A survivin-mediated oncolytic adenovirus induces non-apoptotic cell death in lung cancer cells and shows antitumoral potential in vivo
Version of Record online: 10 AUG 2006
Copyright © 2006 John Wiley & Sons, Ltd.
The Journal of Gene Medicine
Volume 8, Issue 10, pages 1232–1242, October 2006
How to Cite
Li, B., Liu, X., Fan, J., Qi, R., Bo, L., Gu, J., Qian, Q., Qian, C. and Liu, X. (2006), A survivin-mediated oncolytic adenovirus induces non-apoptotic cell death in lung cancer cells and shows antitumoral potential in vivo. J. Gene Med., 8: 1232–1242. doi: 10.1002/jgm.953
- Issue online: 25 SEP 2006
- Version of Record online: 10 AUG 2006
- Manuscript Accepted: 15 JUN 2006
- Manuscript Revised: 21 MAY 2006
- Manuscript Received: 3 APR 2006
- Key Project of the Chinese Academy of Sciences. Grant Number: KSCX2-3-06
- National Natural Science Foundation of China. Grant Number: 30120160823
- Chinese National ‘863’ High Tech Project Foundation. Grant Number: 2002AA216021
- 973 Project. Grant Number: 2004CB518804
- oncolytic adenovirus;
- survivin promoter;
- non-apoptotic cell death
Conditionally replicating adenoviruses or oncolytic adenoviruses, which can replicate selectively in tumor cells and kill them, represent an innovative class of promising cancer therapeutics. Survivin is the smallest member of the inhibitor of apoptosis (IAP) family, which is transcriptionally upregulated exclusively in most malignant tissues but not in normal tissues. It has been reported that activity of the survivin promoter is tumor-specific, which makes the survivin promoter a good candidate to construct oncolytic viral vectors.
A luciferase reporter assay was used to determine the activity of the survivin promoter in tumor and normal cells. An oncolytic adenovirus (Ad.SP/E1A) was generated by homologous recombination. The oncolytic efficacy of Ad.SP/E1A was evaluated in cell lines and in a human lung xenograft tumor mouse model.
Survivin expression was highly upregulated in tumor cells both at the protein and mRNA level. The luciferase reporter assay showed that survivin promoter activity is tumor-specific. Ad.SP/E1A expressed E1A selectively in tumor cells and induced cytotoxicity, but not in normal cells. Moreover, in animal experiments, intratumoral administration of Ad.SP/E1A significantly suppressed the growth of xenograft tumors. Further investigation showed that Ad.SP/E1A induced cell death by an apoptosis-independent pathway.
Ad.SP/E1A could be a potent therapeutic agent for cancer gene therapy. The investigation of the mechanisms of oncolytic virus-induced cell death in this work will shed light on the construction of more powerful vectors for cancer therapy. Copyright © 2006 John Wiley & Sons, Ltd.