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Research Articles: Therapeutics, Targets, and Development

Bcl-2 down-regulation and tubulin subtype composition are involved in resistance of ovarian cancer cells to vinflunine

¹ Centre National de la Recherche Scientifique, Formation de Recherche en Evolution 2737, Université de la Méditerranée, Marseille, France; ² Pierre Fabre Oncology Research Institute, Toulouse, France; and ³ Department of Obstetrics and Gynaecology, Università Cattolica Sacro Cuore, Rome, Italy

Requests for reprints: Diane Braguer, Centre National de la Recherche Scientifique, Formation de Recherche en Evolution 2737, UFR Pharmacie, 27 Boulevard Jean Moulin, 13005 Marseille, France. Phone: 33-4-91-83-56-35; Fax: 33-4-91-83-56-35. E-mail: diane.braguer{at}pharmacie.univ-mrs.fr

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 IC₅₀ and IC₇₀, respectively. We showed that P-glycoprotein minimally participated in this cell resistance. The examination of tubulin composition revealed increased levels of acetylated -tubulin, ßII-tubulin, and ßIII-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 G₂ 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. [Mol Cancer Ther 2006;5(11):2824–33]

Grant support: Association pour la Recherche contre le Cancer (grant 3220).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

⁴ Personal data.

Received 5/15/06; revised 8/31/06; accepted 9/11/06.

This article has been cited by other articles:

				J. Bennouna, J.-P. Delord, M. Campone, and L. Nguyen Vinflunine: A New Microtubule Inhibitor Agent Clin. Cancer Res., March 15, 2008; 14(6): 1625 - 1632. [Abstract] [Full Text] [PDF]