Peroxisome proliferator-activated receptor alpha and gamma ligands inhibit the growth of human ovarian cancer

Abstract

In this study, we investigated the inhibitory effect of clofibric acid (CA), a ligand for peroxisome proliferator-activated receptor (PPAR)alpha, and pioglitazone, a ligand for PPARgamma, on ovarian cancer in in vivo experiments using human ovarian cancer cell lines, and we aimed to elucidate the molecular mechanism of their anticancer effect. The antitumor effects of CA (3,000 ppm in the daily diet), pioglitazone (240 ppm in the daily diet) or the combination were studied in female nu/nu mice, xenografted with subcutaneous OVCAR-3 tumors or with intraperitoneal DISS tumors. The tumor tissues were quantified for expression levels of AP-1, cyclooxygenase-2 (COX-2) and vascular endothelial growth factor (VEGF) using Western blot analysis or immunohistochemistry. CD-31-stained microvessel density (MVD) was measured in the tumors. The induction of apoptosis was quantified by the TUNEL method. Treatment with CA or pioglitazone significantly suppressed the growth of subcutaneously xenotransplanted OVCAR-3 tumors and prolonged the survival of mice with malignant ascites derived from DISS cells as compared to the control. Combination of both agents enhanced the anticancer effect. Increase of apoptosis and necrosis as well as decrease of VEGF expression and MVD were found in solid OVCAR-3 tumors treated with CA, pioglitazone or the combination. The combination significantly induced apoptotic cells, compared to CA or pioglitazone alone. The combination significantly reduced expression of AP-1, which is a transcriptional regulator of COX-2, and also significantly decreased COX-2 expression in OVCAR-3 tumors compared to the control, CA or pioglitazone alone, although CA or pioglitazone alone decreased them with a marginal significance compared to the control. These findings indicate that the combination of CA and pioglitazone produces a potent antitumor effect on ovarian cancer through reduction of AP-1 expression.