title: A G-quadruplex stabilizer induces M-phase cell cycle arrest.
abstract: G-quadruplex stabilizers such as telomestatin and HXDV bind with exquisite specificity to G-quadruplexes, but not to triplex, duplex, or single-stranded DNAs. Studies have suggested that the antiproliferative and possibly anti-tumor activities of these compounds are linked to their inhibitory effect on telomerase and/or telomere function. In the current studies, we show that HXDV, a synthetic analog of telomestatin, exhibits antiproliferative activity against both telomerase-positive and -negative cells and induces robust apoptosis within 16 h of treatment, suggesting a mode of action independent of telomerase. HXDV was also shown to inhibit cell cycle progression causing M-phase cell cycle arrest, as evidenced by accumulation of cells with 4 n DNA content, increased mitotic index, separated centrosomes, elevated histone H3 phosphorylation at Ser-10 (an M-phase marker), and defective chromosome alignment and spindle fiber assembly (revealed by time-lapse microscopy). The M-phase arrest caused by HXDV paralleled with reduction in the expression level of the major M-phase checkpoint regulator Aurora A. All these cellular effects appear to depend on the G-quadruplex binding activity of HXDV as its non-G-quadruplex binding analog, TXTLeu, is completely devoid of all these effects. In the aggregate, our results suggest that HXDV, which exhibits anti-proliferative and apoptotic activities, is also a novel M-phase blocker, with a mode of action dependent on its G-quadruplex binding activity.
authors.affiliation: Department of Pharmacology, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Piscataway, New Jersey 08854-5635, USA.
authors.forename: Yuan-Chin
authors.initials: YC
authors.lastname: Tsai
authors.forename: Haiyan
authors.initials: H
authors.lastname: Qi
authors.forename: Chao-Po
authors.initials: CP
authors.lastname: Lin
authors.forename: Ren-Kuo
authors.initials: RK
authors.lastname: Lin
authors.forename: John E
authors.initials: JE
authors.lastname: Kerrigan
authors.forename: Suzanne G
authors.initials: SG
authors.lastname: Rzuczek
authors.forename: Edmond J
authors.initials: EJ
authors.lastname: LaVoie
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Rice
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Pilch
authors.forename: Yi Lisa
authors.initials: YL
authors.lastname: Lyu
authors.forename: Leroy F
authors.initials: LF
authors.lastname: Liu
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects* / Q000235:genetics*; D002455:Cell Division / Q000187:drug effects*; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019084:Fluorescent Antibody Technique, Indirect; D054856:G-Quadruplexes / Q000187:drug effects*; D006801:Humans; D047028:Macrocyclic Compounds / Q000737:chemistry / Q000494:pharmacology; D008853:Microscopy; D019098:Telomerase / Q000235:genetics / Q000502:physiology
chemical_list: D000970:Antineoplastic Agents; D047028:Macrocyclic Compounds; D019098:Telomerase