A novel telomerase substrate precursor rapidly induces telomere dysfunction in telomerase positive cancer cells but not telomerase silent normal cells
Open Access
- 22 August 2015
- journal article
- Published by Impact Journals, LLC in Oncoscience
- Vol. 2 (8), 693-695
- https://doi.org/10.18632/oncoscience.213
Abstract
Although telomerase is an almost universal target for cancer therapy, there has been no effective telomerase targeted inhibitor that has progressed to late stage human clinical trials. Recently, we reported that a telomerase-mediated telomere-disrupting compound, 6-thio-2'-deoxyguanosine (6-thio-dG), was very effective at targeting telomerase positive cancer cells while sparing telomerase silent normal cells. 6-thio-dG, a nucleoside analogue of the already-approved drug 6-thioguanine, is incorporated into telomeres by telomerase, resulting in disruption of the telomere-protecting shelterin complex. This disruption leads to Telomere dysfunction-Induced Foci (TIFs) formation and rapid cell death for the vast majority of cancer cells. Since most chemotherapies eventually fail due to drug acquired resistance, novel drugs such as 6-thio-dG, as a single first line agent or in the maintenance setting, may represent an effective new treatment for cancer patients.Keywords
This publication has 10 references indexed in Scilit:
- Induction of Telomere Dysfunction Mediated by the Telomerase Substrate Precursor 6-Thio-2′-DeoxyguanosineCancer Discovery, 2015
- A randomized phase II study of the telomerase inhibitor imetelstat as maintenance therapy for advanced non-small-cell lung cancerPublished by Elsevier BV ,2014
- Shelterin: the protein complex that shapes and safeguards human telomeresGenes & Development, 2005
- A low threshold level of expression of mutant-template telomerase RNA inhibits human tumor cell proliferationProceedings of the National Academy of Sciences of the United States of America, 2001
- Transient Expression of Human Telomerase Extends the Life Span of Normal Human FibroblastsBiochemical and Biophysical Research Communications, 2000
- Subsenescent Telomere Lengths in Fibroblasts Immortalized by Limiting Amounts of TelomerasePublished by Elsevier BV ,2000
- Mammalian Telomeres End in a Large Duplex LoopCell, 1999
- A survey of telomerase activity in human cancerEuropean Journal Of Cancer, 1997
- Specific Association of Human Telomerase Activity with Immortal Cells and CancerScience, 1994
- A highly conserved repetitive DNA sequence, (TTAGGG)n, present at the telomeres of human chromosomes.Proceedings of the National Academy of Sciences of the United States of America, 1988