Dual inhibition of nuclear factor kappa-B and Mdm2 enhance the antitumor effect of radiation therapy for pancreatic cancer.

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. 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. Combination therapy of radiation with nafamostat mesilate exerts enhanced anti-tumor effect against human pancreatic cancer.

Shirai Y ，Shiba H ，Iwase R ，Haruki K ，Fujiwara Y ，Furukawa K ，Uwagawa T ，Ohashi T ，Yanaga K ... -  《-》

Nafamostat mesilate can prevent adhesion, invasion and peritoneal dissemination of pancreatic cancer thorough nuclear factor kappa-B inhibition.

Fujiwara Y ，Furukawa K ，Haruki K ，Shimada Y ，Iida T ，Shiba H ，Uwagawa T ，Ohashi T ，Yanaga K ... -  《-》

Combination chemotherapy of serine protease inhibitor nafamostat mesilate with oxaliplatin targeting NF-κB activation for pancreatic cancer.

In this study, we assessed if nafamostat mesilate may enhance anti-tumor effects of oxaliplatin on Panc-1 cells and pancreatic cancer mouse model. In combination treatment with nafamostat mesilate and oxaliplatin, NF-κB activation was inhibited by suppressing IκBα phosphorylation, and caspase-8-mediated apoptosis was more prominent than that treated with oxaliplatin alone, both in vitro and in vivo. Nafamostat mesilate reduced proliferation rate of Panc-1 cells as compared with oxaliplatin alone in vitro and enhanced oxaliplatin-induced tumor growth inhibition in vivo. Combination chemotherapy using nafamostat mesilate and oxaliplatin induces synergistic cytotoxicity in pancreatic cancer and could be a novel strategy for treatment.

Gocho T ，Uwagawa T ，Furukawa K ，Haruki K ，Fujiwara Y ，Iwase R ，Misawa T ，Ohashi T ，Yanaga K ... -  《-》

Combination treatment using adenovirus vector-mediated tumor necrosis factor-alpha gene transfer and a NF-κB inhibitor for pancreatic cancer in mice.

Gene therapy using an adenoviral vector expressing tumor necrosis factor-alpha (TNF-α) is a new therapeutic approach for pancreatic cancer. However, the efficacy of TNF-α is limited, because it activates nuclear factor-κB (NF-κB). We investigated the combined use of AxCAhTNF-α, adenoviral vector-expressing human TNF-α, and nafamostat mesilate, a serine-protease inhibitor, a NF-κB inhibitor, using pancreatic cancer in mice. In vitro, nafamostat mesilate inhibited TNF-α-induced NF-κB activation and enhanced TNF-α-induced apoptosis in human cancer cell line (MIAPaCa-2). In vivo, we assessed combination treatment of AxCAhTNF-α and nafamostat mesilate using xenograft models in nude mice by subcutaneous injection of MIAPaCa-2. When the implanted tumor size reached 8.0mm, TNF-α group (n=12), was injected AxCAhTNF-α intra-tumorally once a week, while combination group (n=12), was injected AxCAhTNF-α intra-tumorally once a week and nafamostat mesilate intraperitoneally thrice a week. In combination group, tumor growth was significantly slower, and the number of apoptosis cells was significantly greater than those in AxCAhTNF-α group (p<0.05). In conclusion, adenovirus vector-mediated TNF-α gene therapy combined with nafamostat mesilate was effective for pancreatic cancer in mice.

Furukawa K ，Ohashi T ，Haruki K ，Fujiwara Y ，Iida T ，Shiba H ，Uwagawa T ，Kobayashi H ，Yanaga K ... -  《-》

Anti-tumor effect by inhibition of NF-kappaB activation using nafamostat mesilate for pancreatic cancer in a mouse model.

Furukawa K ，Iida T ，Shiba H ，Fujiwara Y ，Uwagawa T ，Shimada Y ，Misawa T ，Ohashi T ，Yanaga K ... -  《-》