Targeting pancreatic cancer with a G-quadruplex ligand.

TitleTargeting pancreatic cancer with a G-quadruplex ligand.
Publication TypeJournal Article
Year of Publication2011
AuthorsGunaratnam M, de la Fuente M, Hampel SM, Todd AK, Reszka AP, Schätzlein A, Neidle S
JournalBioorg Med Chem
Volume19
Issue23
Pagination7151-7
Date Published2011 Dec 1
ISSN1464-3391
KeywordsAnimals, Antineoplastic Agents, Cell Line, Tumor, Female, G-Quadruplexes, HSP90 Heat-Shock Proteins, Humans, Imides, Ligands, Mice, Mice, Nude, Naphthalenes, Pancreatic Neoplasms, Promoter Regions, Genetic, Telomerase, Xenograft Model Antitumor Assays
Abstract

The integrity of telomeres in most cancer cells is maintained by the action of the telomerase enzyme complex, which catalyzes the synthesis of telomeric DNA repeats in order to replace those lost during replication. Telomerase is especially up-regulated in metastatic cancer and is thus emerging as a major therapeutic target. One approach to telomerase inhibition involves the sequestration of the single-stranded 3' ends of telomeric DNA into higher-order quadruplex structures. We have recently shown that tetra-substituted naphthalene diimide compounds are potent quadruplex-stabilizing molecules with telomerase inhibitory activity in cells. We show here that one such compound, BMSG-SH-3, which has been optimized by computer modeling, has significant in vivo antitumor activity against a model for pancreatic cancer, a cancer that is especially resistant to current therapies. A large reduction in telomerase activity in treated tumors was observed and the naphthalene diimide compound was found to be selectively localized in the treated tumors. We find that the expression of the therapeutically important chaperone protein HSP90, a regulator of telomerase is also reduced in vivo by BMSG-SH-3 treatment. The compound is a potent stabilizer of two G-quadruplex sequences found in the promoter region of the HSP90 gene, as well as a G-quadruplex from human telomeric DNA. It is proposed that the simultaneous targeting of these quadruplexes may be an effective anti-tumor strategy.

DOI10.1016/j.bmc.2011.09.055
Alternate JournalBioorg. Med. Chem.
PubMed ID22041170
Grant ListC129/A4489 / / Cancer Research UK / United Kingdom