Science Library
Induction of telomere dysfunction mediated by the telomerase substrate precursor 6-thio-2'-deoxyguanosine.
Published: 12/16/2014, Cancer discovery
Unlabelled
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.
Sign-Up For Science Library Updates
Copyright © 2017 Telomere Science Library. All Rights Reserved. All trademarks used are the properties of their respective owners.
This website is funded by a grant from T.A. Sciences®
