Prevention of early liver metastasis after pancreatectomy by perioperative administration of a nuclear factor-κB inhibitor in mice

Abstract

Background: Liver metastasis is a common problem after pancreatectomy for pancreatic cancer. In pancreatic cancer cells, nuclear factor-kB is activated constitutively. Nuclear factor-kB activates matrix metalloproteinase-2/9, which plays an important role in cancer metastasis. Because the serine protease inhibitor FUT-175 suppresses nuclear factor-kB, we hypothesized that perioperative treatment with FUT-175 for pancreatic cancer may help to prevent liver metastasis. Methods: We compared in vitro cell viability, cell invasiveness, nuclear factor-kB signaling, and the expression levels of matrix metalloproteinase signals between the control group (C group) and the FUT-175 group (F group) using the murine pancreatic cancer cells PAN02. In addition, we evaluated the in vivo effect of pretreatment with FUT-175 using an established model of liver metastasis in mice. Metastatic liver lesions were assessed with magnetic resonance imaging. Liver recurrence and overall survival were evaluated. Also, the antimetastatic effect of systemic administration of FUT-175 was examined. Results: FUT-175 did not suppress the cell viability of PAN02 cells at or after 24 hours of treatment (P > .05); however, cell invasion was suppressed in the F group compared with the C group (P < .05). The levels of nuclear factor-kB activation, membrane type-1 (MT-1) matrix metalloproteinase (MMP)/ matrix metalloproteinase-14 (MMP-14), and matrix metalloproteinase-2/9 (MMP-2/9) were lower in the F group compared with the C group. In vivo, both disease-free and overall survivals were prolonged in the F group compared with the C group. Systemic administration was also effective in suppressing the number of metastases. Conclusion: Perioperative treatment with FUT-175 may help to prevent early liver metastasis after pancreatectomy for pancreatic cancer.

Nafamostat mesylate prevents metastasis and dissemination of neuroblastoma through vascular endothelial growth factor inhibition

“…3A ). Inhibition of NF-κB by nafamostat mesylate has been reported to suppress VEGF expression ( 8 , 12 ). To determine whether nafamostat mesylate inhibits the activity of the NF-κB pathway, western blot analysis was performed to assess the expression levels of NF-κB in Neuro-2a cells after nafamostat mesylate treatment.…”

“…Nafamostat mesylate is a synthetic serine protease inhibitor that has been used to treat DIC and acute pancreatitis. Although the anticancer activity of nafamostat was demonstrated in several cancers (8,(10)(11)(12)14), the effect of nafamostat mesylate on neuroblastoma has not yet been explored. The present study demonstrated that nafamostat mesylate suppressed neuroblastoma cell dissemination by inhibiting VEGF production from neuroblastoma cells.…”

“…Nafamostat mesylate reportedly inhibited cell proliferation and cell invasion in colorectal cancer and squamous cell carcinoma via inhibition of the NF-κB ( 10 , 14 ). However, Saito et al ( 12 ) and Fujiwara et al ( 8 ) reported that nafamostat mesylate suppressed cell adhesion and invasion, but not cell viability, in pancreatic cancer by downregulating NF-κB levels. Although NF-κB upregulation in cancer cells is the main stimulator of cell proliferation, nafamostat mesylate did not alter the expression level of NF-κB in Neuro-2a cells at 24 h (data not shown).…”

“…VEGF is the most potent inducer of angiogenesis ( 6 ). Several investigators have reported that inhibition of NF-κB by nafamostat mesylate suppressed VEGF expression ( 8 , 12 ). However, the present study demonstrated that nafamostat mesylate suppressed VEGF production from Neuro-2a cells without NF-κB inhibition.…”

“…This agent inhibits thrombin, plasmin, kallikrein, trypsin, and C1 esterase in the complement system and factors VIIa, Xa, and XIIa in the coagulation cascade. Moreover, nafamostat mesylate inhibits the metastasis of colon cancer, pancreatic cancer, breast cancer, and squamous cell carcinoma (8)(9)(10)(11)(12)(13)(14). However, the effects of nafamostat mesylate on other types of cancer have been less extensively studied.…”