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.
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Article info
Publication history
Accepted:
May 28,
2013
Identification
Copyright
© 2013 Mosby, Inc. Published by Elsevier Inc. All rights reserved.
