Clofibric acid, a peroxisome proliferator-activated receptor α ligand, inhibits growth of human ovarian cancer

Yoshihito Yokoyama, Bing Xin, Tatsuhiko Shigeto, Mika Umemoto, Akiko Kasai-Sakamoto, Masayuki Futagami, Shigeki Tsuchida, Fahd Al-Mulla, Hideki Mizunuma

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Abstract

Recent reports have shown that peroxisome proliferator-activated receptor (PPAR)α 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 PPARα 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 E2 (PGE2) to PGF2α, in implanted OVCAR-3 tumors as well as cultured cells. CA treatment decreased PGE2 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 PGE2 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.

Original languageEnglish
Pages (from-to)1379-1386
Number of pages8
JournalMolecular Cancer Therapeutics
Volume6
Issue number4
DOIs
Publication statusPublished - 1 Apr 2007

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    Yokoyama, Y., Xin, B., Shigeto, T., Umemoto, M., Kasai-Sakamoto, A., Futagami, M., Tsuchida, S., Al-Mulla, F., & Mizunuma, H. (2007). Clofibric acid, a peroxisome proliferator-activated receptor α ligand, inhibits growth of human ovarian cancer. Molecular Cancer Therapeutics, 6(4), 1379-1386. https://doi.org/10.1158/1535-7163.MCT-06-0722