Adenovirus‐mediated tBid overexpression results in therapeutic effects on p53‐resistant hepatocellular carcinoma

• Published in: International journal of cancer 2006-10, Vol.119 (8), p.1985-1993
• Main Authors: Miao, Ji, Chen, George G., Chun, Suk‐Ying, Yun, Jing‐Ping, Chak, Ernest C.W., Ho, Rocky L.K., Lai, Paul B.S.
• Format: Article
• Language: English
• Subjects: Adenoviridae - genetics; alpha-Fetoproteins; Animals; Apoptosis; BH3 Interacting Domain Death Agonist Protein - genetics; BH3 Interacting Domain Death Agonist Protein - metabolism; Biological and medical sciences; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Carcinoma, Hepatocellular - therapy; Caspases - metabolism; Cell Line; DNA, Recombinant - genetics; DNA-Binding Proteins - genetics; Enzyme Activation; Gene Expression - genetics; gene therapy; Genetic Therapy; hepatocellular carcinoma; Medical sciences; Mice; Mice, Inbred BALB C; Mice, Nude; Other treatments; Promoter Regions, Genetic - genetics; tBid; Treatment. General aspects; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Tumors; Xenograft Model Antitumor Assays
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.22040

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide with a very high mortality. Because the success of the conventional therapies is limited, gene therapy may represent an alternative for HCC management. Our earlier study has shown that Bid plays a role in the development of HCC. The aim of our study is to evaluate the possibility of using truncated Bid (tBid) as a novel therapy for HCC treatment. Two HCC cell lines, Hep3B and PLC/PRF/5, were used in the experiment. Hep3B was a p53‐resistant while PLC/PRF/5 a p53‐sensitive. A recombinant adenovirus‐Ad/AFPtBid, which contained a tBid gene driven by an α‐fetoprotein (AFP) promoter, was constructed. Both Hep3B and PLC/PRF/5 cells infected with Ad/AFPtBid showed a significant decrease in cell viability. The decrease in cell viability by Ad/AFPtBid resulted from apoptosis of HCC cells, evident by enhanced activity of caspases and increased release of cytochrome c. In vivo experiment was performed by the intratumor injection of Ad/AFPtBid in nude mice inoculated with Hep3B. Ad/AFPtBid injection significantly inhibited tumor growth, and tumor tissues showed a marked increase in TUNEL‐positive cells. Our experiment also demonstrated that Ad/AFPtBid only targeted AFP‐producing cells but not those non‐AFP producing cells. In conclusion, these results indicate that the introduction of Ad/AFPtBid can not only significantly but specifically kill HCC cells that produce AFP. The cell death induced by Ad/AFPtBid in HCC cells is via an apoptotic pathway that can be independent of p53 status. © 2006 Wiley‐Liss, Inc.