Anti-tumor effect by inhibition of NF-kappaB activation using nafamostat mesilate for pancreatic cancer in a mouse model.
Constitutive NF-kappaB activation plays a key role in the aggressive behavior of pancreatic cancer. We have reported that nafamostat mesilate, a serine-protease inhibitor, inhibited NF-kappaB activation and induced apoptosis in human pancreatic cancer cells. The aim of this study is to evaluate the therapeutic efficacy of nafamostat mesilate against pancreatic cancer. In vitro, nafamostat mesilate inhibited NF-kappaB activation of human pancreatic cancer cell line (Panc-1) by suppressing IkappaBalpha phosphorylation and induced caspase-8 mediated apoptosis. In vivo, Panc-1 was implanted into the back of nude mice. Five weeks after implantation, nafamostat mesilate was injected intraperitoneally as the treatment group (n=11) three times a week for six weeks, while the control group (n=13) received vehicle only. At the end of six-week treatment, the tumors grew up to 12.89+/-4.27 mm (mean +/- SD) in the treatment group, and 17.93+/-4.45 mm in the control group, respectively. The tumor volume and weight of the treatment group were reduced by 43 and 61% as compared with the control group. The tumor growth was significantly inhibited in the treatment group (p<0.0001). Assays of primary tumors also indicated that nafamostat mesilate inhibited NF-kappaB activation by suppressing IkappaBalpha phosphorylation, resulting in caspase-8 mediated apoptosis. These results suggested that nafamostat mesilate has anti-neoplastic property against experimental pancreatic cancer.
Furukawa
Kenei
K
Jikei University School of Medicine, Minato-ku, Tokyo 105-8461, Japan. k-furukawa@jikei.ac.jp
Iida
Tomonori
T
Shiba
Hiroaki
H
Fujiwara
Yuki
Y
Uwagawa
Tadashi
T
Shimada
Yohta
Y
Misawa
Takeyuki
T
Ohashi
Toya
T
Yanaga
Katsuhiko
K
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001550:Benzamidines; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002469:Cell Separation; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006146:Guanidines / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D001550:Benzamidines; D006146:Guanidines; D016328:NF-kappa B; C032855:nafamostat