Inhibition of nuclear factor kappa-B enhances the antitumor effect of combination treatment with tumor necrosis factor-alpha gene therapy and gemcitabine for pancreatic cancer in mice.

Abstract

BACKGROUND:

Combination therapy with tumor necrosis factor-alpha (TNF-α) gene delivery and gemcitabine is a new therapeutic approach for pancreatic cancer. However, the efficacy of both TNF-α and gemcitabine is suppressed due to activation of nuclear factor-kappa B (NF-κB). We hypothesized that nafamostat mesilate (FUT175), an NF-κB inhibitor, enhances the antitumor effect of combination treatment with an adenoviral vector-expressing TNF-α (AxCAhTNF-α) and gemcitabine for pancreatic cancer in mice.

STUDY DESIGN:

In vitro, we assessed that FUT175 inhibited both TNF-α- and gemcitabine-induced NF-κB activation and enhanced apoptosis in human pancreatic cancer cell lines (MIAPaCa-2 and AsPC-1). In vivo, we established a xenograft pancreatic cancer model in mice by subcutaneous injection of MIAPaCa-2 and AsPC-1. The animals were treated with AxCAhTNF-α intratumorally and gemcitabine intraperitoneally once a week (combination group) or AxCAhTNF-α intratumorally and gemcitabine intraperitoneally once a week as well as FUT175 intraperitoneally 3 times a week (triple combination group).

RESULTS:

In vitro, FUT175 inhibited both TNF-α- and gemcitabine-induced NF-κB activation and enhanced induction of apoptosis. In the triple combination group, tumor growth in vivo was significantly slower and there were more apoptotic cells than in the combination group (p < 0.05).

CONCLUSIONS:

Inhibition of NF-κB by FUT175 enhances the antitumor effect of combined TNF-α gene therapy and gemcitabine for pancreatic cancer.

• Authors: Yuki Fujiwara, Hiroaki Shiba, Ryota Iwase, Koichiro Haruki, Kenei Furukawa, Tadashi Uwagawa, Takeyuki Misawa, Toya Ohashi, Katsuhiko Yanaga
• Journal: Journal of the American College of Surgeons (J Am Coll Surg) Vol. 216 Issue 2 Pg. 320-32.e3 (Feb 2013) ISSN: 1879-1190 [Electronic] United States
• PMID: 23219147 (Publication Type: Journal Article)
• Copyright: Copyright © 2013 American College of Surgeons. Published by Elsevier Inc. All rights reserved.

Chemical References

• Benzamidines
• Guanidines
• NF-kappa B
• Tumor Necrosis Factor-alpha
• Deoxycytidine
• nafamostat
• Gemcitabine

Topics

• Adenoviridae
• Analysis of Variance
• Animals
• Benzamidines
• Blotting, Western
• Cell Cycle
• Cell Line, Tumor
• Cell Proliferation
• Combined Modality Therapy
• Deoxycytidine (analogs & derivatives, pharmacology)
• Enzyme-Linked Immunosorbent Assay
• Gene Transfer Techniques
• Genetic Therapy (methods)
• Genetic Vectors
• Guanidines (pharmacology)
• Humans
• In Situ Nick-End Labeling
• Mice
• Mice, Nude
• NF-kappa B (antagonists & inhibitors)
• Pancreatic Neoplasms (therapy)
• Reverse Transcriptase Polymerase Chain Reaction
• Transfection
• Tumor Necrosis Factor-alpha (pharmacology)
• Xenograft Model Antitumor Assays
• Gemcitabine