Adenovirus-mediated tBid overexpression results in therapeutic effects on p53-resistant hepatocellular carcinoma.
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 alpha-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.
Miao
Ji
J
Department of Surgery, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong.
Chen
George G
GG
Chun
Suk-Ying
SY
Yun
Jing-Ping
JP
Chak
Ernest C W
EC
Ho
Rocky L K
RL
Lai
Paul B S
PB
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D017209:Apoptosis; D051023:BH3 Interacting Domain Death Agonist Protein / Q000235:genetics* / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy*; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D004274:DNA, Recombinant / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D004789:Enzyme Activation; D015870:Gene Expression / Q000235:genetics; D015316:Genetic Therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D011401:Promoter Regions, Genetic / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays; D000509:alpha-Fetoproteins
C097353:AFP protein, human; D051023:BH3 Interacting Domain Death Agonist Protein; D004274:DNA, Recombinant; D004268:DNA-Binding Proteins; D016159:Tumor Suppressor Protein p53; D000509:alpha-Fetoproteins; D020169:Caspases