Thiazolidinediones (TZD) are a new class of antidiabetic drugs that have also been shown to possess antitumoral properties in different human cancers. TZD bind and activate the peroxisome proliferator-activated receptor (PPAR), which is a nuclear receptor acting as a transcription factor in several tissues. In the present study, we evaluated PPAR mRNA and protein expression in tissue samples of human adrenocortical carcinomas (ACC), of normal adrenal glands and in the human ACC cell line H295R. PPAR mRNA was expressed in 6 out of 8 ACC, in 2 out of 3 normal adrenal glands, as well as in the H295R cells. These results were confirmed by immunohistochemistry.

PPAR transcriptional activity in H295R cells, monitored by a reporter gene assay, was induced 2- to 3-fold by TZD, such as rosiglitazone (RGZ) and pioglitazone (PGZ), while in PPAR- transfected cells RGZ alone or RGZ plus 9-cis retinoic acid further increased reporter activity.

TZD inhibited both the proliferation and invasiveness of H295R cells in a dose-dependent manner. Thymidine incorporation was reduced by about 60% by 20 µM of both TZD. Co-treatment with the RXR ligand 9-cis retinoic acid had an additive effect.

TZD increased the number of cells in the G0/G1 phase and decreased them in the S phase. Western blot analysis showed that TZD increased the expression of the cell cycle inhibitors p21 and p27 and reduced the expression of cyclin D1 (CD1).

Twenty µM of RGZ and PGZ reduced H295R invasiveness through Matrigel by about 85%.

Zymography and ELISA tests showed that TZD inhibited metalloproteinase-2 (MMP-2) secretion by H295R cells in a dose-dependent manner.

These data suggest that TZD reduce the malignant potential of the H295R ACC cell line and, therefore, might potentially constitute a novel tool in the medical treatment of human ACC.