title: Telomere uncapping by the G-quadruplex ligand RHPS4 inhibits clonogenic tumour cell growth in vitro and in vivo consistent with a cancer stem cell targeting mechanism.
abstract: The pentacyclic acridinium methosulfate salt RHPS4 induces the 3'single-stranded guanine-rich telomeric overhang to fold into a G-quadruplex structure. Stabilisation of the latter is incompatible with an attachment of telomerase to the telomere and thus G-quadruplex ligands can effectively inhibit both the catalytic and capping functions of telomerase. In this study, we examined mechanisms underlying telomere uncapping by RHPS4 in uterus carcinoma cells (UXF1138L) with short telomeres and compared the susceptibility of bulk and clonogenic cancer cells to the G-quadruplex ligand. We show that treatment of UXF1138L cells with RHPS4 leads to the displacement of the telomerase catalytic subunit (hTERT) from the nucleus, induction of telomere-initiated DNA-damage signalling and chromosome fusions. We further report that RHPS4 is more potent against cancer cells that grow as colonies in soft agar than cells growing as monolayers. Human cord blood and HEK293T embryonic kidney cell colony forming units, however, were more resistant to RHPS4. RHPS4-treated UXF1138L xenografts had a decreased clonogenicity, showed loss of nuclear hTERT expression and an induction of mitotic abnormalities compared with controls. Although single-agent RHPS4 had limited in vivo efficacy, a combination of RHPS4 with the mitotic spindle poison Taxol caused tumour remissions and further enhancement of telomere dysfunction.
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Marlene and Stewart Greenebaum Cancer Center, School of Medicine, University of Maryland, Baltimore, MD 21201, USA. aburger@som.umaryland.edu
authors.forename: P
authors.initials: P
authors.lastname: Phatak
authors.forename: J C
authors.initials: JC
authors.lastname: Cookson
authors.forename: F
authors.initials: F
authors.lastname: Dai
authors.forename: V
authors.initials: V
authors.lastname: Smith
authors.forename: R B
authors.initials: RB
authors.lastname: Gartenhaus
authors.forename: M F G
authors.initials: MF
authors.lastname: Stevens
authors.forename: A M
authors.initials: AM
authors.lastname: Burger
mesh_terms: D000166:Acridines / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006801:Humans; D051379:Mice; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D017239:Paclitaxel / Q000494:pharmacology; D019098:Telomerase / Q000037:antagonists & inhibitors*; D016615:Telomere / Q000187:drug effects*
chemical_list: C438609:3,11-difluoro-6,8,13-trimethyl-8H-quino(4,3,2-kl)acridinium; D000166:Acridines; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D019098:Telomerase; D017239:Paclitaxel