Document Detail


Microtubule-disrupting chemotherapeutics result in enhanced proteasome-mediated degradation and disappearance of tubulin in neural cells.
MedLine Citation:
PMID:  20587529     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
We sought to examine the effects of microtubule-targeting agents (MTA) on neural cells to better understand the problem of neurotoxicity, their principal side effect, and to possibly develop a model of clinical toxicity. Studies showed that microtubule-depolymerizing agents (MDA) not only disassembled microtubules in neural HCN2 cells but also led to rapid disappearance of tubulin, and that this was specific for MDAs. Tubulin levels decreased to 20% as early as 8 hours after adding vincristine, and to 1% to 30% (mean, 9.8 +/- 7.6%; median of 7%) after 100 nmol/L vincristine for 24 hours. This disappearance was reversible. An increase in both glu-terminated and acetylated tubulin, markers of stable tubulin, preceded reaccumulation of soluble tubulin, suggesting a priority for stabilizing tubulin first as microtubules before replenishing the soluble pool. Similar results were shown with other MDAs. Furthermore, microtubule reassembly did not arise from a central focus but instead appeared to involve dispersed nucleation, as evidenced by the appearance of small, stable microtubule stubs throughout the cytoplasm. In contrast, experiments with four nonneural "normal" cell lines and four cancer cell lines resulted in microtubule destabilization but only modest tubulin degradation. Evidence for proteasome-mediated degradation was obtained by demonstrating that adding a proteasome inhibitor before vincristine prevented tubulin disappearance. In summary, MDAs lead to rapid disappearance of tubulin in neural but not in other normal or cancer cells. These results underscore the fine control that occurs in neural cells and may further our understanding of neurotoxicity following MDAs.
Authors:
Lyn M Huff; Dan L Sackett; Marianne S Poruchynsky; Tito Fojo
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Intramural     Date:  2010-06-29
Journal Detail:
Title:  Cancer research     Volume:  70     ISSN:  1538-7445     ISO Abbreviation:  Cancer Res.     Publication Date:  2010 Jul 
Date Detail:
Created Date:  2010-07-16     Completed Date:  2010-08-24     Revised Date:  2013-05-29    
Medline Journal Info:
Nlm Unique ID:  2984705R     Medline TA:  Cancer Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  5870-9     Citation Subset:  IM    
Copyright Information:
(c)2010 AACR.
Affiliation:
Medical Oncology Branch, Center for Cancer Research, National Cancer Institute and Laboratory of Integrative and Medical Biophysics, The Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland 20892, USA. lyn@mail.nih.gov
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MeSH Terms
Descriptor/Qualifier:
Antibiotics, Antineoplastic / pharmacology
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
DNA Damage
Doxorubicin / pharmacology
Humans
Microtubules / drug effects*,  metabolism
Neurons / cytology,  drug effects*,  metabolism*
Proteasome Endopeptidase Complex / metabolism*
Tubulin / metabolism*
Grant Support
ID/Acronym/Agency:
Z99 CA999999/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Antibiotics, Antineoplastic; 0/Antineoplastic Agents; 0/Tubulin; 23214-92-8/Doxorubicin; EC 3.4.25.1/Proteasome Endopeptidase Complex
Comments/Corrections

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


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