Document Detail


Bcl-2 down-regulation and tubulin subtype composition are involved in resistance of ovarian cancer cells to vinflunine.
MedLine Citation:
PMID:  17121929     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Vinflunine, a new microtubule-targeting drug, has a marked antitumor activity in vitro and in vivo. Here, we studied the mechanisms mediating resistance to vinflunine. We investigated the response to vinflunine of ovarian cancer cells initially selected as paclitaxel-resistant cells (A2780-TC1 cells). By comparison with A2780-wild-type (wt) cells, we showed that A2780-TC1 cells were highly resistant to vinflunine, with resistance factors reaching 800 and 1,830 for IC(50) and IC(70), respectively. We showed that P-glycoprotein minimally participated in this cell resistance. The examination of tubulin composition revealed increased levels of acetylated alpha-tubulin, betaII-tubulin, and betaIII-tubulin in A2780-TC1 cells before vinflunine treatment. As a consequence, vinflunine unequally affected microtubule network organization and function in A2780-wt and A2780-TC1 cells. Whereas the drug depolymerized microtubules and induced a mitotic block in A2780-wt cells, it did not depolymerize microtubules and induced a G(2) block in A2780-TC1 cells. Elsewhere, the mitochondrial protein Bcl-2 was down-regulated in A2780-TC1 cells. This down-regulation was related to resistance, as A2780-TC1 cells stably transfected with a Bcl-2 construct recovered a partial sensitivity to vinflunine. Lastly, we confirmed the role played by Bcl-2 by showing that the mitochondrial membrane potential was only disrupted by vinflunine in cells expressing Bcl-2. Altogether, our results indicate that modifications acquired during treatment (i.e., paclitaxel) have significant consequences on cell response to the following drug (i.e., vinflunine). Especially, this study shows that a specific pool of tubulin subtypes and a down-regulation of Bcl-2 are associated with resistance of ovarian cancer cells to vinflunine.
Authors:
Marie-Anne Estève; Manon Carré; Véronique Bourgarel-Rey; Anna Kruczynski; Giuseppina Raspaglio; Cristiano Ferlini; Diane Braguer
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Molecular cancer therapeutics     Volume:  5     ISSN:  1535-7163     ISO Abbreviation:  Mol. Cancer Ther.     Publication Date:  2006 Nov 
Date Detail:
Created Date:  2006-11-23     Completed Date:  2007-02-15     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101132535     Medline TA:  Mol Cancer Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2824-33     Citation Subset:  IM    
Affiliation:
Centre National de la Recherche Scientifique, Formation de Recherche en Evolution 2737, UFR Pharmacie, 27 Boulevard Jean Moulin, 13005 Marseille, France.
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MeSH Terms
Descriptor/Qualifier:
Antineoplastic Agents, Phytogenic / pharmacology*
Dose-Response Relationship, Drug
Down-Regulation*
Drug Resistance, Neoplasm
Female
Humans
Microtubules / physiology,  ultrastructure
Ovarian Neoplasms / drug therapy,  metabolism*
P-Glycoprotein / metabolism
Proto-Oncogene Proteins c-bcl-2 / genetics,  metabolism*
Tubulin / classification,  genetics,  metabolism*
Tubulin Modulators / pharmacology*
Tumor Cells, Cultured
Vinblastine / analogs & derivatives*,  pharmacology
Chemical
Reg. No./Substance:
0/Antineoplastic Agents, Phytogenic; 0/P-Glycoprotein; 0/Proto-Oncogene Proteins c-bcl-2; 0/Tubulin; 0/Tubulin Modulators; 162652-95-1/vinflunine; 865-21-4/Vinblastine

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


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