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New troglitazone derivatives devoid of PPARγ agonist activity display an increased antiproliferative effect in both hormone-dependent and hormone-independent breast cancer cell lines

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Abstract

Numerous recent studies indicate that most anticancer effects of PPARγ agonists like thiazolidinediones are the result of PPARγ-independent pathways. These conclusions were obtained by several approaches including the use of thiazolidinedione derivatives like Δ2-Troglitazone (Δ2-TGZ) that does not activate PPARγ. Since biotinylation has been proposed as a mechanism able to increase the specificity of drug delivery to cancer cells which could express a high level of vitamin receptor, a biotinylated derivative of Δ2-TGZ (bΔ2-TGZ) has been synthetized. In the present article, we have studied the in vitro effects of this molecule on both hormone-dependent (MCF-7) and hormone-independent (MDA-MB-231) breast cancer cells. In both cell lines, bΔ2-TGZ was more efficient than Δ2-TGZ to decrease cell viability. bΔ2-TGZ was also more potent than Δ2-TGZ to induce the proteasomal degradation of cyclin D1 in both cell lines and those of ERα in MCF-7 cells. However, in competition experiments, the presence of free biotin in the culture medium did not decrease the antiproliferative action of bΔ2-TGZ. Besides, other compounds that had no biotin but that were substituted at the same position of the phenolic group of the chromane moiety of Δ2-TGZ decreased cell viability similarly to bΔ2-TGZ. Hence, we concluded that the increased antiproliferative action of bΔ2-TGZ was not due to biotin itself but to the functionalization of the terminal hydroxyl group. This should be taken into account for the design of new thiazolidinedione derivatives able to affect not only hormone-dependent but also hormone-independent breast cancer cells in a PPARγ-independent pathway.

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Acknowledgments

This work was supported by grants of the “Université Henri Poincaré (BQR),” “Conseil Régional de Lorraine,” “Association pour la Recherche sur le Cancer,” “Ligue Contre le Cancer, comité de la Haute-Marne”, “Cancéropôle Grand Est.” Julie Lecomte was recipient of a grant of the “Ligue Contre le Cancer, comité de la Haute-Marne.” Christelle Colin was recipient of a grant of the “Ministère de l’enseignement supérieur et de la recherche”. We would like to thank SANOFI-AVENTIS for a studentship to Stéphane Salamone. We acknowledge Alexandra Kleinclauss for fruitful contribution to cell culture and western blotting. We also thank Martine Chillet, Brigitte Fernette, Sandrine Adach, and François Dupire for their technical assistance. The pPPRE3tkLuc construct was a generous gift from Pr. Philippe Becuwe.

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Authors and Affiliations

  1. EA 4421 Signalisation, Génomique et Recherche Translationnelle en Oncologie (SIGRETO), Faculté des Sciences, Université Henri Poincaré, Nancy-Université, BP 70239, 54506, Vandœuvre-lès-Nancy Cedex, France

    Christelle Colin, Isabelle Grillier-Vuissoz, Sandra Kuntz, Julie Lecomte & Stéphane Flament

  2. Groupe S.U.C.R.E.S., UMR 7565 Nancy-Université, CNRS, BP 70239, 54506, Vandœuvre-lès-Nancy Cedex, France

    Stéphane Salamone, Michel Boisbrun & Yves Chapleur

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  1. Christelle Colin
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Correspondence to Stéphane Flament.

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Colin, C., Salamone, S., Grillier-Vuissoz, I. et al. New troglitazone derivatives devoid of PPARγ agonist activity display an increased antiproliferative effect in both hormone-dependent and hormone-independent breast cancer cell lines. Breast Cancer Res Treat 124, 101–110 (2010). https://doi.org/10.1007/s10549-009-0700-y

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