title: Identification of a quinoxaline derivative that is a potent telomerase inhibitor leading to cellular senescence of human cancer cells.
abstract: Telomere maintenance is essential for the continued proliferation of dividing cells, and is implicated in chromosome stability and cell immortalization. Telomerase activity allows cells to maintain their telomeric DNA and contributes to the indefinite replicative capacity of cancer cells. Telomerase is expressed in most cancer cells, but not in normal somatic cells, suggesting that telomerase is an attractive target for cancer chemotherapy. Here we screened a chemical library for inhibition of human telomerase, and identified 2,3,7-trichloro-5-nitroquinoxaline (TNQX) as a potent inhibitor. TNQX showed a potent inhibitory effect, with 50% inhibition at approximately 1.4 microM, and did not inhibit DNA and RNA polymerases, including retroviral reverse trancriptase. A series of enzyme kinetic experiments suggested that TNQX is a mixed-type non-competitive inhibitor, with an inhibitor-binding site distinct from the binding sites for the telomeric substrate (TS) primer and the dNTPs. Long-term cultivation of the MCF7 cell line with a drug concentration that did not cause acute cytotoxicity resulted in progressive telomere erosion followed by an increased incidence of chromosome abnormalities and induction of the senescence phenotype. The results presented here indicate that TNQX is a highly potent and selective anti-telomerase agent with good potential for further development as a promising anti-cancer agent.
authors.affiliation: DNA Link, Inc, Milk Building, Yonsei University, Seoul 120-110, Korea.
authors.forename: Jun Hyun
authors.initials: JH
authors.lastname: Kim
authors.forename: Joo Hee
authors.initials: JH
authors.lastname: Kim
authors.forename: Gun Eui
authors.initials: GE
authors.lastname: Lee
authors.forename: Sang Woong
authors.initials: SW
authors.lastname: Kim
authors.forename: In Kwon
authors.initials: IK
authors.lastname: Chung
mesh_terms: D001665:Binding Sites; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects*; D017931:DNA Primers / Q000737:chemistry; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism; D012321:DNA-Directed RNA Polymerases / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D005434:Flow Cytometry; D006801:Humans; D007700:Kinetics; D010641:Phenotype; D012150:Polymorphism, Restriction Fragment Length; D011810:Quinoxalines / Q000737:chemistry / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019098:Telomerase / Q000037:antagonists & inhibitors*; D016615:Telomere / Q000378:metabolism; D014407:Tumor Cells, Cultured; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: C476383:2,3,7-trichloro-5-nitroquinoxaline; D017931:DNA Primers; D004791:Enzyme Inhibitors; D011810:Quinoxalines; D019098:Telomerase; D012321:DNA-Directed RNA Polymerases; D004259:DNA-Directed DNA Polymerase; D001616:beta-Galactosidase