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Research Articles: Therapeutics, Targets, and Development

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

¹ Department of Obstetrics and Gynecology, and ² Second Department of Biochemistry, Hirosaki University School of Medicine, Hirosaki, Aomori, Japan; and ³ Department of Pathology, Faculty of Medicine, Kuwait University, Safat, Kuwait

Requests for reprints: Yoshihito Yokoyama, Department of Obstetrics and Gynecology, Hirosaki University School of Medicine, 5-Zaifu-cho, Hirosaki, 036-8562, Japan. Phone: 81-172-39-5107; Fax: 81-172-37-6842. E-mail: yokoyama{at}cc.hirosaki-u.ac.jp

Abstract

Recent reports have shown that peroxisome proliferator–activated receptor (PPAR) 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 PPAR 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 PGF₂, 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. [Mol Cancer Ther 2007;6(4):1379–86]

Grant support: Grant-in Aid for Cancer Research (16591632) from the Ministry of Education, Science and Culture of Japan and the Karoji Memorial Fund of the Hirosaki University School of Medicine.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 11/22/06; revised 1/23/07; accepted 2/22/07.

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