New treatment strategy with nuclear factor-κB inhibitor for pancreatic cancer.

ABSTRACT

BACKGROUND: 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. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: NM enhances the antitumor effect of GEM/nPTX chemotherapy for orthotopic pancreatic cancer by inhibition of NF-κB activation.