Induction of telomere dysfunction mediated by the telomerase substrate precursor 6-thio-2′-deoxyguanosine

Ilgen Mender, Sergei Gryaznov, Z. Gunnur Dikmen, Woodring E. Wright, Jerry W. Shay

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

The relationships between telomerase and telomeres represent attractive targets for new anticancer agents. Here, we report that the nucleoside analogue 6-thio-2′- deoxyguanosine (6-thio-dG) is recognized by telomerase and is incorporated into de novo –synthesized telomeres. This results in modified telomeres, leading to telomere dysfunction, but only in cells expressing telomerase. 6-Thio-dG, but not 6-thioguanine, induced telomere dysfunction in telomerase-positive human cancer cells and hTERT-expressing human fibroblasts, but not in telomerase-negative cells. Treatment with 6-thio-dG resulted in rapid cell death for the vast majority of the cancer cell lines tested, whereas normal human fibroblasts and human colonic epithelial cells were largely unaffected. In A549 lung cancer cell–based mouse xenograft studies, 6-thio-dG caused a decrease in the tumor growth rate superior to that observed with 6-thioguanine treatment. In addition, 6-thio-dG increased telomere dysfunction in tumor cells in vivo . These results indicate that 6-thio-dG may provide a new telomereaddressed telomerase-dependent anticancer approach. Significance: Telomerase is an almost universal oncology target, yet there are few telomerasedirected therapies in human clinical trials. In the present study, we demonstrate a small-molecule telomerase substrate approach that induces telomerase-mediated targeted “telomere uncapping,” but only in telomerase-positive cancer cells, with minimal effects in normal telomerase-negative cells.

Original languageEnglish (US)
Pages (from-to)82-95
Number of pages14
JournalCancer Discovery
Volume5
Issue number1
DOIs
StatePublished - 2015

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alpha-2'-deoxythioguanosine
Telomerase
Telomere
Thioguanine
Neoplasms
Fibroblasts

ASJC Scopus subject areas

  • Oncology

Cite this

Induction of telomere dysfunction mediated by the telomerase substrate precursor 6-thio-2′-deoxyguanosine. / Mender, Ilgen; Gryaznov, Sergei; Dikmen, Z. Gunnur; Wright, Woodring E.; Shay, Jerry W.

In: Cancer Discovery, Vol. 5, No. 1, 2015, p. 82-95.

Research output: Contribution to journalArticle

Mender, Ilgen ; Gryaznov, Sergei ; Dikmen, Z. Gunnur ; Wright, Woodring E. ; Shay, Jerry W. / Induction of telomere dysfunction mediated by the telomerase substrate precursor 6-thio-2′-deoxyguanosine. In: Cancer Discovery. 2015 ; Vol. 5, No. 1. pp. 82-95.
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