Document Detail


Mitotic block induced in HeLa cells by low concentrations of paclitaxel (Taxol) results in abnormal mitotic exit and apoptotic cell death.
MedLine Citation:
PMID:  8631019     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Paclitaxel at low concentrations (10 nM for 20 h) induces approximately 90% mitotic block at the metaphase/anaphase transition in HeLa cells, apparently by suppressing dynamics of spindle microtubules (M. A. Jordan et al., Proc. Natl. Acad. Sci. USA, 90: 9552-9556, 1993). It is not known, however, whether inhibition of mitosis by such low paclitaxel concentrations results in cell death. In the present work, we found that after removal of paclitaxel (10 nM-1 microM), blocked cells did not resume proliferation. Instead, cells exited mitosis abnormally within 24 h. They did not progress through anaphase or cytokinesis but entered an interphase-like state (chromatin decondensed, and an interphase-like microtubule array and nuclear membranes reformed). Many cells (> or = 55%) contained multiple nuclei. Additional DNA synthesis and polyploidy did not occur. DNA degradation into nucleosome-sized fragments characteristic of apoptosis began during drug incubation and increased after drug removal. Cells died within 48-72 h. Incubation with paclitaxel (10 nM for 20 h) resulted in high intracellular drug accumulation (8.3 microM) and little efflux after paclitaxel removal; intracellular retention of paclitaxel may contribute to its efficacy. The results support the hypothesis that the most potent chemotherapeutic mechanism of paclitaxel is kinetic stabilization of spindle microtubule dynamics.
Authors:
M A Jordan; K Wendell; S Gardiner; W B Derry; H Copp; L Wilson
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Cancer research     Volume:  56     ISSN:  0008-5472     ISO Abbreviation:  Cancer Res.     Publication Date:  1996 Feb 
Date Detail:
Created Date:  1996-07-03     Completed Date:  1996-07-03     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  2984705R     Medline TA:  Cancer Res     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  816-25     Citation Subset:  IM    
Affiliation:
Department of Molecular, Cellular, and Developmental Biology, University of California Santa Barbara 93106, USA.
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MeSH Terms
Descriptor/Qualifier:
Anaphase
Antineoplastic Agents, Phytogenic / metabolism,  toxicity*
Biological Transport
Cell Cycle / drug effects*
Cell Death / drug effects
Cell Division / drug effects
Chromatin / drug effects,  ultrastructure
Chromosomes, Human / drug effects,  ultrastructure
DNA, Neoplasm / drug effects,  isolation & purification
Hela Cells
Humans
Kinetics
Metaphase
Microtubules / drug effects,  ultrastructure
Mitosis / drug effects
Paclitaxel / metabolism,  toxicity*
Time Factors
Grant Support
ID/Acronym/Agency:
CA 57291/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Antineoplastic Agents, Phytogenic; 0/Chromatin; 0/DNA, Neoplasm; 33069-62-4/Paclitaxel

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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