Abstract
A previous study reported that combinatorial human endostatin and soluble tumor necrosis factor (TNF)-related apoptosis-inducing ligand (sTRAIL) gene transfer suppresses human hepatocellular carcinoma (HCC) growth and angiogenesis using the pVAX1 plasmid vector. The current study investigated the antitumor efficacy in HCC through adenovirus-mediated combination gene therapy. Human endostatin and sTRAIL (114 to 281 AA) genes were amplified and cloned into the Adeno-X expression vector. The recombinant adenoviruses (Ad-E and Ad-T) were packaged, amplified in the HEK 293 cells and used to infect human umbilical vein endothelial cells (HUVECs) and HepG2 cells, respectively. The results revealed that a significant cell growth inhibition was observed in the two types of cells using a cell viability assay. Intratumoral administration with Ad-E and Ad-T revealed a significant enhanced regression of the tumors compared with treatment with either recombinant adenovirus alone. Histology and immunohistochemistry examination further indicated that the inhibition of tumor growth appeared to result from increased apoptosis and reduced angiogenesis in tumor xenografts. In conclusion, these data further confirm the enhancement of antitumor efficacy through combined endostatin and TRAIL gene therapy and provide a promising application prospect by virtue of adenovirus-mediated anti-angiogenic and pro-apoptotic cancer gene therapy.
Highlights
Hepatocellular carcinoma (HCC) is one of the most common types of primary cancer in the world [1], ranking the sixth most prevalent cancer and the third most frequent cause of cancer‐related mortality [2]
In order to examine whether endostatin and TRAIL genes inserted into the adenovirus vector were able to express and secrete, the supernatants of human umbilical vein endothelial cells (HUVECs) and HepG2 cells infected with Ad-E or Ad-T was detected by western blotting using anti-endostatin and anti-TRAIL antibodies, respectively
Results revealed that an endostatin protein band of 20 kDa and a TRAIL protein band of 18.5 kDa were able to be detected, whereas no such band was present in the control supernatants of cells infected with Ad-EGFP virus
Summary
Hepatocellular carcinoma (HCC) is one of the most common types of primary cancer in the world [1], ranking the sixth most prevalent cancer and the third most frequent cause of cancer‐related mortality [2]. Hepatocellular carcinoma has a poor 5-year survival rate of approximately 7% despite treatment [4]. The gene therapy of liver cancer has covered a variety of gene transfer strategies aimed to treat patients with primary and secondary liver tumors, including gene-directed enzyme/pro-drug therapy, inhibition of oncogenes and restoration of tumor-suppressor genes, immunotherapy, antiangiogenesis and virotherapy [7]. Several of these strategies have reached early clinical development with little success. It may be possible to achieve a more effective control of tumor growth through selecting effective gene delivery approaches and an appropriate combination of therapeutic genes
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