title: Ellipticine binds to a human telomere sequence: an additional mode of action as a putative anticancer agent?
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.
authors.affiliation: Biophysics Division, Saha Institute of Nuclear Physics , Block-AF, Sector- I, Bidhan Nagar, Kolkata 700064, India.
authors.forename: Saptaparni
authors.initials: S
authors.lastname: Ghosh
authors.forename: Anirban
authors.initials: A
authors.lastname: Kar
authors.forename: Shantanu
authors.initials: S
authors.lastname: Chowdhury
authors.forename: Dipak
authors.initials: D
authors.lastname: Dasgupta
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy; D002152:Calorimetry, Differential Scanning; D045744:Cell Line, Tumor; D002942:Circular Dichroism; D004247:DNA / Q000737:chemistry; D004611:Ellipticines / Q000494:pharmacology*; D005260:Female; D054856:G-Quadruplexes; D006801:Humans; D007364:Intercalating Agents / Q000494:pharmacology; D009690:Nucleic Acid Conformation; D011485:Protein Binding; D013050:Spectrometry, Fluorescence; D016615:Telomere / Q000187:drug effects* / Q000648:ultrastructure*
chemical_list: D000970:Antineoplastic Agents; D004611:Ellipticines; D007364:Intercalating Agents; C034192:ellipticine; D004247:DNA