The peroxisome proliferator-activated receptor γ ligands, pioglitazone and 15-deoxy-Δ12,14-prostaglandin J2, have antineoplastic effects against hepatitis B virus-associated hepatocellular carcinoma cells

Chronic hepatitis B virus (HBV) infection is the most common cause of hepatocellular carcinoma (HCC) worldwide. This study investigated the antineoplastic effects of intrinsic and extrinsic peroxisome proliferator-activated receptor γ (PPARγ) ligands against HBV-associated HCC cells in vitro. Four cell lines that were established from patients with HBV-associated HCC were used. The cells were cultured in various concentrations of the following PPARγ ligands: troglitazone, pioglitazone, rosiglitazone and 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2). Cell proliferation, cell cycle and apoptosis were analyzed. PPARγ was expressed in all the cell lines studied. Among the PPARγ ligands, pioglitazone and 15d-PGJ2 clearly inhibited the HBV-associated HCC cell growth and increased the proportion of cells in the sub-G1 phase in the cell-cycle analysis. In apoptosis assays, DNA fragments increased significantly, and the activities of caspase-3 and -9 also increased. A pan-caspase inhibitor and a caspase-3 inhibitor suppressed the PPARγ ligand-induced apoptosis in a dose-dependent manner. These two PPARγ ligands decreased the expression of bcl-2 in most of the cell lines studied. The results suggest that pioglitazone and 15d-PGJ2 have antineoplastic effects on HBV-associated HCC cells. Both of these PPARγ ligands could be candidates for cancer prevention or the chemotherapy of HBV-associated HCC.