title: New treatment strategy with nuclear factor-κB inhibitor for pancreatic cancer.
abstract: Because of difficulties with early diagnosis, most patients with pancreatic cancer receive chemotherapy. The National Comprehensive Cancer Network guidelines (version 2.2015) suggest therapy with gemcitabine (GEM) plus nab-paclitaxel (nPTX) as a category 1 recommendation for metastatic pancreatic ductal adenocarcinoma. According to the results of many studies, the activation of chemotherapeutic agents-induced nuclear factor-κB (NF-κB) causes chemoresistance. Hence, we hypothesized that the addition of nafamostat mesilate (NM), a potent NF-κB inhibitor, to GEM/nPTX therapy could enhance the antitumor effect in the treatment of pancreatic ductal adenocarcinoma.
  
  
  
  In vitro, we assessed NF-κB activity and apoptosis under treatment with NM alone (80 μg/mL), with GEM/nPTX, or with a combination of NM and GEM/nPTX in human pancreatic cancer cell lines (PANC-1, MIA PaCa-2, and AsPC-1). In vivo, orthotopic pancreatic cancer mice (BALBc nu/nu) were divided into four groups: control (n = 13), NM (n = 13), GEM/nPTX (n = 13), and triple combination (n = 13). NM (30 mg/kg) was delivered intraperitoneally three times a week, and GEM/nPTX was injected intravenously once a week to orthotopic pancreatic cancer model mice. In the triple combination group, mice received NM followed by GEM/nPTX on the first day to avoid GEM/nPTX-induced NF-κB activation.
  
  
  
  In vitro and in vivo, NM inhibited GEM/nPTX-induced NF-κB activation, and a synergistic effect of apoptosis was observed in the triple combination group. Furthermore, tumor growth was significantly suppressed in the triple combination group compared with the other groups.
  
  
  
  NM enhances the antitumor effect of GEM/nPTX chemotherapy for orthotopic pancreatic cancer by inhibition of NF-κB activation.
authors.affiliation: Department of Surgery, The Jikei University School of Medicine, Tokyo, Japan. Electronic address: horiuchi@jikei.ac.jp.
authors.forename: Takashi
authors.initials: T
authors.lastname: Horiuchi
authors.affiliation: Department of Surgery, 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: Yoshihiro
authors.initials: Y
authors.lastname: Shirai
authors.affiliation: Department of Surgery, 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: 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: 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: 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: D000418:Albumins / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001550:Benzamidines; D015415:Biomarkers / Q000378:metabolism; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D004334:Drug Administration Schedule; D006146:Guanidines / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D017239:Paclitaxel / Q000494:pharmacology / Q000627:therapeutic use*; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: C520255:130-nm albumin-bound paclitaxel; D000418:Albumins; D000970:Antineoplastic Agents; D001550:Benzamidines; D015415:Biomarkers; D006146:Guanidines; D016328:NF-kappa B; D003841:Deoxycytidine; D017239:Paclitaxel; C032855:nafamostat; D000093542:Gemcitabine
keywords: Gemcitabine; NF-κB; Nab-paclitaxel; Nafamostat mesilate; Orthotopic mouse model; Pancreatic cancer