Combination chemotherapy of nafamostat mesilate with gemcitabine for pancreatic cancer targeting NF-kappaB activation.
OBJECTIVE
Gemcitabine is currently the standard first-line chemotherapeutic agent for pancreatic cancer. However, chemoresistance to gemcitabine because of gemcitabine-induced nuclear factor-kappaB (NF-kappaB) activation has been reported. We previously reported that the synthetic serine protease inhibitor nafamostat mesilate inhibited NF-kappaB activation and induced apoptosis of pancreatic cancer cells. In this study, whether or not nafamostat mesilate could enhance the anticancer effect of gemcitabine was investigated.


METHODS
NF-kappaB activation in pancreatic cancer cells treated with various agents was examined by electrophoretic mobility shift assay (in vitro) and immunohistochemistry by investigating the location of p65 in cancer cells (in vivo). Apoptosis of the cancer cells treated with agents was examined by flow cytometry.


RESULTS
Nafamostat mesilate inhibited gemcitabine-induced NF-kappaB activation, enhanced apoptosis by gemcitabine and suppressed pancreatic tumor growth. Interestingly, the combination treatment improved the body weight loss of mice induced by gemicitabine.


CONCLUSIONS
This combination chemotherapy could be a potential novel strategy for pancreatic cancer.
Uwagawa
Tadashi
T
Department of Surgery, Jikei University School of Medicine, 3-25-8 Nishi-shinbashi, Minato-ku, Tokyo 105-8461, Japan. uwatadashi@msn.com
Chiao
Paul J
PJ
Gocho
Takeshi
T
Hirohara
Shouichi
S
Misawa
Takeyuki
T
Yanaga
Katsuhiko
K
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D001550:Benzamidines; D002453:Cell Cycle; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004359:Drug Therapy, Combination; D024202:Electrophoretic Mobility Shift Assay; D006146:Guanidines / Q000494:pharmacology*; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D000093542:Gemcitabine
D000964:Antimetabolites, Antineoplastic; D001550:Benzamidines; D006146:Guanidines; D016328:NF-kappa B; D015842:Serine Proteinase Inhibitors; D003841:Deoxycytidine; D012264:Ribonucleotide Reductases; C032855:nafamostat; D000093542:Gemcitabine