| A G-quadruplex stabilizer induces M-phase cell cycle arrest. | |
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MedLine Citation:
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PMID: 19531483 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Yuan-Chin Tsai; Haiyan Qi; Chao-Po Lin; Ren-Kuo Lin; John E Kerrigan; Suzanne G Rzuczek; Edmond J LaVoie; Joseph E Rice; Daniel S Pilch; Yi Lisa Lyu; Leroy F Liu |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2009-06-16 |
Journal Detail:
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Title: The Journal of biological chemistry Volume: 284 ISSN: 1083-351X ISO Abbreviation: J. Biol. Chem. Publication Date: 2009 Aug |
Date Detail:
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Created Date: 2009-08-17 Completed Date: 2009-10-06 Revised Date: 2013-06-02 |
Medline Journal Info:
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Nlm Unique ID: 2985121R Medline TA: J Biol Chem Country: United States |
Other Details:
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Languages: eng Pagination: 22535-43 Citation Subset: IM |
Affiliation:
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Department of Pharmacology, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Piscataway, New Jersey 08854-5635, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Antineoplastic Agents
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chemistry,
pharmacology Apoptosis / drug effects Cell Cycle / drug effects*, genetics* Cell Division / drug effects* Cell Line Cell Line, Tumor Cell Proliferation / drug effects Fluorescent Antibody Technique, Indirect G-Quadruplexes / drug effects* Humans Macrocyclic Compounds / chemistry, pharmacology Microscopy Telomerase / genetics, physiology |
| Grant Support | |
ID/Acronym/Agency:
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CA039662/CA/NCI NIH HHS; CA102463/CA/NCI NIH HHS; T32 CA108455/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Antineoplastic Agents; 0/Macrocyclic Compounds; EC 2.7.7.49/Telomerase |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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