title: Bcl-2 down-regulation and tubulin subtype composition are involved in resistance of ovarian cancer cells to vinflunine.
abstract: 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.affiliation: Centre National de la Recherche Scientifique, Formation de Recherche en Evolution 2737, UFR Pharmacie, 27 Boulevard Jean Moulin, 13005 Marseille, France.
authors.forename: Marie-Anne
authors.initials: MA
authors.lastname: Estève
authors.forename: Manon
authors.initials: M
authors.lastname: Carré
authors.forename: Véronique
authors.initials: V
authors.lastname: Bourgarel-Rey
authors.forename: Anna
authors.initials: A
authors.lastname: Kruczynski
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Raspaglio
authors.forename: Cristiano
authors.initials: C
authors.lastname: Ferlini
authors.forename: Diane
authors.initials: D
authors.lastname: Braguer
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D008870:Microtubules / Q000502:physiology / Q000648:ultrastructure; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D014404:Tubulin / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D050257:Tubulin Modulators / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D014747:Vinblastine / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D019253:Proto-Oncogene Proteins c-bcl-2; D014404:Tubulin; D050257:Tubulin Modulators; C111217:vinflunine; D014747:Vinblastine