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

Abstract

BACKGROUND:

Constitutive activation of nuclear factor kappa-B (NF-κB) contributes to the aggressive behavior of pancreatic cancer. Over-expression of downstream target genes of NF-κB such as intercellular adhesion molecule-1 (ICAM-1), interleukin-8 (IL-8), vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP-9) leads to the promotion of cell adhesion, angiogenesis, invasion and metastasis. We previously reported that nafamostat mesilate, a synthetic serine protease inhibitor, blocks NF-κB activation in pancreatic cancer. We hypothesized that nafamostat mesilate may inhibit cell adhesion, angiogenesis, invasion and metastases in peritoneal dissemination of pancreatic cancer.

METHODS:

In vitro, we assessed inhibition of NF-κB, phosphorylated IκBα, ICAM-1, VEGF and MMP-9 activity by nafamostat mesilate using human pancreatic cancer cell lines (AsPC-1, BxPC-3 and PANC-1). Changes in adhesion and invasion abilities of cancer cells were then evaluated by nafamostat mesilate treatment. In vivo, the efficacy of nafamostat mesilate treatment was assessed using peritoneal dissemination of pancreatic cancer in mice.

RESULTS:

In vitro, nafamostat mesilate inhibited activities of NF-κB, phosphorylated IκBα, ICAM-1, VEGF and MMP-9. Moreover, nafamostat mesilate not only inhibited cell adhesion and invasion but also increased the sensitivity of anoikis. In vivo, tumor growth using AsPC-1 cells of the treatment group was significantly slower, and survival rate was significantly better, than those in control group (p < 0.05).

CONCLUSION:

Nafamostat mesilate reduced peritoneal metastasis and prolonged survival of pancreatic cancer-bearing mice.

• Authors: Yuki Fujiwara, Kenei Furukawa, Koichiro Haruki, Yohta Shimada, Tomonori Iida, Hiroaki Shiba, Tadashi Uwagawa, Toya Ohashi, Katsuhiko Yanaga
• Journal: Journal of hepato-biliary-pancreatic sciences (J Hepatobiliary Pancreat Sci) Vol. 18 Issue 5 Pg. 731-9 (Sep 2011) ISSN: 1868-6982 [Electronic] Japan
• PMID: 21484229 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Benzamidines
• Guanidines
• Interleukin-8
• NF-kappa B
• Protease Inhibitors
• nafamostat

Topics

• Animals
• Benzamidines
• Blotting, Western
• Cell Adhesion (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Enzyme-Linked Immunosorbent Assay
• Guanidines (pharmacology)
• Humans
• Interleukin-8 (metabolism)
• Male
• Mice
• Mice, Inbred BALB C
• NF-kappa B (antagonists & inhibitors, metabolism)
• Neoplasm Invasiveness (pathology, prevention & control)
• Neoplasms, Experimental (pathology)
• Pancreatic Neoplasms (drug therapy, metabolism, pathology)
• Peritoneal Neoplasms (metabolism, pathology, prevention & control)
• Protease Inhibitors (pharmacology)
• Tumor Cells, Cultured