title: A novel telomerase substrate precursor rapidly induces telomere dysfunction in telomerase positive cancer cells but not telomerase silent normal cells.
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.
authors.affiliation: University of Texas Southwestern Medical Center, Department of Cell Biology, Dallas, TX, USA ; Hacettepe University, Faculty of Medicine, Department of Biochemistry, Ankara, Turkey.
authors.forename: Ilgen
authors.initials: I
authors.lastname: Mender
authors.affiliation: AuraSense Therapeutics, Skokie, IL, USA.
authors.forename: Sergei
authors.initials: S
authors.lastname: Gryaznov
authors.affiliation: University of Texas Southwestern Medical Center, Department of Cell Biology, Dallas, TX, USA ; Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia.
authors.forename: Jerry W
authors.initials: JW
authors.lastname: Shay
keywords: 6-thio-2′deoxyguanosine; 6-thioguanine; cancer; telomere induced foci; telomere shortening