Combination of PPARgamma activation and temozolomide chemotherapy leads to antineoplastic effects in glioma cells

Gliomas are the most common primary tumors of the central nervous system. They initially respond to radiotherapy and to a lesser extent to chemotherapy, however, they invariably recur. Despite considerable research efforts no curative therapy exists and the majority of patients die within the first year after diagnosis.

Peroxisome proliferator-activated receptors (PPARs) belong to the group of nuclear hormone receptors. To date, a number of different synthetic ligands of PPARs has been developed, including the group of thiazolidinediones (TZDs), of which some are already in clinical use as oral antidiabetic drugs for non-insulin dependent type 2 diabetes. In recent years an antineoplastic action of TZDs has been identified in different tumor cell types, including gliomas. We therefore investigated whether the TZD pioglitazone (PIO) bears synergistic antitumoral effects when administered in combination with temozolomide in glioma cells in vitro.

Different concentrations of temozolomide (10microM-100microM) and PIO (1microM-30microM) were tested separately as well as in combination on human A172, rat C6 and mouse GL261 glioma cells at different time points (1–7d). A dose- and time-dependent reduction of cellular viability was observed in the glioma cells as assessed by crystal violet staining and colorimetric MTT assay. Combination of temozolomide (50microM) and PIO (10microM) lead to a significant stronger loss of cellular viability in C6 and A172 glioma cells as compared to single treatment alone, whereas GL261 glioma cells were just merely affected.

Western blot analysis was performed to detect levels of cell cycle (p53, p21) as well as apoptosis-related proteins (Bcl-2, Bax, Bad). A decrease of anti-apoptotic Bcl-2 was accompanied by an increase of pro-apoptotic Bad and Bax, indicating an induction of apoptosis in glioma cells by combined treatment. Therefore, a combination therapy of PIO and temozolomide may represent a promising approach for therapy of malignant gliomas.