title: Dual inhibition of nuclear factor kappa-B and Mdm2 enhance the antitumor effect of radiation therapy for pancreatic cancer.
abstract: BACKGROUND
  Radiation therapy, alone or in combination with chemotherapy, is effective for patients with locally advanced and recurrent pancreatic cancer. Ionizing radiation induces cell cycle arrest and cell apoptosis through enhancement several signals such as p53, p21(Waf1/Cip1), and caspase. However, the therapeutic efficacy is attenuated by radiation-induced activation of NF-κB. Nafamostat mesilate, a synthetic serine protease inhibitor, inhibits NF-κB activation in pancreatic cancer. Therefore, we hypothesized that nafamostat mesilate inhibited radiation-induced activation of NF-κB and improves therapeutic outcome.
  
  
  RESULTS
  In combination group, NF-κB activation was significantly inhibited in comparison with that of radiation group. Nafamostat mesilate obviously down-regulated the expression levels of Mdm2 compared with control cells or irradiated cells. Consequently, p53 expression was stabilized inversely in correlation with Mdm2 protein expression level. The expression levels of p53, p21(Waf1/Cip1), cleaved caspase-3 and -8 were the highest in the combination group. Nafamostat mesilate enhanced ionizing radiation-induced cell apoptosis and G2/M cell cycle arrest. In combination group, cell proliferation and tumor growth were significantly slower than those in other groups.
  
  
  CONCLUSIONS
  Combination therapy of radiation with nafamostat mesilate exerts enhanced anti-tumor effect against human pancreatic cancer.
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.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Shiba
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: Ryota
authors.initials: R
authors.lastname: Iwase
authors.affiliation: Department of Surgery, The Jikei University School of Medicine, Tokyo, Japan.
authors.forename: Koichiro
authors.initials: K
authors.lastname: Haruki
authors.affiliation: Department of Surgery, The Jikei University School of Medicine, Tokyo, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Fujiwara
authors.affiliation: Department of Surgery, The Jikei University School of Medicine, Tokyo, Japan.
authors.forename: Kenei
authors.initials: K
authors.lastname: Furukawa
authors.affiliation: Department of Surgery, The Jikei University School of Medicine, Tokyo, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Uwagawa
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; D017209:Apoptosis / Q000187:drug effects; D001550:Benzamidines; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D006146:Guanidines / Q000494:pharmacology*; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000502:physiology; D010190:Pancreatic Neoplasms / Q000473:pathology / Q000532:radiotherapy*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors* / Q000502:physiology; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology
chemical_list: D001550:Benzamidines; D006146:Guanidines; D016328:NF-kappa B; D011838:Radiation-Sensitizing Agents; D015842:Serine Proteinase Inhibitors; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; C032855:nafamostat
keywords: Mdm2; NF-κB; Nafamostat mesilate; Pancreatic cancer; Radiation