Clofibric acid, a peroxisome proliferator-activated receptor alpha ligand, inhibits growth of human ovarian cancer.
Recent reports have shown that peroxisome proliferator-activated receptor (PPAR)alpha ligands reduce growth of some types of malignant tumors and prevent carcinogenesis. In this study, we investigated the inhibitory effect of clofibric acid (CA), a ligand for PPARalpha on growth of ovarian malignancy, in in vivo and in vitro experiments using OVCAR-3 and DISS cells derived from human ovarian cancer and aimed to elucidate the molecular mechanism of its antitumor effect. CA treatment significantly suppressed the growth of OVCAR-3 tumors xenotransplanted s.c. and significantly prolonged the survival of mice with malignant ascites derived from DISS cells as compared with control. CA also dose-dependently inhibited cell proliferation of cultured cell lines. CA treatment increased the expression of carbonyl reductase (CR), which promotes the conversion of prostaglandin E(2) (PGE(2)) to PGF(2alpha), in implanted OVCAR-3 tumors as well as cultured cells. CA treatment decreased PGE(2) level as well as vascular endothelial growth factor (VEGF) amount in both of OVCAR-3-tumor and DISS-derived ascites. Reduced microvessel density and induced apoptosis were found in solid OVCAR-3 tumors treated by CA. Transfection of CR expression vector into mouse ovarian cancer cells showed significant reduction of PGE(2) level as well as VEGF expression. These results indicate that CA produces potent antitumor effects against ovarian cancer in conjunction with a reduction of angiogenesis and induction of apoptosis. We conclude that CA could be an effective agent in ovarian cancer and should be tested alone and in combination with other anticancer drugs.
Yokoyama
Yoshihito
Y
Department of Obstetrics and Gynecology, Hirosaki University School of Medicine, Hirosaki, Amori, Japan. yokoyama@cc.hirosaki-u.ac.jp
Xin
Bing
B
Shigeto
Tatsuhiko
T
Umemoto
Mika
M
Kasai-Sakamoto
Akiko
A
Futagami
Masayuki
M
Tsuchida
Shigeki
S
Al-Mulla
Fahd
F
Mizunuma
Hideki
H
D000429:Alcohol Oxidoreductases / Q000096:biosynthesis; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001201:Ascites / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002995:Clofibric Acid / Q000008:administration & dosage / Q000494:pharmacology*; D015232:Dinoprostone / Q000097:blood; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000378:metabolism; D008024:Ligands; D051379:Mice; D008807:Mice, Inbred BALB C; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology; D010051:Ovarian Neoplasms / Q000098:blood supply / Q000201:enzymology / Q000473:pathology*; D047493:PPAR alpha / Q000378:metabolism*; D010538:Peritonitis; D000071876:Prostaglandin-E Synthases; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
D000924:Anticholesteremic Agents; D008024:Ligands; D047493:PPAR alpha; D042461:Vascular Endothelial Growth Factor A; D002995:Clofibric Acid; D000429:Alcohol Oxidoreductases; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases; D015232:Dinoprostone