Isothiazolone Derivatives Selectively Inhibit Telomerase from Human and Rat Cancer Cells in Vitro
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- 作者：Nobuki Hayakawa ; Katsura Nozawa ; Akio Ogawa ; Naoki Kato ; Kenji Yoshida ; Ken-ichi Akamatsu ; Masayuki Tsuchiya ; Akio Nagasaka ; and Shonen Yoshida
- 刊名：Biochemistry
- 出版年：1999
- 出版时间：August 31, 1999
- 年：1999
- 卷：38
- 期：35
- 页码：11501 - 11507
- 全文大小：132K
- 年卷期：v.38,no.35(August 31, 1999)
- ISSN：1520-4995
文摘
The telomere hypothesis postulates stabilization of telomere length and telomerase activationas key events in cellular immortalization and carcinogeneses. Accordingly, telomerase has been suggestedas a novel and highly selective target for design of antitumor drugs. Screening of a chemical libraryincluding 16 000 synthetic compounds yielded six that strongly inhibited telomerase activity in extractsof cultured human cells, including four isothiazolone derivatives and two unrelated compounds. The mostpotent inhibitor was 2-[3-(trifluoromethyl)phenyl]isothiazolin-3-one (TMPI), a concentration of 1.0 
Minhibited telomerase activity by 50% according to a telomere repeat amplification protocol (TRAP) assay.Analysis using partially purified telomerase from AH7974 rat hepatoma cells demonstrated noncompetitiveinhibition with the telomere-repeat primer and mixed inhibition with the dNTPs; the inhibition constantwas 2.5 M. TMPI did not inhibit eukaryotic DNA polymerase 
, 
, or human immunodeficiency virusreverse transcriptase (HIV RT). Thus, inhibition by TMPI was highly selective for telomerase. Inhibitionby TMPI was quenched by 1 mM of dithiothreitol or glutathione, suggesting that TMPI inhibits telomeraseby acting at a cystein residue. TMPI inhibition of this enzyme may find application as an antineoplasticagent.
Minhibited telomerase activity by 50% according to a telomere repeat amplification protocol (TRAP) assay.Analysis using partially purified telomerase from AH7974 rat hepatoma cells demonstrated noncompetitiveinhibition with the telomere-repeat primer and mixed inhibition with the dNTPs; the inhibition constantwas 2.5 M. TMPI did not inhibit eukaryotic DNA polymerase , , or human immunodeficiency virusreverse transcriptase (HIV RT). Thus, inhibition by TMPI was highly selective for telomerase. Inhibitionby TMPI was quenched by 1 mM of dithiothreitol or glutathione, suggesting that TMPI inhibits telomeraseby acting at a cystein residue. TMPI inhibition of this enzyme may find application as an antineoplasticagent.