title: Combination of ciglitazone, a peroxisome proliferator-activated receptor gamma ligand, and cisplatin enhances the inhibition of growth of human ovarian cancers.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Obstetrics and Gynecology, Hirosaki University Graduate School of Medicine, 5-Zaifu-cho, Hirosaki, Aomori 036-8562, Japan. yokoyama@cc.hirosaki-u.ac.jp
authors.forename: Yoshihito
authors.initials: Y
authors.lastname: Yokoyama
authors.forename: Bing
authors.initials: B
authors.lastname: Xin
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Shigeto
authors.forename: Hideki
authors.initials: H
authors.lastname: Mizunuma
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D001201:Ascites / Q000209:etiology / Q000378:metabolism; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002945:Cisplatin / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D051546:Cyclooxygenase 2 / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism*; D004195:Disease Models, Animal; D004357:Drug Synergism; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D020287:In Situ Nick-End Labeling; D019746:Intramolecular Oxidoreductases / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D008833:Microcirculation / Q000187:drug effects; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D010051:Ovarian Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D047495:PPAR gamma / Q000378:metabolism*; D010534:Peritoneal Neoplasms / Q000188:drug therapy / Q000556:secondary; D000071876:Prostaglandin-E Synthases; D058308:Receptors, Prostaglandin E, EP3 Subtype / Q000378:metabolism; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D014183:Transplantation, Heterologous; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D047495:PPAR gamma; D058308:Receptors, Prostaglandin E, EP3 Subtype; D045162:Thiazolidinediones; D042461:Vascular Endothelial Growth Factor A; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases; D015232:Dinoprostone; D002945:Cisplatin; C039671:ciglitazone