Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
Hum Gene Ther. 2010 Jul;21(7):855-64. doi: 10.1089/hum.2009.207.
Melanoma differentiation-associated gene-7/interleukin-24 (mda-7/IL-24), identified by subtraction hybridization 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, including 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 caspases 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.
黑色素瘤分化相关基因-7/白细胞介素-24（mda-7/IL-24）于 20 世纪 90 年代中期通过消减杂交法鉴定，是一种用于癌症的有效基因治疗方法。它使用复制缺陷型腺病毒作为载体，可在不伤害正常细胞或组织的情况下诱导多种癌细胞凋亡。为了最大限度地发挥 IL-24 的抗癌能力，在这项研究中，我们利用一种复制型溶瘤腺病毒 MUD55 作为基因递送载体，生成了一种新型基因-病毒治疗剂 MUD55-IL-24。研究结果表明，MUD55-IL-24 在体外和体内对胃癌均具有更强的抗肿瘤活性，其安全性与复制缺陷型腺病毒 Ad-IL-24 相当。MUD55-IL-24 显著增强了 IL-24 的独特特性，包括诱导凋亡、抗血管生成和抗迁移。在研究其潜在机制后，我们发现 MUD55-IL-24 感染的 SG-7901 细胞中细胞内 ROS（活性氧）的产生可能导致了凋亡的诱导、线粒体功能障碍和半胱天冬酶的激活。综上所述，这些结果表明 MUD55-IL-24 可能为未来人类胃癌的治疗提供一种潜在的策略。
