An Oncolytic Adenoviral Vector of Smac Increases Antitumor Activity of TRAIL Against HCC

Hepatocellular carcinoma (HCC) displays a high resistance to tumor necrosis factor–related apopto-sis–inducing ligand (TRAIL)–mediated cell death. To increase sensitivity ofHCCcells toTRAIL,we have constructed an oncolytic adenoviral vector (ZD55) and used this vector to deliver secondmito-chondria-derived activator of caspases (Smac) and TRAIL genes (ZD55-Smac and ZD55-TRAIL, respectively) intoHCCcells.Our data showed that humanHCCcells express high levels of inhibitor of apoptosis proteins (IAPs). Transfected HCC cells expressing exogenous X-linked IAPs (XIAPs) displayed more resistance to TRAIL. The expression of Smac led to rapid and potent activation of apoptosis inHCC cells after infectionwith ZD55-Smac. The activation of caspases and induction of apoptosis could be enhanced further through coinfection with ZD55-TRAIL. The combined treat-mentofZD55-SmacandZD55-TRAILresulted in significant reductionofXIAPexpression levels. In addition, our in vivo data in mice showed only a partial response in the established tumor treated either by ZD55-Smac or ZD55-TRAIL alone. By contrast, complete tumor regression was observed by combination of ZD55-Smac and ZD55-TRAIL in all treated animals. This strong antitumoral activity achieved by this combinationwas due to a dramatic induction of tumor cell apoptosis in the treated tumors. In conclusion, our data indicate that Smac antagonizes the IAPs inHCC tumor cell