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 ... -  《-》

Inhibition of the NF-κB pathway by nafamostat mesilate suppresses colorectal cancer growth and metastasis.

Nafamostat mesilate is an anti-inflammatory drug that is usually used to treat pancreatitis. Recent studies show that it can suppress pancreatic cancer via inhibition of the nuclear factor κB (NF-κB) pathway. However, whether it has anti-tumor activity in some other cancer, including colorectal cancer (CRC), has not been investigated and remained unclear. Here, our study showed that nafamostat mesilate abrogated the constitutive NF-κB activation in CRC cells, which is mediated through inhibition of phosphorylation of IκBα and nuclear translocation of p65. Also, we found that nafamostat mesilate inhibited phosphorylation of Erk in CRC cells. Consistently, our study demonstrated that nafamostat mesilate inhibited the CRC cell proliferation, invasion and migration and induced mitochondria-dependent apoptosis. Furthermore, nafamostat mesilate could reverse oxaliplatin induced NF-κB and Erk activation in CRC cells, and enhance the sensitivity of CRC cells to oxaliplatin. Nafamostat mesilate combined with oxaliplatin repressed subcutaneous tumor growth and hepatic metastasis in vivo. Overall, our data suggest that nafamostat mesilate, a relatively non-toxic drug that targets NF-κB and Erk, may, in combination with oxaliplatin, represent a novel therapeutic strategy for CRC treatment.

Lu YX ，Ju HQ ，Wang F ，Chen LZ ，Wu QN ，Sheng H ，Mo HY ，Pan ZZ ，Xie D ，Kang TB ，Chen G ，Yun JP ，Zeng ZL ，Xu RH ... -  《-》

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 ... -  《-》

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 ... -  《-》

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 ... -  《-》