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.

Δ2-Troglitazone promotes cytostatic rather than pro-apoptotic effects in breast cancer cells cultured in high serum conditions

“…12 In the current study, the IC 50 values obtained by a crystal violet staining assay were 7.1 mM for MDA-MB-231 cells and 11.5 mM for MCF-7 cells after 48 h of treatment in similar low serum conditions (1%). It was not surprising that these values were lower since treatment duration was longer (48 h).…”

“…40 This G 0 / G 1 arrest was in agreement with the reduced level of cyclin D1 since this protein is required for driving the G 1 /S transition. 12,41 This is probably the result of proteolysis of cyclin D1 through an ubiquitin-dependent mechanism implicating the F-box protein b-transducin repeat-containing protein (b-TrCP) which has been described in several studies. 42,43 To conclude, the present study shows that in high serum conditions (10% FCS), D2-TGZ still displayed anticancer effects on MDA-MB-231 and MCF-7 breast cancer cells.…”

“…10,11 In breast cancer cell lines, the number of viable cells was reduced after exposure to D2-TGZ. 12 Such a treatment induced a proteasome-dependent proteolysis of both cyclin D1 and estrogen receptor a in hormone-dependent breast cancer cell lines. [12][13][14][15] Besides, D2-TGZ induced an early increase in intracellular calcium followed by the ERK-dependent expression of early growth response gene-1.…”

“…12 Such a treatment induced a proteasome-dependent proteolysis of both cyclin D1 and estrogen receptor a in hormone-dependent breast cancer cell lines. [12][13][14][15] Besides, D2-TGZ induced an early increase in intracellular calcium followed by the ERK-dependent expression of early growth response gene-1. 16 D2-TGZ also triggered endoplasmic reticulum (ER) stress followed by apoptosis in both MCF-7 and MDA-MB-231 breast cancer cells.…”

“…This compound was tested previously either in high serum conditions (5% or 10% fetal calf serum (FCS)-containing medium) 14,22 or in a low serum environment (1% or 0% FCS-containing medium). 10,12,13,[15][16][17] Most data from our laboratory were obtained from breast cancer cell lines (MDA-MB-231 and MCF-7) cultured in 1% FCS-containing medium. In order to determine the impact of serum deprivation, we studied the effects of D2-TGZ on cells maintained in 10% FCS-containing medium.…”