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Research ArticleArticle

Potent Inhibition of Human Telomerase by Nitrostyrene Derivatives

Joo Hee Kim, Jun Hyun Kim, Gun Eui Lee, Jong Eun Lee and In Kwon Chung
Molecular Pharmacology May 2003, 63 (5) 1117-1124; DOI: https://doi.org/10.1124/mol.63.5.1117
Joo Hee Kim
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Jun Hyun Kim
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Gun Eui Lee
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Jong Eun Lee
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In Kwon Chung
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Abstract

Telomerase activity is expressed in most types of cancer cells but not in normal somatic cells, suggesting that telomerase may be an important target for cancer chemotherapy. Inhibition of telomerase results in telomere erosion, leading to the subsequent growth arrest of cancer cells followed by senescence or cell death. In this study, we screened a chemical library for the inhibition of human telomerase, identifying three inhibitors. All compounds contained a common nitrostyrene moiety conjugated to different side chains. One of these compounds, 3-(3,5-dichlorophenoxy)-nitrostyrene (DPNS), showed the most potent inhibitory effect, with 50% inhibition at ∼0.4 μM and did not inhibit DNA and RNA polymerases, including retroviral reverse transcriptase. A series of enzyme kinetic experiments suggests that DPNS is a mixed-type noncompetitive inhibitor, with an inhibitor-binding site distinct from the binding sites for the telomeric substrate primer and the deoxynucleoside-5′-triphosphates. Extensive propagation of cancer cell line in the presence of DPNS resulted in progressive telomere erosion followed by the induction of senescence phenotype. The results presented here demonstrate that DPNS is a highly selective, small-molecule telomerase inhibitor in vitro and could be useful as a lead molecule for the further development of inhibitors with an improved potential for efficacy in vivo.

Footnotes

  • This work was supported in part by a grant from the Ministry of Health & Welfare through the Molecular Aging Research Center, grant R02-2001-000-00034-0 from the Korea Science and Engineering Foundation (KOSEF), and a grant from KOSEF through the Protein Network Research Center.

  • Joo Hee Kim and Jun Hyun Kim contributed equally to this work.

  • Abbreviations:
    hTERT
    human telomerase reverse transcriptase
    TRAP
    telomeric repeat amplification protocol
    TRF
    terminal restriction fragment
    DPNS
    3-(3,5-dichlorophenoxy)-nitrostyrene
    DNS
    2,3-dichloro-nitrostyrene
    NVN
    2-(2-nitrovinyl)-naphthalene
    SA-β-gal
    senescence-associated β-galactosidase
    PD
    population doubling
    TS
    telomeric substrate
    dNTP
    deoxynucleoside-5′-triphosphate
    PBS
    phosphate-buffered saline
    CHAPS
    3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acid
    PCR
    polymerase chain reaction
    TRF
    terminal restriction fragment
    kb
    kilobase
    BRACO19
    3,6,9-trisubstituted acridine 9-[4-(N,N-dimethylamino)phenylamino]-3,6-bis(3-pyrrolodinopropionamido) acridine
    BIBR1532
    2-[(E)-3-naphtalen-2-yl-but-2-enoylamino]-benzoic acid
    • Received November 6, 2002.
    • Accepted February 3, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 63 (5)
Molecular Pharmacology
Vol. 63, Issue 5
1 May 2003
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Research ArticleArticle

Potent Inhibition of Human Telomerase by Nitrostyrene Derivatives

Joo Hee Kim, Jun Hyun Kim, Gun Eui Lee, Jong Eun Lee and In Kwon Chung
Molecular Pharmacology May 1, 2003, 63 (5) 1117-1124; DOI: https://doi.org/10.1124/mol.63.5.1117

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Research ArticleArticle

Potent Inhibition of Human Telomerase by Nitrostyrene Derivatives

Joo Hee Kim, Jun Hyun Kim, Gun Eui Lee, Jong Eun Lee and In Kwon Chung
Molecular Pharmacology May 1, 2003, 63 (5) 1117-1124; DOI: https://doi.org/10.1124/mol.63.5.1117
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