Antitumor Effect Of Combining IL24 And MnSOD Mediated By Oncolytic Poxvirus In Cancer

I At present, cancer is one of the most serious disease to human healthy threat. Thus, it is particularly urgent to find a way to treat cancer. Gene therapy and the first or second generation oncolytic viruses were not ideal for the treatment of cancer. Oncolytic vaccinia virus as the third generation of oncolytic virus has more advantages,such as wide host rage, rapid replicatation, well-known side effect, large amounts of foreign DNA insertion, high antitumor immunogenic. Vaccinia virus deleting TK gene or B18 R gene can enhance targeting of tumor cells and not affect the replication. Thus, oncolytic vaccinia virus is an ideal gene therapy vectors.It was reported that vaccinia virus deleting TK region-mediated an exogenous gene has very good anticancer effect. To enhance the killing effect of oncolytic vaccinia virus to cancer cells, we inserted IL24 and MnSOD genes into the vaccinia virus TK and B18 R region, respectively and constructed recombinant virus the OncoPox-IL24- MnSOD. Since IL24 and MnSOD genes as tumor suppressor found in recent years were downregulated expression in a variety of cancer cells. It can inhibit normal cells transforming to cancer cells, induce immune response, arrest the growth of cancer cells and promote their apoptosis.In this study, we successfully constructed recombinant virus OncoPox- MnSOD(TK-), and OncoPox-IL24(TK-)-MnSOD(B18R-), by inserting MnSOD genes into the vaccinia virus TK and B18 R region. The results showed that these viruses can efficiently mediate the exogenous gene expression in cancer cells, so as to induce cancer cell apoptosis. We also found OncoPox-IL24, OncoPox-MnSOD or OncoPox-IL24-MnSOD virus have different cytotoxicity effects on different cancer cells. Among them, however OncoPox-IL24-MnSOD virus had better anticancer effect. Thus, cancer targeting double gene-viro-therapy will be a new strategy in cancer gene therapy.II Cancer stem cells(CSCs), also known as tumor-initiating cells, are highly metastatic, chemo-resistant and tumorigenic, and are critical for cancer development, maintenance and recurrence. Oncolytic adenovirus was reported to target and kill CSCs and acted as a promising anticancer agent. Currently, ZD55 was developed to target liver cancer and exhibited obvious cytotoxicity effect. However, it still remained to be confirmed that whether ZD55 could also effectively eliminate liver CSCs. We first utilized the suspension culture to enrich the liver CSCs-like cells, which acquired the properties of liver CSCs in self-renewal, differentiation, quiescence, chemo-resistance. The results indicated that ZD55 could significantly elicit cytotoxicity in liver CSC-like cells, and exhibited stronger oncolytic effect in liver CSC-like cells. Furthermore, ZD55 could remarkedly induce the apoptosis of liver CSC-like cells in vitro. Thus, ZD55 might virtually represent an attractive therapeutic agent for targeting liver CSCs to achieve better clinical outcomes for HCC patients.