Inhibition of nuclear factor-κB enhances the antitumor effect of paclitaxel against gastric cancer with peritoneal dissemination in mice.
BACKGROUND
Intraperitoneal (i.p.) administration of paclitaxel is useful for treating malignant tumors with peritoneal dissemination, but the therapeutic efficacy is limited. Chemoresistance due to paclitaxel-induced nuclear factor-kappa B (NF-κB) activation is an important cause of suboptimal therapeutic efficacy.


OBJECTIVE
The purpose of this study was to prove that addition of nafamostat mesilate (FUT-175), a synthetic serine protease inhibitor and an NF-κB inhibitor, to i.p. paclitaxel enhances antitumor effects of paclitaxel against gastric cancer with peritoneal dissemination.


METHODS
In vitro, we assessed NF-κB activity and apoptosis in response to treatment with FUT-175 alone, paclitaxel alone, or a combination of FUT-175 and paclitaxel in a human gastric cancer cell line (MKN-45). In vivo, we established peritoneal dissemination in nude mice by i.p. injection of MKN-45 cells. The animals received i.p. injections of FUT-175 alone three times a week (FUT-175 group), of paclitaxel alone once a week (paclitaxel group), or a combination of FUT-175 and paclitaxel (combination group) three times and once a week, respectively.


RESULTS
In the combination group, paclitaxel-induced NF-κB activation was inhibited and apoptosis was enhanced in comparison with those in the other groups both in vitro and in vivo. In the combination group, number and weight of peritoneal nodules were significantly lower than those in the paclitaxel group (p = 0.0009 and p = 0.0417, respectively). In the survival analysis, the combination group had a significantly better survival than the paclitaxel group (p = 0.0048).


CONCLUSIONS
FUT-175 enhances the antitumor effect of i.p. paclitaxel against gastric cancer with peritoneal dissemination by inhibiting NF-κB activation in mice.
Department of Surgery, The Jikei University School of Medicine, 3-25-8, Nishi-Shinbashi, Minato-ku, Tokyo, 105-8461, Japan. haruki@jikei.ac.jp
Koichiro
K
Haruki
Hiroaki
H
Shiba
Yuki
Y
Fujiwara
Kenei
K
Furukawa
Ryota
R
Iwase
Tadashi
T
Uwagawa
Takeyuki
T
Misawa
Toya
T
Ohashi
Katsuhiko
K
Yanaga
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001550:Benzamidines; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005786:Gene Expression Regulation / Q000502:physiology; D006146:Guanidines / Q000627:therapeutic use*; D006801:Humans; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009374:Neoplasms, Experimental / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology; D017239:Paclitaxel / Q000627:therapeutic use*; D010534:Peritoneal Neoplasms / Q000556:secondary*; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000473:pathology
D000970:Antineoplastic Agents; D001550:Benzamidines; D006146:Guanidines; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D000072000:NF-KappaB Inhibitor alpha; D011065:Poly(ADP-ribose) Polymerases; D053148:Caspase 3; D053181:Caspase 8; D017239:Paclitaxel; C032855:nafamostat