title: Nafamostat mesilate can prevent adhesion, invasion and peritoneal dissemination of pancreatic cancer thorough nuclear factor kappa-B inhibition.
abstract: BACKGROUND
  Constitutive activation of nuclear factor kappa-B (NF-κB) contributes to the aggressive behavior of pancreatic cancer. Over-expression of downstream target genes of NF-κB such as intercellular adhesion molecule-1 (ICAM-1), interleukin-8 (IL-8), vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP-9) leads to the promotion of cell adhesion, angiogenesis, invasion and metastasis. We previously reported that nafamostat mesilate, a synthetic serine protease inhibitor, blocks NF-κB activation in pancreatic cancer. We hypothesized that nafamostat mesilate may inhibit cell adhesion, angiogenesis, invasion and metastases in peritoneal dissemination of pancreatic cancer.
  
  
  METHODS
  In vitro, we assessed inhibition of NF-κB, phosphorylated IκBα, ICAM-1, VEGF and MMP-9 activity by nafamostat mesilate using human pancreatic cancer cell lines (AsPC-1, BxPC-3 and PANC-1). Changes in adhesion and invasion abilities of cancer cells were then evaluated by nafamostat mesilate treatment. In vivo, the efficacy of nafamostat mesilate treatment was assessed using peritoneal dissemination of pancreatic cancer in mice.
  
  
  RESULTS
  In vitro, nafamostat mesilate inhibited activities of NF-κB, phosphorylated IκBα, ICAM-1, VEGF and MMP-9. Moreover, nafamostat mesilate not only inhibited cell adhesion and invasion but also increased the sensitivity of anoikis. In vivo, tumor growth using AsPC-1 cells of the treatment group was significantly slower, and survival rate was significantly better, than those in control group (p < 0.05).
  
  
  CONCLUSIONS
  Nafamostat mesilate reduced peritoneal metastasis and prolonged survival of pancreatic cancer-bearing mice.
authors.affiliation: Department of Surgery, The Jikei University School of Medicine, 3-25-8, Nishi-Shinbashi, Minato-ku, Tokyo 105-8461, Japan. sheetan@jikei.ac.jp
authors.forename: Yuki
authors.initials: Y
authors.lastname: Fujiwara
authors.forename: Kenei
authors.initials: K
authors.lastname: Furukawa
authors.forename: Koichiro
authors.initials: K
authors.lastname: Haruki
authors.forename: Yohta
authors.initials: Y
authors.lastname: Shimada
authors.forename: Tomonori
authors.initials: T
authors.lastname: Iida
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Shiba
authors.forename: Tadashi
authors.initials: T
authors.lastname: Uwagawa
authors.forename: Toya
authors.initials: T
authors.lastname: Ohashi
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Yanaga
mesh_terms: D000818:Animals; D001550:Benzamidines; D015153:Blotting, Western; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D006146:Guanidines / Q000494:pharmacology*; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009361:Neoplasm Invasiveness / Q000473:pathology / Q000517:prevention & control*; D009374:Neoplasms, Experimental / Q000473:pathology*; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D010534:Peritoneal Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control; D011480:Protease Inhibitors / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D001550:Benzamidines; D006146:Guanidines; D016209:Interleukin-8; D016328:NF-kappa B; D011480:Protease Inhibitors; C032855:nafamostat