Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Journal of Hepato-Biliary-Pancreatic Sciences
Published in: Journal of Hepato-Biliary-Pancreatic Sciences 5/2011

01-09-2011 | Original article

Nafamostat mesilate can prevent adhesion, invasion and peritoneal dissemination of pancreatic cancer thorough nuclear factor kappa-B inhibition

Authors: Yuki Fujiwara, Kenei Furukawa, Koichiro Haruki, Yohta Shimada, Tomonori Iida, Hiroaki Shiba, Tadashi Uwagawa, Toya Ohashi, Katsuhiko Yanaga

Published in: Journal of Hepato-Biliary-Pancreatic Sciences | Issue 5/2011

Login to get access

Abstract

Background

Constitutive activation of nuclear factor kappa-B (NF-κB) contributes to the aggressive behavior of pancreatic cancer. Over-expression of downstream target genes of NF-κB such as intercellular adhesion molecule-1 (ICAM-1), interleukin-8 (IL-8), vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP-9) leads to the promotion of cell adhesion, angiogenesis, invasion and metastasis. We previously reported that nafamostat mesilate, a synthetic serine protease inhibitor, blocks NF-κB activation in pancreatic cancer. We hypothesized that nafamostat mesilate may inhibit cell adhesion, angiogenesis, invasion and metastases in peritoneal dissemination of pancreatic cancer.

Methods

In vitro, we assessed inhibition of NF-κB, phosphorylated IκBα, ICAM-1, VEGF and MMP-9 activity by nafamostat mesilate using human pancreatic cancer cell lines (AsPC-1, BxPC-3 and PANC-1). Changes in adhesion and invasion abilities of cancer cells were then evaluated by nafamostat mesilate treatment. In vivo, the efficacy of nafamostat mesilate treatment was assessed using peritoneal dissemination of pancreatic cancer in mice.

Results

In vitro, nafamostat mesilate inhibited activities of NF-κB, phosphorylated IκBα, ICAM-1, VEGF and MMP-9. Moreover, nafamostat mesilate not only inhibited cell adhesion and invasion but also increased the sensitivity of anoikis. In vivo, tumor growth using AsPC-1 cells of the treatment group was significantly slower, and survival rate was significantly better, than those in control group (p < 0.05).

Conclusion

Nafamostat mesilate reduced peritoneal metastasis and prolonged survival of pancreatic cancer-bearing mice.
Appendix
Available only for authorised users
Literature
1.
Evans DB, Abbruzzesse JL, Willett CG. Cancer of the pancreas. In: De Vita VT, Hellman S, Rosenberg SA, editors. Cancer––principles and practice of oncology. 6th ed. Philadelphia: Lippincott Williams and Wilkins; 2001. p. 1126–61.
2.
Niederhuber JE, Brennan MF, Menck HR. The National Cancer Data Base report on pancreatic cancer. Cancer. 1995;76:1671–7.PubMedCrossRef
3.
Chen F, Castranova V, Shi X. New insights into the role of nuclear factor-κB in cell growth regulation. Am J Pathol. 2001;159:387–97.PubMedCrossRef
4.
Beg AA, Baltimore D. An essential role for NF-kB in preventing TNF-alpha-induced cell death. Science. 1996;274:782–4.PubMedCrossRef
5.
Van ADJ, Martin SJ, Kafri T, Green DR, Verma IM. Suppression of TNF-alpha-induced apoptosis by NF-kB. Science. 1996;274:787–9.CrossRef
6.
Karin M, Lin A. NF-κB at the crossroads of life and death. Nature Immunol. 2002;3:221–7.CrossRef
7.
Weixin W, James LA, Douglas BE, Lillie L, Karen RC, Paul JC. The nuclear factor-kB RelA transcription factor is constitutively activated in human pancreatic adenocarcinoma cells. Clin Cancer Res. 1999;5:119–27.
8.
Weixin W, James LA, Douglas BE, Paul JC. Overexpression of urokinase-type plasminogen activator in pancreatic adenocarcinoma is regulated by constitutively activated RelA. Oncogene. 1999;18:4554–63.CrossRef
9.
Fujioka S, Sclabas GM, Schmidit C, Niu J, Frederick WA, Dong QG, et al. Inhibition of constitutive NF-kB activity by IkBαM suppresses tumorigenesis. Oncogene. 2003;22:1365–70.PubMedCrossRef
10.
Fujioka S, Sclabas GM, Schmidit C, Frederick WA, Dong QG, Abbruzzese JL, et al. Function of nuclear κB in pancreatic cancer metastasis. Clin Cancer Res. 2003;9:346–54.PubMed
11.
Rosette C, Roth RB, Oeth P, Braun A, Kammerer S, et al. Role of ICAM1 in invasion of human breast cancer cells. Carcinogenesis. 2005;26:943–50.PubMedCrossRef
12.
Huang S, Robinson JB, Deguzman A, Bucana CD, Fidler IJ. Blockade of nuclear factor-kappaB signaling inhibits angiogenesis and tumorigenicity of human ovarian cancer cells by suppressing expression of vascular endothelial growth factor and interleukin 8. Cancer Res. 2000;60:5334–9.PubMed
13.
Nakagawa Y, Aoki T, Kasuya K, Tsuchida A, Koyanagi Y. Histologic features of venous invasion, expression of vascular endothelial growth factor and matrix metalloproteinase-2 and matrix metalloproteinase-9, and the relation with liver metastasis in pancreatic cancer. Pancreas. 2002;24:169–78.CrossRef
14.
Fujii S, Hitomi Y. New synthetic inhibitors of C1r, C1 esterase, thrombin, kallikrein and trypsin. Biochim Biophys Acta. 1981;661:342–5.PubMed
15.
Aoyama T, Ino Y, Ozeki M, Oda M, Sato T, Koshiyama Y, et al. Pharmacological studies of FUT-175, nafamstat mesilate. I. Inhibition of protease activity in in vitro and in vivo experiments. Jpn J Pharmacol. 1984;35:207–27.
16.
Iwaki M, Ino Y, Motoyoshi A, Ozeki M, Sato T, Kurumi M, et al. Pharmacological studies of FUT-175, nafamostat mesilate. IV. Effects on the pancreatic enzymes and experimental acute pancreatitis in rats. Jpn J Phamacol. 1986;41:155–62.CrossRef
17.
Takahashi H, Takizawa S, Tatewaki W, Nagai K, Wada K, Hanano M, et al. Nafamostat mesilate (FUT-175) in the treatment of patients with disseminated intravascular coagulations. Thomb Haemost. 1989;62:372.
18.
Ohtake Y, Hirasawa H, Sugai T, Oda S, Shiga H, Matsuda K, et al. Nafamostat mesilate as anticoagulant in continuous hemofiltration and continuous hemodiafiltration. Contrib Nephrol. 1991;93:215–7.PubMed
19.
Uwagawa T, Li Z, Chang Z, Xia Q, Peng B, Sclabas GM, et al. Mechanisms of synthetic serine protease inhibitor (FUT-175)-mediated cell death. Cancer. 2007;109:2142–53.PubMedCrossRef
20.
Furukawa K, Iida T, Shiba H, Fujiwara Y, Uwagawa T, Shimada Y, et al. Anti-tumor effect by inhibition of NF-κB activation using nafamostat mesilate for pancreatic cancer in a mouse model. Oncol Rep. 2010;24:843–50.PubMedCrossRef
21.
Uwagawa T, Chiano PJ, Gocho T, Hirohara S, Misawa T, Yanaga K. Combination chemotherapy of nafamostat mesilate with gemcitabine for pancreatic cancer targeting NF-kB activation. Anticancer Res. 2009;29:3173–8.PubMed
22.
Uwagawa T, Misawa T, Sakamoto T, Ito R, Gocho T, Shiba H, et al. A phase I study of full-dose gemcitabine and regional arterial infusion of nafamostat mesilate for advanced pancreatic cancer. Ann Oncol. 2009;20:239–43.PubMedCrossRef
23.
Richter A, Niedergethmann M, Sturm JW, Lorenz D, Post S, Trede M. Long-term results of partial pancreaticoduodenectomy for ductal adenocarcinoma of the pancreatic head: 25-year experience. World J Surg. 2003;27:324–9.PubMedCrossRef
24.
Sperti C, Pasquali C, Piccoli A, Pedrazzoli S. Recurrence after resection for ductal adenocarcinoma of the pancreas. World J Surg. 1997;21:195–200.PubMedCrossRef
25.
Nitecki SS, Sarr MG, Colby TV, Van Heerden JA. Long-term survival after resection for ductal adenocarcinoma of pancreas. Ann Surg. 1995;221:59–66.PubMedCrossRef
26.
Kobayashi S, Asano T, Ochiai T. A proposal of no-touch isolation technique in pancreatoduodectomy for periampullary carcinomas. Hepatogastroenterology. 2001;48:372–4.PubMed
27.
Nomoto S, Nakao A, Kasai Y, Harada A, Nonami T, Takagi H. Detection of ras gene mutation in perioperative blood with pancreatic adenocarcinoma. Jpn J Cancer Res. 1996;87:793–7.PubMed
28.
Hirota M, Shimada S, Yamamoto K, Tanaka E, Sugita H, Egami H, et al. Pancreatectomy using non-touch isolation technique followed by extensive intraoperative peritoneal lavage to prevent cancer cell dissemination: a pilot study. JOP. 2005;6:143–51.PubMed
29.
Shimada Y, Fukuda T, Aoki K, Yukawa T, Iwamuro S, Ohkawa K, et al. A protocol for immunoaffinity separation of the accumulated ubiquitin–protein conjugates solubilized with sodium dodecyl sulfate. Anal Biochem. 2008;377:77–82.PubMedCrossRef
30.
Tsuzuki H, Tani T, Hanazawa K. Regulation of NF-κB. Iyakunomonn. 2003;43:162–7. (in Japanese).
31.
Kimura T, Fuchimoto S, Iwagaki H, Hizuta A, Orita K. Inhibitory effect of nafamostat mesilate on metastasis into the livers of mice and on invasion of the extracellular matrix by cancer cells. J Int Med Res. 1992;20:343–52.PubMed
32.
Ohta T, Shimizu K, Yi S, Takamura H, Amaya K, Kitagawa M, et al. Protease-activated receptor-2 expression and the role of trypsin in cell proliferation in human pancreatic cancers. Int J Oncol. 2003;23:61–6.PubMed
33.
Tajima H, Ohta T, Elnemr A, Yasui T, Kitagawa H, Fushida S, et al. Enhanced invasion of pancreatic adenocarcinoma cells stably transfected with cationic trypsinogen cDNA. Int J Cancer. 2001;94:699–704.PubMedCrossRef
34.
Lin YC, Shun CT, Wu MS, Chen CC. A novel anticancer effect of thalidomide: inhibition of intercellular adhesion molecule-1-mediated cell invasion and metastasis through suppression of nuclear factor-kappaB. Clin Cancer Res. 2006;12:7165–73.PubMedCrossRef
35.
Aggarwal BB, Shishodia S, Takada Y, Banerjee S, Newman RA, Bueso-Ramos CE, et al. Curcumin suppresses the paclitaxel-induced nuclear factor-kappaB pathway in breast cancer cells and inhibits lung metastasis of human breast cancer in nude mice. Clin Cancer Res. 2005;11:7490–8.PubMedCrossRef
36.
Takahashi H, Funahashi H, Sawai H, Sakamoto M, Matsuo Y, Yamamoto M, et al. Glial cell line-derived neurotrophic factor enhances nuclear factor-kappaB activity and invasive potential in human pancreatic cancer cells. Pancreas. 2004;29:22–7.PubMedCrossRef
37.
Uwagawa T, Misawa T, Yanaga K. Treatment for pancreatic cancer with nafamostat mesilate. Surg Frontier. 2007;4:229–35. (in Japanese).
Metadata
Title
Nafamostat mesilate can prevent adhesion, invasion and peritoneal dissemination of pancreatic cancer thorough nuclear factor kappa-B inhibition
Authors
Yuki Fujiwara
Kenei Furukawa
Koichiro Haruki
Yohta Shimada
Tomonori Iida
Hiroaki Shiba
Tadashi Uwagawa
Toya Ohashi
Katsuhiko Yanaga
Publication date
01-09-2011
Publisher
Springer Japan
Published in
Journal of Hepato-Biliary-Pancreatic Sciences / Issue 5/2011
Print ISSN: 1868-6974
Electronic ISSN: 1868-6982
DOI
https://doi.org/10.1007/s00534-011-0390-9

Other articles of this Issue 5/2011

Journal of Hepato-Biliary-Pancreatic Sciences 5/2011 Go to the issue

Image of interest

Life-threatening hemorrhage from the papilla following stent removal (with video)

Topics

Endoscopic bilateral metallic stenting for malignant hilar obstruction using newly designed stents

Topics

Stent selection and tips on placement technique of EUS-guided biliary drainage: transduodenal and transgastric stenting

Topics

Stent selection for both biliary and pancreatic strictures caused by chronic pancreatitis: multiple plastic stents or metallic stents?

Original article

Gene expression analysis for predicting gemcitabine resistance in human cholangiocarcinoma

Topics

Comparison of axial force and cell width of self-expandable metallic stents: which type of stent is better suited for hilar biliary strictures?