Inhibition of nuclear factor kappa-b enhances the antitumor effect of combination treatment with tumor necrosis factor-alpha gene therapy and gemcitabine for pancreatic cancer in mice

摘要

Background: Combination therapy with tumor necrosis factor-alpha (TNF-??) gene delivery and gemcitabine is a new therapeutic approach for pancreatic cancer. However, the efficacy of both TNF-?? and gemcitabine is suppressed due to activation of nuclear factor-kappa B (NF-??B). We hypothesized that nafamostat mesilate (FUT175), an NF-??B inhibitor, enhances the antitumor effect of combination treatment with an adenoviral vector-expressing TNF-?? (AxCAhTNF-??) and gemcitabine for pancreatic cancer in mice. Study Design: In vitro, we assessed that FUT175 inhibited both TNF-??- and gemcitabine-induced NF-??B activation and enhanced apoptosis in human pancreatic cancer cell lines (MIAPaCa-2 and AsPC-1). In vivo, we established a xenograft pancreatic cancer model in mice by subcutaneous injection of MIAPaCa-2 and AsPC-1. The animals were treated with AxCAhTNF-?? intratumorally and gemcitabine intraperitoneally once a week (combination group) or AxCAhTNF-?? intratumorally and gemcitabine intraperitoneally once a week as well as FUT175 intraperitoneally 3 times a week (triple combination group). Results: In vitro, FUT175 inhibited both TNF-??- and gemcitabine-induced NF-??B activation and enhanced induction of apoptosis. In the triple combination group, tumor growth in vivo was significantly slower and there were more apoptotic cells than in the combination group (p < 0.05). Conclusions: Inhibition of NF-??B by FUT175 enhances the antitumor effect of combined TNF-?? gene therapy and gemcitabine for pancreatic cancer. ? 2013 by the American College of Surgeons.