Xin Bing, Yokoyama Yoshihito, Shigeto Tatsuhiko, Futagami Masayuki, Mizunuma Hideki
Department of Obstetrics and Gynecology, Hirosaki University School of Medicine, Hirosaki, Aomori, Japan.
Cancer. 2007 Aug 15;110(4):791-800. doi: 10.1002/cncr.22854.
It was recently reported that high expression of peroxisome proliferator-activated receptor gamma (PPARgamma) and low expression of cyclooxygenase-2 (COX-2) might be involved in the inhibition of ovarian tumor progression and confirmed that PPARgamma activation could suppress COX-2 expression via the nuclear factor-kappaB pathway in ovarian cancer cells.
The current study investigated whether meloxicam, a selective COX-2 inhibitor, and ciglitazone, a ligand for PPARgamma, inhibit the growth of human ovarian cancer cell lines and aimed to elucidate the molecular mechanism of their antitumor effect. Tumor growth and survival were examined in female nu/nu mice xenografted with subcutaneous OVCAR-3 tumors or with intraperitoneal DISS tumors and treated with meloxicam (162 ppm in diet, every day) or ciglitazone (15 mg/kg intraperitoneally once a week).
Both meloxicam and ciglitazone treatments significantly suppressed the growth of OVCAR-3 tumors xenotransplanted subcutaneously and significantly prolonged the survival of mice with malignant ascites derived from DISS cells as compared with controls. Meloxicam treatment decreased COX-2 expression in tumors by 2.5-fold compared with that observed in untreated tumors. Although ciglitazone treatment did not alter COX-2 expression in tumors, it reduced the expression of microsomal prostaglandin (PG) E synthase, which converts COX-derived PGH(2) to PGE(2). Both meloxicam and ciglitazone decreased PGE(2) levels in serum as well as in ascites. Reduced microvessel density and induced apoptosis were found in solid OVCAR-3 tumors treated with either meloxicam or ciglitazone.
These results indicate that both meloxicam and ciglitazone produce antitumor effects against ovarian cancer in conjunction with reduced angiogenesis and induction of apoptosis.
最近有报道称，过氧化物酶体增殖物激活受体γ（PPARγ）高表达和环氧合酶-2（COX-2）低表达可能参与抑制卵巢肿瘤进展，并证实PPARγ激活可通过核因子-κB途径抑制卵巢癌细胞中COX-2的表达。
本研究调查了选择性COX-2抑制剂美洛昔康和PPARγ配体环格列酮是否能抑制人卵巢癌细胞系的生长，并旨在阐明其抗肿瘤作用的分子机制。在皮下接种OVCAR-3肿瘤或腹腔接种DISS肿瘤的雌性裸鼠中检测肿瘤生长和存活情况，并分别用美洛昔康（饮食中162 ppm，每日）或环格列酮（腹腔注射15 mg/kg，每周一次）进行治疗。
与对照组相比，美洛昔康和环格列酮治疗均显著抑制了皮下异种移植的OVCAR-3肿瘤的生长，并显著延长了源自DISS细胞的恶性腹水小鼠的存活时间。与未治疗的肿瘤相比，美洛昔康治疗使肿瘤中COX-2的表达降低了2.5倍。虽然环格列酮治疗未改变肿瘤中COX-2的表达，但它降低了微粒体前列腺素（PG）E合酶的表达，该酶可将COX衍生的PGH2转化为PGE2。美洛昔康和环格列酮均降低了血清以及腹水中的PGE2水平。在用美洛昔康或环格列酮治疗的实体OVCAR-3肿瘤中发现微血管密度降低和细胞凋亡诱导。
这些结果表明，美洛昔康和环格列酮均对卵巢癌产生抗肿瘤作用，同时伴有血管生成减少和细胞凋亡诱导。
