAS, etc. Small
molecules with the potential to stabilize the telomeric DNA quadruplex
have emerged as potential anticancer agents. We have studied the interaction
of ellipticine, a putative anticancer agent from a plant source, with
a human telomeric DNA sequence (H24). Spectroscopic and calorimetric
studies indicate that the association of ellipticine with H24 is an
entropically driven phenomenon with a 2:3 (H24:ellipticine) stoichiometry.
Though ellipticine binding does not induce any major structural perturbation
in H24, the association leads to formation of a complex with enhanced
thermal stability. An assay with the telomerase repeat amplification
protocol shows that ellipticine inhibits telomerase activity in MDAMB-231
breast cancer cell line extracts. This is the first report of the
quadruplex binding ability of ellipticine. Using the results, we propose
that along with DNA intercalation and/or topoisomerase II inhibition,
interaction with the telomeric DNA region and the resultant inhibition
of telomerase activity might be an additional mode of action for its
anticancer property