Cancer targeting Gene-Viro-Therapy specific for liver cancer by α-fetoprotein-controlled oncolytic adenovirus expression of SOCS3 and IL-24

The combination of gene therapy and virotherapy for cancer treatment has received close attention and has become a trend in the field of cancer biotherapy. A strategy called 'Cancer Targeting Gene-Viro-Therapy' (CTGVT) or 'Gene Armed Oncolytic Viral Therapy' (GAOVT) has been proposed, in which an antitumor gene is inserted into an oncolytic viral vector. In our previous study, a dual-regulated oncolytic adenovirus with enhanced safety for normal cells and strict liver cancer-targeting ability, designated Ad center dot enAFP center dot E1A center dot E1B (Delta 55) (briefly Ad center dot enAFP center dot D55), was successfully constructed. In the current work, interleukin-24 (IL-24) and suppressor of cytokine signaling 3 (SOCS3) genes were packaged into Ad center dot enAFP center dot D55. The new constructs, Ad center dot enAFP center dot D55-(IL-24) and Ad center dot enAFP center dot D55-(SOCS3), showed improved tumoricidal activity in hepatoma cell lines compared with the oncolytic viral vector Ad center dot enAFP center dot D55. The co-administration of Ad center dot enAFP center dot D55-(IL-24) and Ad center dot enAFP center dot D55-(SOCS3) showed much better antitumor effect than Ad center dot enAFP center dot D55-(IL-24) or Ad center dot enAFP center dot D55-(SOCS3) alone both in vitro and in a nude mouse xenograft model. Moreover, our results also showed that blockade of the Jak/ Stat3 pathway by Ad center dot enAFP center dot D55-(SOCS3) infection in HuH-7 cells could down-regulate some anti-apoptosis proteins, such as XIAP, Bcl-xL, and survivin, which might sensitize the cells to Ad center dot enAFP center dot D55-(IL-24)-induced apoptosis. These results indicate that co-administration of Ade center dot nAFP center dot D55-(IL-24) and Ad center dot enAFP center dot D55-(SOCS3) may serve as a candidate therapeutic approach for the treatment of liver cancer.