Digestive Diseases and Sciences

, Volume 58, Issue 1, pp 123–131

Inhibition of Nuclear Factor-κB Enhances the Antitumor Effect of Paclitaxel Against Gastric Cancer with Peritoneal Dissemination in Mice

  • Koichiro Haruki
  • Hiroaki Shiba
  • Yuki Fujiwara
  • Kenei Furukawa
  • Ryota Iwase
  • Tadashi Uwagawa
  • Takeyuki Misawa
  • Toya Ohashi
  • Katsuhiko Yanaga
Original Article

DOI: 10.1007/s10620-012-2311-4

Cite this article as:
Haruki, K., Shiba, H., Fujiwara, Y. et al. Dig Dis Sci (2013) 58: 123. doi:10.1007/s10620-012-2311-4

Abstract

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.

Aims

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).

Conclusion

FUT-175 enhances the antitumor effect of i.p. paclitaxel against gastric cancer with peritoneal dissemination by inhibiting NF-κB activation in mice.

Keywords

Nafamostat mesilate Paclitaxel Gastric cancer Peritoneal dissemination Intraperitoneal chemotherapy 

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Koichiro Haruki
    • 1
    • 2
  • Hiroaki Shiba
    • 1
  • Yuki Fujiwara
    • 1
    • 2
  • Kenei Furukawa
    • 1
  • Ryota Iwase
    • 1
    • 2
  • Tadashi Uwagawa
    • 1
  • Takeyuki Misawa
    • 1
  • Toya Ohashi
    • 2
  • Katsuhiko Yanaga
    • 1
  1. 1.Department of SurgeryThe Jikei University School of MedicineTokyoJapan
  2. 2.Department of Gene Therapy, Institute of DNA MedicineThe Jikei University School of MedicineTokyoJapan

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