The peroxisome proliferator-activated receptor gamma ligands, pioglitazone and 15-deoxy-Delta(12,14)-prostaglandin J(2), 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 gamma (PPARgamma) 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 PPARgamma ligands: troglitazone, pioglitazone, rosiglitazone and 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)). Cell proliferation, cell cycle and apoptosis were analyzed. PPARgamma was expressed in all the cell lines studied. Among the PPARgamma ligands, pioglitazone and 15d-PGJ(2) 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 PPARgamma ligand-induced apoptosis in a dose-dependent manner. These two PPARgamma ligands decreased the expression of bcl-2 in most of the cell lines studied. The results suggest that pioglitazone and 15d-PGJ(2) have antineoplastic effects on HBV-associated HCC cells. Both of these PPARgamma ligands could be candidates for cancer prevention or the chemotherapy of HBV-associated HCC.
Shim
Jaejun
J
Department of Internal Medicine, Kyung Hee University School of Medicine, Dongdaemun-gu, Seoul, Korea.
Kim
Byung-Ho
BH
Kim
Young Il
YI
Kim
Kyung Yup
KY
Hwangbo
Young
Y
Jang
Jae Young
JY
Dong
Seok Ho
SH
Kim
Hyo Jong
HJ
Chang
Young Woon
YW
Chang
Rin
R
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000821:virology; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D006515:Hepatitis B virus / Q000378:metabolism*; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007155:Immunologic Factors / Q000494:pharmacology; D008024:Ligands; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000821:virology; D047495:PPAR gamma / Q000378:metabolism*; D000077205:Pioglitazone; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology; D045162:Thiazolidinediones / Q000494:pharmacology*
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D000970:Antineoplastic Agents; D007004:Hypoglycemic Agents; D007155:Immunologic Factors; D008024:Ligands; D047495:PPAR gamma; D045162:Thiazolidinediones; D053148:Caspase 3; D053453:Caspase 9; D015230:Prostaglandin D2; D000077205:Pioglitazone