Cheng Pei-Hsin, Rao Xiao-Mei, Duan Xiaoxian, Li Xiao-Feng, Egger Michael E, McMasters Kelly M, Zhou H Sam
Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY, 40292, USA.
J Mol Med (Berl). 2015 Feb;93(2):211-23. doi: 10.1007/s00109-014-1214-6. Epub 2014 Nov 8.
Oncolytic virotherapy can selectively destroy cancer cells and is a potential approach in cancer treatment. A strategy to increase tumor-specific selectivity is to control the expression of a key regulatory viral gene with a tumor-specific promoter. We have previously found that cyclin E expression is augmented in cancer cells after adenovirus (Ad) infection. Thus, the cyclin E promoter that is further activated by Ad in cancer cells may have unique properties for enhancing oncolytic viral replication. We have shown that high levels of viral E1a gene expression are achieved in cancer cells infected with Ad-cycE, in which the endogenous Ad E1a promoter was replaced with the cyclin E promoter. Ad-cycE shows markedly selective oncolytic efficacy in vitro and destroys various types of cancer cells, including those resistant to ONYX-015/dl1520. Furthermore, Ad-cycE shows a strong capacity to repress A549 xenograft tumor growth in nude mice and significantly prolongs survival. This study suggests the potential of Ad-cycE in cancer therapy and indicates the advantages of using promoters that can be upregulated by virus infection in cancer cells in development of oncolytic viruses. Key messages: Cyclin E promoter activity is high in cancer cells and enhanced by adenovirus infection. Cyclin E promoter is used to control the E1a gene of a tumor-specific oncolytic adenovirus. Ad-cycE efficiently targets cancer cells and induces oncolysis. Ad-cycE significantly repressed xenograft tumor and prolonged survival.
溶瘤病毒疗法可选择性地破坏癌细胞，是癌症治疗的一种潜在方法。提高肿瘤特异性选择性的一种策略是用肿瘤特异性启动子控制关键调节病毒基因的表达。我们之前发现，腺病毒（Ad）感染后癌细胞中细胞周期蛋白E的表达会增加。因此，在癌细胞中被Ad进一步激活的细胞周期蛋白E启动子可能具有增强溶瘤病毒复制的独特特性。我们已经表明，在用细胞周期蛋白E启动子取代内源性Ad E1a启动子的Ad-cycE感染的癌细胞中，可实现高水平的病毒E1a基因表达。Ad-cycE在体外显示出明显的选择性溶瘤功效，并能破坏各种类型的癌细胞，包括对ONYX-015/dl1520耐药的癌细胞。此外，Ad-cycE在裸鼠中显示出强大的抑制A549异种移植肿瘤生长的能力，并显著延长生存期。这项研究表明Ad-cycE在癌症治疗中的潜力，并指出在溶瘤病毒开发中使用可被癌细胞中病毒感染上调的启动子的优势。关键信息：细胞周期蛋白E启动子活性在癌细胞中较高，并被腺病毒感染增强。细胞周期蛋白E启动子用于控制肿瘤特异性溶瘤腺病毒的E1a基因。Ad-cycE有效靶向癌细胞并诱导溶瘤。Ad-cycE显著抑制异种移植肿瘤并延长生存期。
