Department of Obstetrics and Gynecology, Hirosaki University Graduate School of Medicine, 5-Zaifu-cho, Hirosaki, Aomori 036-8562, Japan.
J Cancer Res Clin Oncol. 2011 Aug;137(8):1219-28. doi: 10.1007/s00432-011-0993-1. Epub 2011 Jun 17.
We have recently reported that peroxisome proliferator-activated receptor gamma (PPARγ) ligands produce antitumor effects against human ovarian cancer in conjunction with reduction in angiogenesis and induction of apoptosis via regulating prostaglandin (PG) E(2) level. In this study, we investigated the effects of combination of ciglitazone, a PPARγ ligand, and cisplatin, a cytotoxic anti-cancer drug, on growth of ovarian cancer.
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 cisplatin alone (5 mg/kg intraperitoneally once on day 1), ciglitazone alone (15 mg/kg intraperitoneally once a week), or the combination.
Ciglitazone alone, cisplatin alone, or their combination significantly suppressed the growth of OVCAR-3 tumors xenotransplated subcutaneously and prolonged the survival of mice with malignant ascites derived from DISS cells as compared with the control. Furthermore, the combination produced a significantly greater antitumor effect than cisplatin or ciglitazone alone and also significantly prolonged the survival time as compared with cisplatin or ciglitazone alone. The combination significantly decreased PGE(2) concentration in serum as well as in ascites, reduced vascular endothelial growth factor as well as microvessel density, and induced apoptosis in solid OVCAR-3 tumor as compared with cisplatin or ciglitazone alone. The combination remarkably decreased the expression of cyclooxygenase-2 (COX-2), microsomal PG E synthase (mPGES), and PG receptor 3 (EP3) in tumors. In vitro experiment showed that ciglitazone enhances the cytotoxicity of cisplatin against ovarian cancer cells.
In conclusion, the combination inhibited the growth of ovarian cancer in conjunction with reduction in angiogenesis and induction of apoptosis resulting from suppression of PGE(2) activation through decreasing the expression of COX-2, mPGES, and EP3. The inhibitory effect of this combination treatment on growth of ovarian cancer suggests a potential to lead a novel therapeutic strategy against ovarian cancer.
我们最近报道过，过氧化物酶体增殖物激活受体γ（PPARγ）配体通过调节前列腺素（PG）E2 水平，与抑制血管生成和诱导细胞凋亡相结合，对人卵巢癌产生抗肿瘤作用。在这项研究中，我们研究了 PPARγ 配体吡格列酮（ciglitazone）与细胞毒性抗癌药物顺铂联合应用对卵巢癌生长的影响。
将皮下接种 OVCAR-3 肿瘤或腹腔内接种 DISS 肿瘤的雌性裸鼠 nu/nu 进行肿瘤生长和生存研究，并单独用顺铂（腹腔内 5mg/kg，第 1 天一次）、吡格列酮（腹腔内 15mg/kg，每周一次）或联合治疗。
与对照组相比，吡格列酮单独、顺铂单独或联合应用均显著抑制了皮下移植的 OVCAR-3 肿瘤的生长，并延长了来自 DISS 细胞的恶性腹水小鼠的存活时间。此外，联合治疗比顺铂或吡格列酮单独治疗产生了更显著的抗肿瘤作用，并且与顺铂或吡格列酮单独治疗相比，也显著延长了生存时间。与顺铂或吡格列酮单独治疗相比，联合治疗还显著降低了血清和腹水 PG 中的 PGE2 浓度，降低了血管内皮生长因子和微血管密度，并诱导了实体 OVCAR-3 肿瘤的凋亡。与顺铂或吡格列酮单独治疗相比，联合治疗还显著降低了肿瘤中 COX-2、微粒体 PG E 合酶（mPGES）和 PG 受体 3（EP3）的表达。体外实验表明，吡格列酮增强了顺铂对卵巢癌细胞的细胞毒性。
总之，该联合治疗通过降低 COX-2、mPGES 和 EP3 的表达抑制了 PGE2 激活，从而抑制了卵巢癌的生长，并伴有血管生成减少和凋亡诱导。这种联合治疗对卵巢癌生长的抑制作用表明，它可能成为治疗卵巢癌的一种新的治疗策略。
