Identification of a quinoxaline derivative that is a potent telomerase inhibitor leading to cellular senescence of human cancer cells

Jun Hyun Kim, Joo Hee Kim, Gun Eui Lee, Sang Woong Kim, In Kwon Chung

Research output: Contribution to journalArticle

50 Citations (Scopus)

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 ∼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.

Original languageEnglish
Pages (from-to)523-529
Number of pages7
JournalBiochemical Journal
Volume373
Issue number2
DOIs
Publication statusPublished - 2003 Jul 15

Fingerprint

Quinoxalines
Cell Aging
Telomerase
Cells
Derivatives
Telomere
Neoplasms
Chromosomes
Binding Sites
Small Molecule Libraries
Enzyme kinetics
Chromosomal Instability
Chemotherapy
MCF-7 Cells
DNA-Directed DNA Polymerase
DNA-Directed RNA Polymerases
Cytotoxicity
Chromosome Aberrations
Erosion
Maintenance

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

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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 ∼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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Identification of a quinoxaline derivative that is a potent telomerase inhibitor leading to cellular senescence of human cancer cells. / Kim, Jun Hyun; Kim, Joo Hee; Lee, Gun Eui; Kim, Sang Woong; Chung, In Kwon.

In: Biochemical Journal, Vol. 373, No. 2, 15.07.2003, p. 523-529.

Research output: Contribution to journalArticle

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