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 Grand, C. L. Articles by Bearss, D. J. Search for Related Content PubMed PubMed Citation Articles by Grand, C. L. Articles by Bearss, D. J.

Arizona Cancer Center, Tucson, Arizona 85724 [C. L. G., H. H., R. M. M., D. D. V. H., L. H. H., D. J. B.]; Institute for Drug Development, San Antonio, Texas 78245 [S. W.]; and College of Pharmacy, The University of Arizona, Tucson, Arizona 85721 [C. L. G., L. H. H.]

Cationic porphyrins are being studied as possible anticancer agents because of their ability to bind to and stabilize DNA guanine quadruplexes (G-quadruplexes). We have shown previously that the cationic porphyrin TMPyP4 is able to bind to and stabilize G-quadruplexes in human telomere sequences, resulting in inhibition of telomerase activity. To better understand the mechanism of action behind telomerase inhibition by TMPyP4, we performed a cDNA microarray analysis on cells treated with TMPyP4 and TMPyP2, a positional isomer of TMPyP4 that has low affinity for G-quadruplexes. Analysis of time course data from the microarray experiments revealed that TMPyP4 and TMPyP2 treatment altered the expression of several gene clusters. We found that c-MYC, an oncogene nearly ubiquitous in human tumors that bears the potential in its promoter to form a G-quadruplex, was among the genes specifically down-regulated by TMPyP4, but not by TMPyP2. The hTERT gene, which encodes the catalytic subunit of telomerase, is transcriptionally regulated by c-MYC, and we have found that TMPyP4 also causes a decrease in human telomerase reverse transcriptase transcripts, suggesting two possible mechanisms for the effect of TMPyP4 on telomerase activity. We also show that TMPyP4, but not TMPyP2, is able to prolong survival and decrease tumor growth rates in two xenograft tumor models. We believe that, because of the actions of TMPyP4 in decreasing both c-MYC protein levels and telomerase activity, as well as its anticancer effects in vivo, it is a worthwhile agent to pursue and develop further.

This article has been cited by other articles:

				R. K. Thakur, P. Kumar, K. Halder, A. Verma, A. Kar, J.-L. Parent, R. Basundra, A. Kumar, and S. Chowdhury Metastases suppressor NM23-H2 interaction with G-quadruplex DNA within c-MYC promoter nuclease hypersensitive element induces c-MYC expression Nucleic Acids Res., November 25, 2008; (2008) gkn919v1. [Abstract] [Full Text] [PDF]

				Z. Du, Y. Zhao, and N. Li Genome-wide analysis reveals regulatory role of G4 DNA in gene transcription Genome Res., February 1, 2008; 18(2): 233 - 241. [Abstract] [Full Text] [PDF]

				R. Zhang, Y. Lin, and C.-T. Zhang Greglist: a database listing potential G-quadruplex regulated genes Nucleic Acids Res., January 11, 2008; 36(suppl_1): D372 - D376. [Abstract] [Full Text] [PDF]

				L. Kelland Targeting the Limitless Replicative Potential of Cancer: The Telomerase/Telomere Pathway Clin. Cancer Res., September 1, 2007; 13(17): 4960 - 4963. [Abstract] [Full Text] [PDF]

				J. O'Neil, J. Grim, P. Strack, S. Rao, D. Tibbitts, C. Winter, J. Hardwick, M. Welcker, J. P. Meijerink, R. Pieters, et al. FBW7 mutations in leukemic cells mediate NOTCH pathway activation and resistance to {gamma}-secretase inhibitors J. Exp. Med., August 6, 2007; 204(8): 1813 - 1824. [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]

				M. W. Freyer, R. Buscaglia, K. Kaplan, D. Cashman, L. H. Hurley, and E. A. Lewis Biophysical Studies of the c-MYC NHE III1 Promoter: Model Quadruplex Interactions with a Cationic Porphyrin Biophys. J., March 15, 2007; 92(6): 2007 - 2015. [Abstract] [Full Text] [PDF]

				J. L. Huppert and S. Balasubramanian G-quadruplexes in promoters throughout the human genome Nucleic Acids Res., January 28, 2007; 35(2): 406 - 413. [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]

				S. Cogoi and L. E. Xodo G-quadruplex formation within the promoter of the KRAS proto-oncogene and its effect on transcription. Nucleic Acids Res., January 1, 2006; 34(9): 2536 - 2549. [Abstract] [Full Text] [PDF]

				J. C. Cookson, F. Dai, V. Smith, R. A. Heald, C. A. Laughton, M. F. G. Stevens, and A. M. Burger Pharmacodynamics of the G-Quadruplex-Stabilizing Telomerase Inhibitor 3,11-Difluoro-6,8,13-trimethyl-8H-quino[4,3,2-kl]acridinium methosulfate (RHPS4) in Vitro: Activity in Human Tumor Cells Correlates with Telomere Length and Can Be Enhanced, or Antagonized, with Cytotoxic Agents Mol. Pharmacol., December 1, 2005; 68(6): 1551 - 1558. [Abstract] [Full Text] [PDF]

				J. Li, J. J. Correia, L. Wang, J. O. Trent, and J. B. Chaires Not so crystal clear: the structure of the human telomere G-quadruplex in solution differs from that present in a crystal Nucleic Acids Res., August 16, 2005; 33(14): 4649 - 4659. [Abstract] [Full Text] [PDF]

				S. Etzioni, A. Yafe, S. Khateb, P. Weisman-Shomer, E. Bengal, and M. Fry Homodimeric MyoD Preferentially Binds Tetraplex Structures of Regulatory Sequences of Muscle-specific Genes J. Biol. Chem., July 22, 2005; 280(29): 26805 - 26812. [Abstract] [Full Text] [PDF]

				J. L. Huppert and S. Balasubramanian Prevalence of quadruplexes in the human genome Nucleic Acids Res., May 24, 2005; 33(9): 2908 - 2916. [Abstract] [Full Text] [PDF]

				A. Yafe, S. Etzioni, P. Weisman-Shomer, and M. Fry Formation and properties of hairpin and tetraplex structures of guanine-rich regulatory sequences of muscle-specific genes Nucleic Acids Res., May 20, 2005; 33(9): 2887 - 2900. [Abstract] [Full Text] [PDF]

				C. L. Grand, T. J. Powell, R. B. Nagle, D. J. Bearss, D. Tye, M. Gleason-Guzman, and L. H. Hurley Mutations in the G-quadruplex silencer element and their relationship to c-MYC overexpression, NM23 repression, and therapeutic rescue PNAS, April 20, 2004; 101(16): 6140 - 6145. [Abstract] [Full Text] [PDF]

				M. A. Shammas, R. J. S. Reis, C. Li, H. Koley, L. H. Hurley, K. C. Anderson, and N. C. Munshi Telomerase Inhibition and Cell Growth Arrest After Telomestatin Treatment in Multiple Myeloma Clin. Cancer Res., January 15, 2004; 10(2): 770 - 776. [Abstract] [Full Text] [PDF]

				E. S. Wang, K. Wu, A. C. Chin, S. Chen-Kiang, K. Pongracz, S. Gryaznov, and M. A. S. Moore Telomerase inhibition with an oligonucleotide telomerase template antagonist: in vitro and in vivo studies in multiple myeloma and lymphoma Blood, January 1, 2004; 103(1): 258 - 266. [Abstract] [Full Text] [PDF]

				M. A. Shammas, R. J. Shmookler Reis, M. Akiyama, H. Koley, D. Chauhan, T. Hideshima, R. K. Goyal, L. H. Hurley, K. C. Anderson, and N. C. Munshi Telomerase inhibition and cell growth arrest by G-quadruplex interactive agent in multiple myeloma Mol. Cancer Ther., September 1, 2003; 2(9): 825 - 833. [Abstract] [Full Text] [PDF]

				M.-Y. Kim, M. Gleason-Guzman, E. Izbicka, D. Nishioka, and L. H. Hurley The Different Biological Effects of Telomestatin and TMPyP4 Can Be Attributed to Their Selectivity for Interaction with Intramolecular or Intermolecular G-Quadruplex Structures Cancer Res., June 15, 2003; 63(12): 3247 - 3256. [Abstract] [Full Text] [PDF]

				J. H. Kim, J. H. Kim, G. E. Lee, J. E. Lee, and I. K. Chung Potent Inhibition of Human Telomerase by Nitrostyrene Derivatives Mol. Pharmacol., May 1, 2003; 63(5): 1117 - 1124. [Abstract] [Full Text] [PDF]

				A. Siddiqui-Jain, C. L. Grand, D. J. Bearss, and L. H. Hurley Direct evidence for a G-quadruplex in a promoter region and its targeting with a small molecule to repress c-MYC transcription PNAS, September 3, 2002; 99(18): 11593 - 11598. [Abstract] [Full Text] [PDF]