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 mat...
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| Format: | Article |
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MDPI AG
2018-10-01
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| Series: | Cancers |
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| Online Access: | http://www.mdpi.com/2072-6694/10/10/386 |
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| author | Hiroshi Sugano Yoshihiro Shirai Takashi Horiuchi Nobuhiro Saito Yohta Shimada Ken Eto Tadashi Uwagawa Toya Ohashi Katsuhiko Yanaga |
| author_facet | Hiroshi Sugano Yoshihiro Shirai Takashi Horiuchi Nobuhiro Saito Yohta Shimada Ken Eto Tadashi Uwagawa Toya Ohashi Katsuhiko Yanaga |
| author_sort | Hiroshi Sugano |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-12T07:44:35Z |
| format | Article |
| id | doaj.art-f4178e7d15c5415ea20a53c5188e7367 |
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| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-12T07:44:35Z |
| publishDate | 2018-10-01 |
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| series | Cancers |
| spelling | doaj.art-f4178e7d15c5415ea20a53c5188e73672023-09-02T21:05:18ZengMDPI AGCancers2072-66942018-10-01101038610.3390/cancers10100386cancers10100386Nafamostat Mesilate Enhances the Radiosensitivity and Reduces the Radiation-Induced Invasive Ability of Colorectal Cancer CellsHiroshi Sugano0Yoshihiro Shirai1Takashi Horiuchi2Nobuhiro Saito3Yohta Shimada4Ken Eto5Tadashi Uwagawa6Toya Ohashi7Katsuhiko Yanaga8Department of Surgery, The Jikei University School of Medicine, 3-25-8, Nishi-Shinbashi, Minato-ku, Tokyo 105-8461, JapanDepartment of Surgery, The Jikei University School of Medicine, 3-25-8, Nishi-Shinbashi, Minato-ku, Tokyo 105-8461, JapanDepartment of Surgery, The Jikei University School of Medicine, 3-25-8, Nishi-Shinbashi, Minato-ku, Tokyo 105-8461, JapanDepartment of Surgery, The Jikei University School of Medicine, 3-25-8, Nishi-Shinbashi, Minato-ku, Tokyo 105-8461, JapanDivision of Gene Therapy, Research Center for Medical Science, The Jikei University School of Medicine, 3-25-8, Nishi-Shinbashi, Minato-ku, Tokyo 105-8461, JapanDepartment of Surgery, The Jikei University School of Medicine, 3-25-8, Nishi-Shinbashi, Minato-ku, Tokyo 105-8461, JapanDepartment of Surgery, The Jikei University School of Medicine, 3-25-8, Nishi-Shinbashi, Minato-ku, Tokyo 105-8461, JapanDivision of Gene Therapy, Research Center for Medical Science, The Jikei University School of Medicine, 3-25-8, Nishi-Shinbashi, Minato-ku, Tokyo 105-8461, JapanDepartment of Surgery, The Jikei University School of Medicine, 3-25-8, Nishi-Shinbashi, Minato-ku, Tokyo 105-8461, JapanNeoadjuvant 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.http://www.mdpi.com/2072-6694/10/10/386nafamostat mesilatecolorectal cancerionizing radiationNF-κBmatrix metalloproteinases |
| spellingShingle | Hiroshi Sugano Yoshihiro Shirai Takashi Horiuchi Nobuhiro Saito Yohta Shimada Ken Eto Tadashi Uwagawa Toya Ohashi Katsuhiko Yanaga Nafamostat Mesilate Enhances the Radiosensitivity and Reduces the Radiation-Induced Invasive Ability of Colorectal Cancer Cells Cancers nafamostat mesilate colorectal cancer ionizing radiation NF-κB matrix metalloproteinases |
| 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 | nafamostat mesilate colorectal cancer ionizing radiation NF-κB matrix metalloproteinases |
| url | http://www.mdpi.com/2072-6694/10/10/386 |
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