Journal
JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
Volume 35, Issue -, Pages -Publisher
BMC
DOI: 10.1186/s13046-016-0353-8
Keywords
Dual gene virotherapy; Oncolytic adenoviruses; Interleukin-12; Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL); Hepatocellular carcinoma
Categories
Funding
- National Science, Technology and Innovation Plan (MARRIFAH)-King Abdul Aziz City for Science and Technology (KACST), the Kingdom of Saudi Arabia [11-MED2065-10]
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Background: Gene-based virotherapy mediated by oncolytic viruses is currently experiencing a renaissance in cancer therapy. However, relatively little attention has been given to the potentiality of dual gene virotherapy strategy as a novel therapeutic approach to mediate triplex anticancer combination effects, particularly if the two suitable genes are well chosen. Both tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and interleukin-12 (IL-12) have been emerged as promising pharmacological candidates in cancer therapy; however, the combined efficacy of TRAIL and IL-12 genes for treatment of human hepatocellular carcinoma (HCC) remains to be determined. Methods: Herein, we investigated the therapeutic efficacy of concurrent therapy with two armed oncolytic adenoviruses encoding human TRAIL gene (Ad-Delta B/TRAIL) and IL-12 gene (Ad-Delta B/IL-12), respectively, on preclinical models of human HCC, and also elucidated the possible underlying mechanisms. The effects of Ad-Delta B/TRAIL+Ad-Delta B/IL-12 combination therapy were assessed both in vitro on Hep3B and HuH7 human HCC cell lines and in vivo on HCC-orthotopic model established in the livers of athymic nude mice by intrahepatic implantation of human Hep3B cells. Results: Compared to therapy with non-armed control Ad-Delta B, combined therapy with Ad-Delta B/TRAIL+Ad-Delta B/IL-12 elicited profound anti-HCC killing effects on Hep3B and HuH7 cells and on the transplanted Hep3B-orthotopic model. Efficient viral replication and TRAIL and IL-12 expression were also confirmed in HCC cells and the harvested tumor tissues treated with this combination therapy. Mechanistically, co-therapy with Ad-Delta B/TRAIL+Ad-Delta B/IL-12 exhibited an enhanced effect on apoptosis promotion, activation of caspase-3 and-8, generation of anti-tumor immune response evidenced by upregulation of interferon gamma (IFN-gamma) production and infiltration of natural killer-and antigen presenting cells, and remarkable repression of intratumor vascular endothelial growth factor (VEGF) and cluster of differentiation 31 (CD31) expression and tumor microvessel density. Conclusions: Overall, our data showed a favorable therapeutic effect of Ad-Delta B/TRAIL+Ad-Delta B/IL-12 combination therapy against human HCC, and may therefore constitute a promising and effective therapeutic strategy for treating human HCC. However, further studies are warranted for its reliable clinical translation.
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