Document Detail


Molecular profiling of docetaxel cytotoxicity in breast cancer cells: uncoupling of aberrant mitosis and apoptosis.
MedLine Citation:
PMID:  17099726     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Among microtubule-targeting agents, docetaxel has received recent interest owing to its good therapeutic index. Clinical trials have underlined its potential for the treatment of advanced breast cancer, although little is known about its molecular mode of action in this context. We characterized the molecular changes induced by docetaxel in two well-known human breast carcinoma cell lines. Two mechanisms of action according to drug concentration were suggested by a biphasic sensitivity curve, and were further validated by cell morphology, cell cycle and cell death changes. Two to four nanomolar docetaxel induced aberrant mitosis followed by late necrosis, and 100 nM docetaxel induced mitotic arrest followed by apoptosis. Passing through mitosis phase was a requirement for hypodiploidy to occur, as shown by functional studies in synchronized cells and by combining docetaxel with the proteasome inhibitor MG132. Transcriptional profiling showed differences according to cell line and docetaxel concentration, with cell cycle, cell death and structural genes commonly regulated in both cell lines. Although p53 targets were mainly induced with low concentration of drug in MCF7 cells, its relevance in the dual mechanism of docetaxel cytotoxicity was ruled out by using an isogenic shp53 cell line. Many of the genes shown in this study may contribute to the dual mechanism by which docetaxel inhibits the growth of breast cancer cells at different concentrations. These findings provide a basis for rationally enhancing docetaxel therapy, considering lower concentrations, and better drug combinations.
Authors:
H Hernández-Vargas; J Palacios; G Moreno-Bueno
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2006-11-13
Journal Detail:
Title:  Oncogene     Volume:  26     ISSN:  0950-9232     ISO Abbreviation:  Oncogene     Publication Date:  2007 May 
Date Detail:
Created Date:  2007-05-03     Completed Date:  2007-06-20     Revised Date:  2013-05-28    
Medline Journal Info:
Nlm Unique ID:  8711562     Medline TA:  Oncogene     Country:  England    
Other Details:
Languages:  eng     Pagination:  2902-13     Citation Subset:  IM    
Affiliation:
Breast and Gynaecological Cancer Group, Molecular Pathology Programme, Spanish National Cancer Centre (CNIO), Madrid, Spain.
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MeSH Terms
Descriptor/Qualifier:
Antineoplastic Agents / pharmacology
Apoptosis / drug effects*,  genetics
Breast Neoplasms / genetics*,  pathology
Carcinoma / genetics*,  pathology
Cell Cycle / drug effects,  genetics
Cell Proliferation / drug effects
Diploidy
Dose-Response Relationship, Drug
Gene Expression Profiling
Gene Expression Regulation, Neoplastic / drug effects*
Humans
Mitosis / drug effects*,  genetics
Taxoids / pharmacology*
Tumor Cells, Cultured
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/Taxoids; 15H5577CQD/docetaxel

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


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