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Cancer Discov. 2015 Jan;5(1):82-95. doi: 10.1158/2159-8290.CD-14-0609. Epub 2014 Dec 16.

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

Author information

1
Department of Cell Biology, The University of Texas Southwestern Medical Center, Dallas, Texas. Faculty of Medicine, Department of Biochemistry, Hacettepe University, Ankara, Turkey.
2
AuraSense Therapeutics, Skokie, Illinois.
3
Faculty of Medicine, Department of Biochemistry, Hacettepe University, Ankara, Turkey.
4
Department of Cell Biology, The University of Texas Southwestern Medical Center, Dallas, Texas.
5
Department of Cell Biology, The University of Texas Southwestern Medical Center, Dallas, Texas. Center for Excellence in Genomics Medicine Research, King Abdulaziz University, Jeddah, Saudi Arabia. jerry.shay@utsouthwestern.edu.

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 telomere-addressed telomerase-dependent anticancer approach.

SIGNIFICANCE:

Telomerase is an almost universal oncology target, yet there are few telomerase-directed 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.

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PMID:
25516420
PMCID:
PMC4293221
DOI:
10.1158/2159-8290.CD-14-0609
[Indexed for MEDLINE]
Free PMC Article

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