title: Combination chemotherapy of nafamostat mesylate with gemcitabine for gallbladder cancer targeting nuclear factor-κB activation.
abstract: BACKGROUND
  Gemcitabine is an effective chemotherapeutic agent for advanced gallbladder cancer. However, chemoresistance attributable to gemcitabine-induced nuclear factor-κB (NF-κB) activation has been reported. We previously reported that nafamostat mesylate inhibited NF-κB activation and induced apoptosis in pancreatic cancer. Therefore, we hypothesized that nafamostat mesylate inhibits gemcitabine-induced NF-κB activation and enhances apoptosis induced by gemcitabine in gallbladder cancer.
  
  
  METHODS
  In vitro, we assessed NF-κB activation of a gallbladder cancer cell line (NOZ) treated with nafamostat mesylate, gemcitabine, or a combination of both. In vivo, we established a xenograft gallbladder cancer model in mice by subcutaneous injection of NOZ cells. Five weeks after implantation, the animals were treated with nafamostat mesylate three times a week in the nafamostat mesylate group, with gemcitabine once a week in the gemcitabine group, or with a combination of nafamostat mesylate three times a week and gemcitabine once a week in the combination group, respectively. In the control group, only the vehicle of gemcitabine and nafamostat mesylate was injected at the same time course.
  
  
  RESULTS
  In the combination group, NF-κB activation was inhibited and apoptosis was enhanced compared with gemcitabine alone in vitro and vivo. Tumor growth in the combination group was significantly slower than that in the gemcitabine group (P < 0.001). At the end of the study, the tumor weight and volume in the combination group were significantly lower than those in the gemcitabine group (P = 0.039 and 0.028, respectively).
  
  
  CONCLUSIONS
  Combination chemotherapy of gemcitabine with nafamostat mesylate enhances the anti-tumor effect against xenograft gallbladder cancer model in mice.
authors.affiliation: Department of Surgery, Jikei University School of Medicine, Tokyo, Japan. ryotaiwa@jikei.ac.jp
authors.forename: Ryota
authors.initials: R
authors.lastname: Iwase
authors.forename: Koichiro
authors.initials: K
authors.lastname: Haruki
authors.forename: Yuki
authors.initials: Y
authors.lastname: Fujiwara
authors.forename: Kenei
authors.initials: K
authors.lastname: Furukawa
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Shiba
authors.forename: Tadashi
authors.initials: T
authors.lastname: Uwagawa
authors.forename: Takeyuki
authors.initials: T
authors.lastname: Misawa
authors.forename: Toya
authors.initials: T
authors.lastname: Ohashi
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Yanaga
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001550:Benzamidines; D002277:Carcinoma / Q000188:drug therapy / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004359:Drug Therapy, Combination; D005706:Gallbladder Neoplasms / Q000188:drug therapy / Q000473:pathology*; D006146:Guanidines / Q000494:pharmacology*; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016328:NF-kappa B / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D001550:Benzamidines; D006146:Guanidines; D016328:NF-kappa B; D015842:Serine Proteinase Inhibitors; D003841:Deoxycytidine; C032855:nafamostat; D000093542:Gemcitabine
keywords: Gallbladder cancer; Gemcitabine; NF-κB; Nafamostat mesylate