title: Recombinant thrombomodulin suppresses tumor growth of pancreatic cancer by blocking thrombin-induced PAR1 and NF-κB activation.
abstract: Thrombomodulin, an anticoagulant that inhibits thrombin-induced growth factor promotion, also has an anti-inflammatory effect. Furthermore, thrombomodulin inhibits nuclear factor-kappa B activation, which plays a crucial role in cancer progression. We assessed the antitumor activity of recombinant thrombomodulin for pancreatic cancer.
  
  
  
  A xenograft orthotopic model was established in mice by implantation of human pancreatic cancer cells. The animals were treated with intraperitoneal injection of recombinant thrombomodulin 5 times a week for 4 weeks. Nuclear factor-kappa B activation was evaluated by measuring nuclear localization of the p65. Efficacy of recombinant thrombomodulin on the signal transduction of nuclear factor-kappa B was measured in vitro under preconditioning with thrombin or epidermal growth factor.
  
  
  
  Tumor growth was suppressed by recombinant thrombomodulin (P < .05). Recombinant thrombomodulin inhibited the expression of IκB kinase β (P < .05) and pIκBα (P < .01), as well as the activation of nuclear factor-kappa B NF-κB (P < .001). Furthermore, recombinant thrombomodulin inhibited thrombin-induced protease activate receptor 1 and nuclear factor-kappa B activation in vitro (P < .05). The number of Ki67-positive cells was decreased by recombinant thrombomodulin (P < .01). Recombinant thrombomodulin also suppressed body weight loss associated with pancreatic cancer (P < .05). No obvious adverse effects were observed.
  
  
  
  Recombinant thrombomodulin significantly suppressed tumor growth against human pancreatic cancer by blocking thrombin-induced nuclear factor-kappa B activation without adverse effects.
authors.affiliation: Department of Surgery, The Jikei University, School of Medicine, Tokyo, Japan; Division of Gene Therapy, Research Center for Medical Science, The Jikei University, School of Medicine, Tokyo, Japan. Electronic address: shirai@jikei.ac.jp.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Shirai
authors.affiliation: Department of Surgery, The Jikei University, School of Medicine, Tokyo, Japan; Division of Clinical Oncology and Hematology, and Department of Internal Medicine, The Jikei University, School of Medicine, Tokyo, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Uwagawa
authors.affiliation: Department of Surgery, The Jikei University, School of Medicine, Tokyo, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Shiba
authors.affiliation: Division of Gene Therapy, Research Center for Medical Science, The Jikei University, School of Medicine, Tokyo, Japan.
authors.forename: Yohta
authors.initials: Y
authors.lastname: Shimada
authors.affiliation: Department of Surgery, The Jikei University, School of Medicine, Tokyo, Japan; Division of Gene Therapy, Research Center for Medical Science, The Jikei University, School of Medicine, Tokyo, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Horiuchi
authors.affiliation: Department of Surgery, The Jikei University, School of Medicine, Tokyo, Japan; Division of Gene Therapy, Research Center for Medical Science, The Jikei University, School of Medicine, Tokyo, Japan.
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Saito
authors.affiliation: Department of Surgery, The Jikei University, School of Medicine, Tokyo, Japan.
authors.forename: Kenei
authors.initials: K
authors.lastname: Furukawa
authors.affiliation: Division of Gene Therapy, Research Center for Medical Science, The Jikei University, School of Medicine, Tokyo, Japan.
authors.forename: Toya
authors.initials: T
authors.lastname: Ohashi
authors.affiliation: Department of Surgery, The Jikei University, School of Medicine, Tokyo, Japan.
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Yanaga
mesh_terms: D000818:Animals; D001707:Biopsy, Needle; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D051550:I-kappa B Kinase / Q000187:drug effects / Q000235:genetics*; D007150:Immunohistochemistry; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D011897:Random Allocation; D012016:Reference Values; D015398:Signal Transduction / Q000187:drug effects; D018180:Thrombomodulin / Q000008:administration & dosage*
chemical_list: D016328:NF-kappa B; D018180:Thrombomodulin; D051550:I-kappa B Kinase