Double-Regulated Oncolytic Adenovirus-Mediated.pdf

Double-Regulated Oncolytic Adenovirus-Mediated Interleukin-24 Overexpression Exhibits Potent Antitumor Activity on Gastric Adenocarcinoma Na Wei,1 Jun Kai Fan,1 Jin Fa Gu,1 and Xin Yuan Liu1,2 Abstract Melanoma differentiation-associated gene-7/interleukin-24 (mda-7/IL-24), identified by subtraction hybridiza- tion in the mid-1990s, is a potent gene therapeutic for cancer. Using a replication-deficient adenovirus as vector, it provokes apoptosis in diverse cancer cells without harming normal cells or tissues. To exploit the anticancer capability of IL-24 to the best, in this study, we generated a novel gene-virotherapy agent MUD55-IL-24, utilizing a replication-competent oncolytic adenovirus MUD55 as the gene delivery vector. It was documented that MUD55-IL-24 exhibited much stronger antitumor activity on gastric carcinoma both in vitro and in vivo, and its safety was comparable to the replication-deficient adenovirus Ad-IL-24. The unique properties of IL-24, in- cluding apoptosis induction, antiangiogenesis, and antimigration, were all significantly enhanced in MUD55-IL- 24. After looking into the underlying mechanism, we found that intracellular ROS (Reactive Oxygen Species) generation may have caused the induction of apoptosis, mitochondrial dysfunction, and the activation of cas- pases in MUD55-IL-24-infected SG-7901 cells. Taken together, these results suggest that MUD55-IL-24 may be able to provide a potential strategy for future treatment of human gastric carcinoma. Introduction Gastric carcinoma, also called stomach cancer, canoriginate in any part of the stomach and spread to other organs nearby, for example, esophagus, small intestine, and liver. According to the National Cancer Institute statistics in 2009, it caused about 21,000 new cases and accounts for 10,000 deaths in the United States. Metastasis occurs in over 80% of individuals with stomach cancer. If it was diagnosed in early stages, the 6-month survival rate is about 65%, but if in late stages,