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-κB is activated constitutively. Nuclear factor-κB activates matrix metalloproteinase-2/9, which plays an important role in cancer metastasis. Because the serine protease inhibitor FUT-175 suppresses nuclear factor-κB, 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-κB 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-κB 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.

• Authors: Nobuhiro Saito, Tadashi Uwagawa, Ryouga Hamura, Naoki Takada, Hiroshi Sugano, Yoshihiro Shirai, Hiroaki Shiba, Toya Ohashi, Katsuhiko Yanaga
• Journal: Surgery (Surgery) Vol. 166 Issue 6 Pg. 991-996 (12 2019) ISSN: 1532-7361 [Electronic] United States
• PMID: 31353078 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Benzamidines
• Guanidines
• NF-kappa B
• Matrix Metalloproteinases
• nafamostat

Topics

• Animals
• Benzamidines
• Cell Line, Tumor (transplantation)
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Disease Models, Animal
• Disease-Free Survival
• Drug Screening Assays, Antitumor
• Gene Expression Regulation, Neoplastic (drug effects)
• Guanidines (administration & dosage)
• Humans
• Injections, Intraperitoneal
• Liver Neoplasms (diagnostic imaging, prevention & control, secondary)
• Male
• Matrix Metalloproteinases (metabolism)
• Mice
• NF-kappa B (antagonists & inhibitors)
• Pancreatectomy
• Pancreatic Neoplasms (mortality, pathology, surgery)
• Perioperative Care (methods)
• Signal Transduction (drug effects)