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 ~1.4 μM, 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.
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July 2003
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Research Article|
July 15 2003
Identification of a quinoxaline derivative that is a potent telomerase inhibitor leading to cellular senescence of human cancer cells
Jun Hyun KIM;
Jun Hyun KIM
1
∗DNA Link, Inc., Milk Building, Yonsei University, Seoul 120-110, Korea
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Joo Hee KIM;
Joo Hee KIM
1
∗DNA Link, Inc., Milk Building, Yonsei University, Seoul 120-110, Korea
2To whom correspondence should be addressed (e-mail topoviro@yonsei.ac.kr).
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Gun Eui Lee;
Gun Eui Lee
†Department of Biology, Molecular Aging Research Center, and Protein Network Research Center, Yonsei University, Seoul 120-749, Korea
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Sang Woong KIM;
Sang Woong KIM
‡LeadGenex, Inc., 103-1 Moonji-Dong, Yusung-Gu, Taejon 305-380, Korea
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I. Kwon CHUNG
I. Kwon CHUNG
2
†Department of Biology, Molecular Aging Research Center, and Protein Network Research Center, Yonsei University, Seoul 120-749, Korea
2To whom correspondence should be addressed (e-mail topoviro@yonsei.ac.kr).
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Publisher: Portland Press Ltd
Received:
March 07 2003
Revision Received:
April 04 2003
Accepted:
April 10 2003
Accepted Manuscript online:
April 10 2003
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London ©2003
2003
Biochem J (2003) 373 (2): 523–529.
Article history
Received:
March 07 2003
Revision Received:
April 04 2003
Accepted:
April 10 2003
Accepted Manuscript online:
April 10 2003
Citation
Jun Hyun KIM, Joo Hee KIM, Gun Eui Lee, Sang Woong KIM, I. Kwon CHUNG; Identification of a quinoxaline derivative that is a potent telomerase inhibitor leading to cellular senescence of human cancer cells. Biochem J 15 July 2003; 373 (2): 523–529. doi: https://doi.org/10.1042/bj20030363
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