Combined oncolytic adenovirus carrying MnSOD and mK5 genes both regulated by survivin promoter has synergistic inhibitory effect on gastric cancer

Abstract

Gastric cancer (GC) is one of the major causes of cancer related mortality. The use of oncolytic virus for cancer gene-virotherapy is a new approach for the treatment of human cancers. In this study, a novel Survivin promoter driven recombinant oncolytic adenovirus carrying mK5 or MnSOD gene was constructed, which was modified after deletion of E1B gene. Human plasminogen Kringle 5 mutant (mK5) and manganese superoxide dismutase (MnSOD) are both potential tumor suppressor genes. To construct Ad-Surp-mK5 and Ad-Surp-MnSOD oncolytic adenovirus, we hypothesized that the combination of the two viruses would enhance the therapeutic efficacy of GC as compared to the virus alone. The results of the in vitro experiments revealed that the combination of adenovirus carrying mK5 and MnSOD gene exhibited stronger cytotoxicity to GC cell lines as compared to the virus alone, Additionally, the virus could selectively kill cancer cells and human somatic cells. Cell staining, flow cytometry and western blot analysis showed that the combination of two adenovirus containing therapeutic genes could promote the apoptosis of cancer cells. In vivo experiments further verified that Ad-Surp-mK5 in combination with Ad-Surp-MnSOD exhibited significant inhibitory effect on the growth of GC tumor xenograft as compared to the virus alone, and no significant difference was observed in the body weight of treatment and the normal mice. In conclusion, the combination of our two newly constructed recombinant oncolytic adenovirus containing mK5 or MnSOD therapeutic genes could significantly inhibit gastric cancer growth by inducing apoptosis, suggestive of its potential for GC therapy.