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.
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| Authors | Saptaparni Ghosh, Anirban Kar, Shantanu Chowdhury, Dipak Dasgupta |
| Journal | Biochemistry (Biochemistry) Vol. 52 Issue 24 Pg. 4127-37 (Jun 18 2013) ISSN: 1520-4995 [Electronic] United States |
| PMID | 23697684 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
| Chemical References |
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