Document Detail


A G-quadruplex stabilizer induces M-phase cell cycle arrest.
MedLine Citation:
PMID:  19531483     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
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:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2009-06-16
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  284     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2009 Aug 
Date Detail:
Created Date:  2009-08-17     Completed Date:  2009-10-06     Revised Date:  2013-06-02    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  22535-43     Citation Subset:  IM    
Affiliation:
Department of Pharmacology, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Piscataway, New Jersey 08854-5635, USA.
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MeSH Terms
Descriptor/Qualifier:
Antineoplastic Agents / 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:
CA039662/CA/NCI NIH HHS; CA102463/CA/NCI NIH HHS; T32 CA108455/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
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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