title: New troglitazone derivatives devoid of PPARγ agonist activity display an increased antiproliferative effect in both hormone-dependent and hormone-independent breast cancer cell lines.
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.
authors.affiliation: EA 4421 Signalisation, Génomique et Recherche Translationnelle en Oncologie, Faculté des Sciences, Université Henri Poincaré, Nancy-Université, BP 70239, 54506 Vandoeuvre-lès-Nancy Cedex, France.
authors.forename: Christelle
authors.initials: C
authors.lastname: Colin
authors.forename: Stéphane
authors.initials: S
authors.lastname: Salamone
authors.forename: Isabelle
authors.initials: I
authors.lastname: Grillier-Vuissoz
authors.forename: Michel
authors.initials: M
authors.lastname: Boisbrun
authors.forename: Sandra
authors.initials: S
authors.lastname: Kuntz
authors.forename: Julie
authors.initials: J
authors.lastname: Lecomte
authors.forename: Yves
authors.initials: Y
authors.lastname: Chapleur
authors.forename: Stéphane
authors.initials: S
authors.lastname: Flament
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D019921:Biotinylation; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002839:Chromans / Q000737:chemistry / Q000494:pharmacology*; D019938:Cyclin D1 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D047628:Estrogen Receptor alpha / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D009376:Neoplasms, Hormone-Dependent / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D047495:PPAR gamma / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D045162:Thiazolidinediones / Q000737:chemistry / Q000494:pharmacology*; D014162:Transfection; D000077288:Troglitazone
chemical_list: D000970:Antineoplastic Agents; C530104:CCND1 protein, human; D002839:Chromans; D047628:Estrogen Receptor alpha; D004967:Estrogens; D047495:PPAR gamma; D045162:Thiazolidinediones; D019938:Cyclin D1; D046988:Proteasome Endopeptidase Complex; D000077288:Troglitazone