Inhibition of the NF-κB pathway by nafamostat mesilate suppresses colorectal cancer growth and metastasis.

Abstract

Nafamostat mesilate is an anti-inflammatory drug that is usually used to treat pancreatitis. Recent studies show that it can suppress pancreatic cancer via inhibition of the nuclear factor κB (NF-κB) pathway. However, whether it has anti-tumor activity in some other cancer, including colorectal cancer (CRC), has not been investigated and remained unclear. Here, our study showed that nafamostat mesilate abrogated the constitutive NF-κB activation in CRC cells, which is mediated through inhibition of phosphorylation of IκBα and nuclear translocation of p65. Also, we found that nafamostat mesilate inhibited phosphorylation of Erk in CRC cells. Consistently, our study demonstrated that nafamostat mesilate inhibited the CRC cell proliferation, invasion and migration and induced mitochondria-dependent apoptosis. Furthermore, nafamostat mesilate could reverse oxaliplatin induced NF-κB and Erk activation in CRC cells, and enhance the sensitivity of CRC cells to oxaliplatin. Nafamostat mesilate combined with oxaliplatin repressed subcutaneous tumor growth and hepatic metastasis in vivo. Overall, our data suggest that nafamostat mesilate, a relatively non-toxic drug that targets NF-κB and Erk, may, in combination with oxaliplatin, represent a novel therapeutic strategy for CRC treatment.

• Authors: Yun-Xin Lu, Huai-Qiang Ju, Feng Wang, Le-Zong Chen, Qi-Nian Wu, Hui Sheng, Hai-Yu Mo, Zhi-Zhong Pan, Dan Xie, Tie-Bang Kang, Gong Chen, Jing-Ping Yun, Zhao-Lei Zeng, Rui-Hua Xu
• Journal: Cancer letters (Cancer Lett) Vol. 380 Issue 1 Pg. 87-97 (09 28 2016) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 27322737 (Publication Type: Journal Article)
• Copyright: Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Benzamidines
• Guanidines
• I-kappa B Proteins
• NF-kappa B
• NFKBIA protein, human
• Organoplatinum Compounds
• RELA protein, human
• Transcription Factor RelA
• Oxaliplatin
• NF-KappaB Inhibitor alpha
• Extracellular Signal-Regulated MAP Kinases
• nafamostat

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Apoptosis (drug effects)
• Benzamidines
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Colorectal Neoplasms (drug therapy, genetics, metabolism, pathology)
• Dose-Response Relationship, Drug
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Female
• Guanidines (pharmacology)
• HCT116 Cells
• HT29 Cells
• Humans
• I-kappa B Proteins (metabolism)
• Liver Neoplasms (genetics, metabolism, prevention & control, secondary)
• Mice, Inbred BALB C
• Mice, Nude
• NF-KappaB Inhibitor alpha
• NF-kappa B (genetics, metabolism)
• Organoplatinum Compounds (pharmacology)
• Oxaliplatin
• Phosphorylation
• RNA Interference
• Signal Transduction (drug effects)
• Time Factors
• Transcription Factor RelA (metabolism)
• Transfection
• Tumor Burden (drug effects)
• Xenograft Model Antitumor Assays