New troglitazone derivatives devoid of PPARgamma agonist activity display an increased antiproliferative effect in both hormone-dependent and hormone-independent breast cancer cell lines.
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Date publication
novembre 2010
Auteurs
Membres identifiés du Cancéropôle Est :
Pr FLAMENT Stéphane, Dr GRILLIER-VUISSOZ Isabelle, Dr KUNTZ Sandra
Tous les auteurs :
Colin C, Salamone S, Grillier-Vuissoz I, Boisbrun M, Kuntz S, Lecomte J, Chapleur Y, Flament S
Lien Pubmed
Résumé
Numerous recent studies indicate that most anticancer effects of PPARgamma agonists like thiazolidinediones are the result of PPARgamma-independent pathways. These conclusions were obtained by several approaches including the use of thiazolidinedione derivatives like Delta2-Troglitazone (Delta2-TGZ) that does not activate PPARgamma. 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 Delta2-TGZ (bDelta2-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, bDelta2-TGZ was more efficient than Delta2-TGZ to decrease cell viability. bDelta2-TGZ was also more potent than Delta2-TGZ to induce the proteasomal degradation of cyclin D1 in both cell lines and those of ERalpha in MCF-7 cells. However, in competition experiments, the presence of free biotin in the culture medium did not decrease the antiproliferative action of bDelta2-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 Delta2-TGZ decreased cell viability similarly to bDelta2-TGZ. Hence, we concluded that the increased antiproliferative action of bDelta2-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 PPARgamma-independent pathway.
Référence
Breast Cancer Res Treat. 2010 Nov;124(1):101-10