This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kim, M.-Y. Articles by Hurley, L. H. Search for Related Content PubMed PubMed Citation Articles by Kim, M.-Y. Articles by Hurley, L. H.

The Different Biological Effects of Telomestatin and TMPyP4 Can Be Attributed to Their Selectivity for Interaction with Intramolecular or Intermolecular G-Quadruplex Structures

College of Pharmacy [M-Y. K., M. G-G., L. H. H.], and Department of Chemistry [L. H. H.], The University of Arizona, Tucson, Arizona 85721; Arizona Cancer Center, Tucson, Arizona 85724 [M-Y. K., M. G-G., L. H. H.]; Institute for Drug Development, San Antonio, Texas 78245 [E. I.]; and Department of Biology, Georgetown University, Washington, DC 20057 [D. N.]

Demonstration of the existence of G-quadruplex structures in telomeres of Stylonychia macronuclei and in the promoter of c-myc in human cells has validated these secondary DNA structures as potential targets for drug design. The next important issue is the selectivity of G-quadruplex-interactive agents for the different types of G-quadruplex structures. In this study, we have taken an important step in associating specific biological effects of these drugs with selective interaction with either intermolecular or intramolecular G-quadruplex structures formed in telomeres. Telomestatin is a natural product isolated from Streptomyces anulatus 3533-SV4 and has been shown to be a very potent telomerase inhibitor through its G-quadruplex interaction. We have demonstrated that telomestatin interacts preferentially with intramolecular versus intermolecular G-quadruplex structures and also has a 70-fold selectivity for intramolecular G-quadruplex structures over duplex DNA. Telomestatin is able to stabilize G-quadruplex structures that are formed from duplex human telomeric DNA as well as from single-stranded DNA. Importantly, telomestatin stabilizes these G-quadruplex structures in the absence of monovalent cations, which is a unique characteristic among G-quadruplex-interactive compounds. At noncytotoxic concentrations, telomestatin suppresses the proliferation of telomerase-positive cells within several weeks. In contrast, TMPyP4, a compound that preferentially facilitates the formation of intermolecular G-quadruplex structures, suppresses the proliferation of alternative lengthening of telomeres (ALT)-positive cells as well as telomerase-positive cells. We have also demonstrated that TMPyP4 induces anaphase bridges in sea urchin embryos, whereas telomestatin did not have this effect, leading us to conclude that the selectivity of telomestatin for intramolecular G-quadruplex structures and TMPyP4 for intermolecular G-quadruplex structures is important in mediating different biological effects: stabilization of intramolecular G-quadruplex structures produces telomerase inhibition and accelerated telomere shortening, whereas facilitation of the formation of intermolecular G-quadruplex structures induces the formation of anaphase bridges.

This article has been cited by other articles:

				D. Sun and L. H Hurley Telomestatin as a Structural Probe for Targeting G-quadruplexes in Telomeric and Promoter Regions Am. Assoc. Cancer Res. Educ. Book, April 12, 2008; 2008(1): 315 - 318. [Abstract] [Full Text] [PDF]

				J. Tang, Z.-y. Kan, Y. Yao, Q. Wang, Y.-h. Hao, and Z. Tan G-quadruplex preferentially forms at the very 3' end of vertebrate telomeric DNA Nucleic Acids Res., March 27, 2008; 36(4): 1200 - 1208. [Abstract] [Full Text] [PDF]

				B. Brassart, D. Gomez, A. D. Cian, R. Paterski, A. Montagnac, K.-H. Qui, N. Temime-Smaali, C. Trentesaux, J.-L. Mergny, F. Gueritte, et al. A New Steroid Derivative Stabilizes G-Quadruplexes and Induces Telomere Uncapping in Human Tumor Cells Mol. Pharmacol., September 1, 2007; 72(3): 631 - 640. [Abstract] [Full Text] [PDF]

				C. M. Barbieri, A. R. Srinivasan, S. G. Rzuczek, J. E. Rice, E. J. LaVoie, and D. S. Pilch Defining the mode, energetics and specificity with which a macrocyclic hexaoxazole binds to human telomeric G-quadruplex DNA Nucleic Acids Res., May 11, 2007; 35(10): 3272 - 3286. [Abstract] [Full Text] [PDF]

				A. Cheng, K. Shin-ya, R. Wan, S.-c. Tang, T. Miura, H. Tang, R. Khatri, M. Gleichman, X. Ouyang, D. Liu, et al. Telomere Protection Mechanisms Change during Neurogenesis and Neuronal Maturation: Newly Generated Neurons Are Hypersensitive to Telomere and DNA Damage J. Neurosci., April 4, 2007; 27(14): 3722 - 3733. [Abstract] [Full Text] [PDF]

				D. Gomez, T. Wenner, B. Brassart, C. Douarre, M.-F. O'Donohue, V. El Khoury, K. Shin-ya, H. Morjani, C. Trentesaux, and J.-F. Riou Telomestatin-induced Telomere Uncapping Is Modulated by POT1 through G-overhang Extension in HT1080 Human Tumor Cells J. Biol. Chem., December 15, 2006; 281(50): 38721 - 38729. [Abstract] [Full Text] [PDF]

				D. Gomez, M.-F. O'Donohue, T. Wenner, C. Douarre, J. Macadre, P. Koebel, M.-J. Giraud-Panis, H. Kaplan, A. Kolkes, K. Shin-ya, et al. The G-quadruplex Ligand Telomestatin Inhibits POT1 Binding to Telomeric Sequences In vitro and Induces GFP-POT1 Dissociation from Telomeres in Human Cells. Cancer Res., July 15, 2006; 66(14): 6908 - 6912. [Abstract] [Full Text] [PDF]

				X. Shi and J. B. Chaires Sequence- and structural-selective nucleic acid binding revealed by the melting of mixtures Nucleic Acids Res., January 23, 2006; 34(2): e14 - e14. [Abstract] [Full Text] [PDF]

				A. J. Zaug, E. R. Podell, and T. R. Cech Human POT1 disrupts telomeric G-quadruplexes allowing telomerase extension in vitro PNAS, August 2, 2005; 102(31): 10864 - 10869. [Abstract] [Full Text] [PDF]

				C. Douarre, D. Gomez, H. Morjani, J.-M. Zahm, M.-F. O'Donohue, L. Eddabra, P. Mailliet, J.-F. Riou, and C. Trentesaux Overexpression of Bcl-2 is associated with apoptotic resistance to the G-quadruplex ligand 12459 but is not sufficient to confer resistance to long-term senescence Nucleic Acids Res., April 14, 2005; 33(7): 2192 - 2203. [Abstract] [Full Text] [PDF]

				I. N. Rujan, J. C. Meleney, and P. H. Bolton Vertebrate telomere repeat DNAs favor external loop propeller quadruplex structures in the presence of high concentrations of potassium Nucleic Acids Res., April 7, 2005; 33(6): 2022 - 2031. [Abstract] [Full Text] [PDF]

				T. Zhou, G. Chen, Y. Wang, Q. Zhang, M. Yang, and T. Li Synthesis of unimolecularly circular G-quadruplexes as prospective molecular probes Nucleic Acids Res., December 8, 2004; 32(21): e173 - e173. [Abstract] [Full Text] [PDF]

				C. Leonetti, S. Amodei, C. D'Angelo, A. Rizzo, B. Benassi, A. Antonelli, R. Elli, M. F. G. Stevens, M. D'Incalci, G. Zupi, et al. Biological Activity of the G-Quadruplex Ligand RHPS4 (3,11-Difluoro-6,8,13-trimethyl-8H-quino[4,3,2-kl]acridinium methosulfate) Is Associated with Telomere Capping Alteration Mol. Pharmacol., November 1, 2004; 66(5): 1138 - 1146. [Abstract] [Full Text] [PDF]

				Y. He, R. D. Neumann, and I. G. Panyutin Intramolecular quadruplex conformation of human telomeric DNA assessed with 125I-radioprobing Nucleic Acids Res., October 8, 2004; 32(18): 5359 - 5367. [Abstract] [Full Text] [PDF]

				D. Gomez, R. Paterski, T. Lemarteleur, K. Shin-ya, J.-L. Mergny, and J.-F. Riou Interaction of Telomestatin with the Telomeric Single-strand Overhang J. Biol. Chem., October 1, 2004; 279(40): 41487 - 41494. [Abstract] [Full Text] [PDF]

				G. Minotti, P. Menna, E. Salvatorelli, G. Cairo, and L. Gianni Anthracyclines: Molecular Advances and Pharmacologic Developments in Antitumor Activity and Cardiotoxicity Pharmacol. Rev., June 1, 2004; 56(2): 185 - 229. [Abstract] [Full Text] [PDF]

				D. Gomez, T. Lemarteleur, L. Lacroix, P. Mailliet, J.-L. Mergny, and J.-F. Riou Telomerase downregulation induced by the G-quadruplex ligand 12459 in A549 cells is mediated by hTERT RNA alternative splicing Nucleic Acids Res., January 16, 2004; 32(1): 371 - 379. [Abstract] [Full Text] [PDF]

				D. Gomez, N. Aouali, A. Londono-Vallejo, L. Lacroix, F. Megnin-Chanet, T. Lemarteleur, C. Douarre, K. Shin-ya, P. Mailliet, C. Trentesaux, et al. Resistance to the Short Term Antiproliferative Activity of the G-quadruplex Ligand 12459 Is Associated with Telomerase Overexpression and Telomere Capping Alteration J. Biol. Chem., December 12, 2003; 278(50): 50554 - 50562. [Abstract] [Full Text] [PDF]