Inhibition of nuclear factor-κB enhances the antitumor effect of tumor necrosis factor-α gene therapy for hepatocellular carcinoma in mice

• Published in: Surgery 2013-09, Vol.154 (3), p.468-478
• Main Authors: Haruki, Koichiro, MD, Shiba, Hiroaki, MD, PhD, Fujiwara, Yuki, MD, PhD, Furukawa, Kenei, MD, PhD, Iwase, Ryota, MD, Uwagawa, Tadashi, MD, PhD, Misawa, Takeyuki, MD, PhD, FACS, Ohashi, Toya, MD, PhD, Yanaga, Katsuhiko, MD, PhD, FACS
• Format: Article
• Language: English
• Subjects: Adenoviridae - genetics; Animals; Apoptosis - drug effects; Genetic Therapy; Guanidines - therapeutic use; Humans; Liver Neoplasms, Experimental - pathology; Liver Neoplasms, Experimental - therapy; Male; Mice; Mice, Inbred BALB C; NF-kappa B - antagonists & inhibitors; Surgery; Tumor Necrosis Factor-alpha - genetics
• ISSN: 0039-6060; 1532-7361
• DOI: 10.1016/j.surg.2013.05.037

Background Hepatocellular carcinoma (HCC) is often resistant to chemotherapy. Gene therapy using an adenoviral vector-expressing tumor necrosis factor (TNF)-α is a new therapeutic approach for chemoresistant malignancies. The efficacy of TNF-α, however, is limited, because it leads to the activation of nuclear factor (NF)-κB. We hypothesized that the NF-κB inhibitor nafamostat mesilate would enhance the antitumor effect of adenovirus vector-mediated TNF-α gene therapy for HCC. Methods In vitro, we assessed the inhibitory effect of nafamostat mesilate on TNF-α–induced NF-κB activation and enhanced apoptosis in human HCC cell lines (Huh-7 and Hep3B). In vivo, we established a xenograft HCC model in mice by subcutaneous injection of Huh-7 and Hep3B cells. The animals received intraperitoneal (IP) injections of nafamostat mesilate 3 times a week (nafamostat mesilate group), intratumoral (IT) injections of the human TNF-α–expressing adenoviral vector (AxCAhTNF-α) once a week (TNF-α group), IT injections of AxCAhTNF-α once a week, or IP injections of nafamostat mesilate 3 times a week (combination group). Results In the combination group, TNF-α–induced NF-κB activation was inhibited and TNF-α–induced apoptosis was enhanced in comparison with the other groups both in vitro and in vivo. In the combination group, tumor growth was significantly slower and the apoptotic cell numbers were significantly greater than those of the TNF-α group. Conclusion Inhibition of NF-κB by nafamostat mesilate enhances the antitumor effect of adenoviral vector-mediated TNF-α gene therapy for HCC in mice.