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

被引:75
作者
Yokoyama, Yoshihito [1 ]
Xin, Bing
Shigeto, Tatsuhiko
Umemoto, Mika
Kasai-Sakamoto, Akiko
Futagami, Masayuki
Tsuchida, Shigeki
Al-Mulla, Fahd
Mizunuma, Hideki
机构
[1] Hirosaki Univ, Sch Med, Dept Obstet & Gynecol, Hirosaki, Aomori 0363562, Japan
[2] Hirosaki Univ, Sch Med, Dept Biochem 2, Hirosaki, Aomori, Japan
[3] Kuwait Univ, Fac Med, Dept Pathol, Safat, Kuwait
关键词
HUMAN CARBONYL REDUCTASE; HUMAN BREAST-CANCER; COLON-CANCER; PROSTAGLANDIN; 9-KETOREDUCTASE; PPAR-GAMMA; EXPRESSION; DIFFERENTIATION; APOPTOSIS; CELLS; MICE;
D O I
10.1158/1535-7163.MCT-06-0722
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Recent reports have shown that peroxisome proliferator-activated receptor (PPAR)alpha ligands reduce growth of some types of malignant tumors and prevent carcinogenesis. In thin; study, Ne investigated the inhibitory effect of clofibric acid (CA), a ligand for PPAR alpha 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 suppressecl 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(2 alpha), 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.
引用
收藏
页码:1379 / 1386
页数:8
相关论文
共 42 条
[31]   Global and regional estimates of cancer mortality and incidence by site: II. Results for the global burden of disease 2000 [J].
Shibuya, K ;
Mathers, CD ;
Boschi-Pinto, C ;
Lopez, AD ;
Murray, CJL .
BMC CANCER, 2002, 2 (1)
[32]  
SORENSON CM, 1988, CANCER RES, V48, P4484
[33]  
Thuillier P, 2000, MOL CARCINOGEN, V29, P134, DOI 10.1002/1098-2744(200011)29:3<134::AID-MC2>3.0.CO
[34]  
2-F
[35]   Fenofibrate, a ligand for PPARα3, inhibits aromatase cytochrome P450 expression in the ovary of mouse [J].
Toda, K ;
Okada, T ;
Miyaura, C ;
Saibara, T .
JOURNAL OF LIPID RESEARCH, 2003, 44 (02) :265-270
[36]   Cyclooxygenase regulates angiogenesis induced by colon cancer cells [J].
Tsujii, M ;
Kawano, S ;
Tsuji, S ;
Sawaoka, H ;
Hori, M ;
DuBois, RN .
CELL, 1998, 93 (05) :705-716
[37]   Carbonyl reductase as a significant predictor of survival and lymph node metastasis in epithelial ovarian cancer [J].
Umemoto, M ;
Yokoyama, Y ;
Sato, S ;
Tsuchida, S ;
Al-Mulla, F ;
Saito, Y .
BRITISH JOURNAL OF CANCER, 2001, 85 (07) :1032-1036
[38]  
VANHAPEREN VWTR, 1993, EUR J CANCER, V29A, P2132
[39]  
WERMUTH B, 1981, J BIOL CHEM, V256, P1206
[40]  
Yang VW, 1998, CANCER RES, V58, P1750