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Nafamostat Mesilate Enhances the Radiosensitivity and Reduces the Radiation-Induced Invasive Ability of Colorectal Cancer Cells

Neoadjuvant chemoradiotherapy followed by radical surgery is the standard treatment for patients with locally advanced low rectal cancer. However, several studies have reported that ionizing radiation (IR) activates nuclear factor kappa B (NF-κB) that causes radioresistance and induces matrix metall...

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Autores principales: Sugano, Hiroshi, Shirai, Yoshihiro, Horiuchi, Takashi, Saito, Nobuhiro, Shimada, Yohta, Eto, Ken, Uwagawa, Tadashi, Ohashi, Toya, Yanaga, Katsuhiko
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6210678/
https://www.ncbi.nlm.nih.gov/pubmed/30336548
http://dx.doi.org/10.3390/cancers10100386
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author Sugano, Hiroshi
Shirai, Yoshihiro
Horiuchi, Takashi
Saito, Nobuhiro
Shimada, Yohta
Eto, Ken
Uwagawa, Tadashi
Ohashi, Toya
Yanaga, Katsuhiko
author_facet Sugano, Hiroshi
Shirai, Yoshihiro
Horiuchi, Takashi
Saito, Nobuhiro
Shimada, Yohta
Eto, Ken
Uwagawa, Tadashi
Ohashi, Toya
Yanaga, Katsuhiko
author_sort Sugano, Hiroshi
collection PubMed
description Neoadjuvant chemoradiotherapy followed by radical surgery is the standard treatment for patients with locally advanced low rectal cancer. However, several studies have reported that ionizing radiation (IR) activates nuclear factor kappa B (NF-κB) that causes radioresistance and induces matrix metalloproteinase (MMP)-2/-9, which promote tumor migration and invasion. Nafamostat mesilate (FUT175), a synthetic serine protease inhibitor, enhances the chemosensitivity to cytotoxic agents in digestive system cancer cells by inhibiting NF-κB activation. Therefore, we evaluated the combined effect of IR and FUT175 on cell proliferation, migration and invasion of colorectal cancer (CRC) cells. IR-induced upregulation of intranuclear NF-κB, FUT175 counteracted this effect. Moreover, the combination treatment suppressed cell viability and induced apoptosis. Similar effects were also observed in xenograft tumors. In addition, FUT175 prevented the migration and invasion of cancer cells caused by IR by downregulating the enzymatic activity of MMP-2/-9. In conclusion, FUT175 enhances the anti-tumor effect of radiotherapy through downregulation of NF-κB and reduces IR-induced tumor invasiveness by directly inhibiting MMP-2/-9 in CRC cells. Therefore, the use of FUT175 during radiotherapy might improve the efficacy of radiotherapy in patients with CRC.
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spelling pubmed-62106782018-11-02 Nafamostat Mesilate Enhances the Radiosensitivity and Reduces the Radiation-Induced Invasive Ability of Colorectal Cancer Cells Sugano, Hiroshi Shirai, Yoshihiro Horiuchi, Takashi Saito, Nobuhiro Shimada, Yohta Eto, Ken Uwagawa, Tadashi Ohashi, Toya Yanaga, Katsuhiko Cancers (Basel) Article Neoadjuvant chemoradiotherapy followed by radical surgery is the standard treatment for patients with locally advanced low rectal cancer. However, several studies have reported that ionizing radiation (IR) activates nuclear factor kappa B (NF-κB) that causes radioresistance and induces matrix metalloproteinase (MMP)-2/-9, which promote tumor migration and invasion. Nafamostat mesilate (FUT175), a synthetic serine protease inhibitor, enhances the chemosensitivity to cytotoxic agents in digestive system cancer cells by inhibiting NF-κB activation. Therefore, we evaluated the combined effect of IR and FUT175 on cell proliferation, migration and invasion of colorectal cancer (CRC) cells. IR-induced upregulation of intranuclear NF-κB, FUT175 counteracted this effect. Moreover, the combination treatment suppressed cell viability and induced apoptosis. Similar effects were also observed in xenograft tumors. In addition, FUT175 prevented the migration and invasion of cancer cells caused by IR by downregulating the enzymatic activity of MMP-2/-9. In conclusion, FUT175 enhances the anti-tumor effect of radiotherapy through downregulation of NF-κB and reduces IR-induced tumor invasiveness by directly inhibiting MMP-2/-9 in CRC cells. Therefore, the use of FUT175 during radiotherapy might improve the efficacy of radiotherapy in patients with CRC. MDPI 2018-10-17 /pmc/articles/PMC6210678/ /pubmed/30336548 http://dx.doi.org/10.3390/cancers10100386 Text en © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Sugano, Hiroshi
Shirai, Yoshihiro
Horiuchi, Takashi
Saito, Nobuhiro
Shimada, Yohta
Eto, Ken
Uwagawa, Tadashi
Ohashi, Toya
Yanaga, Katsuhiko
Nafamostat Mesilate Enhances the Radiosensitivity and Reduces the Radiation-Induced Invasive Ability of Colorectal Cancer Cells
title Nafamostat Mesilate Enhances the Radiosensitivity and Reduces the Radiation-Induced Invasive Ability of Colorectal Cancer Cells
title_full Nafamostat Mesilate Enhances the Radiosensitivity and Reduces the Radiation-Induced Invasive Ability of Colorectal Cancer Cells
title_fullStr Nafamostat Mesilate Enhances the Radiosensitivity and Reduces the Radiation-Induced Invasive Ability of Colorectal Cancer Cells
title_full_unstemmed Nafamostat Mesilate Enhances the Radiosensitivity and Reduces the Radiation-Induced Invasive Ability of Colorectal Cancer Cells
title_short Nafamostat Mesilate Enhances the Radiosensitivity and Reduces the Radiation-Induced Invasive Ability of Colorectal Cancer Cells
title_sort nafamostat mesilate enhances the radiosensitivity and reduces the radiation-induced invasive ability of colorectal cancer cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6210678/
https://www.ncbi.nlm.nih.gov/pubmed/30336548
http://dx.doi.org/10.3390/cancers10100386
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