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.