Potent antitumor effect of TRAIL mediated by a novel adeno‐associated viral vector targeting to telomerase activity for human hepatocellular carcinoma
- 14 March 2008
- journal article
- research article
- Published by Wiley in The Journal of Gene Medicine
- Vol. 10 (5) , 518-526
- https://doi.org/10.1002/jgm.1177
Abstract
Background Adeno-associated virus (AAV) has rapidly become a promising gene delivery vehicle for its excellent advantages of low pathogenicity and long-term gene expression. However, lack of tissue specificity caused low efficiency of AAV transfer to target cells. The promoter of human telomerase reverse transcriptase (hTERT) has been implicated in mediating gene expression in cancer cells as hTERT is transcriptionally upregulated in most cancer cells. Thereby, the hTERT promoter becomes a good candidate to enhance the targeting efficiency of AAV in cancer cells. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) functions as a soluble cytokine to selectively kill various cancer cells without toxicity to most normal cells. It remains to be determined whether the hTERT promoter can efficiently mediate TRAIL gene therapy in cancer cells using AAV vector. Methods A novel AAV vector containing the TRAIL gene under the control of the hTERT promoter (AAV-hTERT-TRAIL) was generated. The specific expression of hTERT-controlled genes was evaluated in cell lines. The antitumor efficacy of AAV-hTERT-TRAIL was assessed in tumor cell lines and human hepatocellular carcinoma xenograft mouse model. Results TRAIL expression was observed in tumor cells infected with AAV-hTERT-TRAIL at both the protein and mRNA level. AAV-hTERT-TRAIL displayed cancer-specific cytotoxicity and induced tumor cell apoptosis. Moreover, in animal experiments, intratumoral administration of AAV-hTERT-TRAIL significantly suppressed the growth of xenograft tumors and resulted in tumor cell death. Conclusions AAVs in combination with hTERT-mediated therapeutic gene expression provide a promising targeting approach for developing effective therapy for human cancers. These data suggest that AAV-hTERT-TRAIL is a potent therapeutic agent for cancer therapy. Copyright © 2008 John Wiley & Sons, Ltd.Keywords
This publication has 34 references indexed in Scilit:
- Modulation of Telomerase Promoter Tumor Selectivity in the Context of Oncolytic AdenovirusesCancer Research, 2007
- Low-Dose Etoposide Enhances Telomerase-Dependent Adenovirus-Mediated Cytosine Deaminase Gene Therapy through Augmentation of Adenoviral Infection and Transgene Expression in a Syngeneic Bladder Tumor ModelCancer Research, 2006
- Detection of cell cycle- and differentiation stage-dependent human telomerase reverse transcriptase expression in single living cancer cellsMolecular Therapy, 2006
- Treatment of human disease by adeno-associated viral gene transferHuman Genetics, 2006
- hTERT, the catalytic component of telomerase, is downregulated in the haematopoietic stem cells of patients with chronic myeloid leukaemiaLeukemia, 2006
- Oral adeno‐associated virus‐sTRAIL gene therapy suppresses human hepatocellular carcinoma growth in mice†Hepatology, 2005
- Telomerase: a potential therapeutic target for cancerEmerging Therapeutic Targets, 2005
- Effective gene–virotherapy for complete eradication of tumor mediated by the combination of hTRAIL (TNFSF10) and plasminogen k5Molecular Therapy, 2005
- AAV-encoded expression of TRAIL in experimental human colorectal cancer leads to tumor regressionGene Therapy, 2004
- Induction of Apoptosis by Apo-2 Ligand, a New Member of the Tumor Necrosis Factor Cytokine FamilyJournal of Biological Chemistry, 1996