Nafamostat mesilate, a nuclear factor kappa B inhibitor, enhances the antitumor action of radiotherapy on gallbladder cancer cells.

Abstract

Nuclear factor kappa B (NF-κB) is a transcriptional factor that can be activated by radiotherapy and chemotherapy. The synthetic protease inhibitor nafamostat mesilate (NM) inhibits NF-κB activity and exerts antitumor actions in various types of cancer. In the present study, we hypothesized that NM might enhance the antitumor action of radiotherapy on gallbladder cancer (GBC) cells by inhibiting radiation-induced NF-κB activity. Thus, we investigated the correlation between radiotherapy and NF-κB activity in GBC cells. We assessed the in vitro effects of radiotherapy with or without NM on NF-κB activity, apoptosis of GBC cells (NOZ and OCUG-1), induction of apoptotic cascade, cell cycle progression, and viability of GBC cells using four treatment groups: 1) radiation (5 Gy) alone; 2) NM (80 μg/mL and 40 μg/mL, respectively) alone; 3) combination (radiation and NM); and 4) vehicle (control). The same experiments were performed in vivo using a xenograft GBC mouse model. In vitro, NM inhibited radiation-induced NF-κB activity. Combination treatment significantly attenuated cell viability and increased cell apoptosis and G2/M phase cell cycle arrest compared with those in the other groups for NOZ and OCUG-1 cells. Moreover, combination treatment upregulated the expression of apoptotic proteins compared with that after the other treatments. In vivo, NM improved the antitumor action of radiation and increased the population of Ki-67-positive cells. Overall, NM enhanced the antitumor action of radiotherapy on GBC cells by suppressing radiation-induced NF-κB activity. Thus, the combination of radiotherapy and NM may be useful for the treatment of locally advanced unresectable GBC.

• Authors: Naoki Takada, Hiroshi Sugano, Yoshihiro Shirai, Nobuhiro Saito, Ryoga Hamura, Tomohiko Taniai, Tadashi Uwagawa, Katsuhiko Yanaga, Toru Ikegami, Toya Ohashi, Ken Eto
• Journal: PloS one (PLoS One) Vol. 16 Issue 9 Pg. e0257019 ( 2021) ISSN: 1932-6203 [Electronic] United States
• PMID: 34473771 (Publication Type: Journal Article)

Chemical References

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

Topics

• Animals
• Apoptosis (drug effects, radiation effects)
• Benzamidines (administration & dosage)
• Cell Line, Tumor
• Cell Proliferation
• Cell Survival (drug effects, radiation effects)
• Combined Modality Therapy (methods)
• G2 Phase Cell Cycle Checkpoints (drug effects, radiation effects)
• Gallbladder Neoplasms (drug therapy, metabolism, pathology, radiotherapy)
• Guanidines (administration & dosage)
• Humans
• M Phase Cell Cycle Checkpoints (drug effects, radiation effects)
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• NF-kappa B (antagonists & inhibitors, metabolism)
• Protease Inhibitors (administration & dosage)
• Signal Transduction (drug effects, radiation effects)
• Treatment Outcome
• Tumor Burden (drug effects)
• Xenograft Model Antitumor Assays