Efficacy of combining ING4 and TRAIL genes in cancer-targeting gene virotherapy strategy: first evidence in preclinical hepatocellular carcinomaopen access
- Authors
- El-Shemi, A. Galal; Ashshi, A. Mohammed; Oh, E.; Jung, B-K; Basalamah, M.; Alsaegh, A.; Yun, C-O
- Issue Date
- Jan-2018
- Publisher
- NATURE PUBLISHING GROUP
- Citation
- GENE THERAPY, v.25, no.1, pp.54 - 65
- Indexed
- SCIE
SCOPUS
- Journal Title
- GENE THERAPY
- Volume
- 25
- Number
- 1
- Start Page
- 54
- End Page
- 65
- URI
- https://scholarworks.bwise.kr/hanyang/handle/2021.sw.hanyang/4749
- DOI
- 10.1038/gt.2017.86
- ISSN
- 0969-7128
- Abstract
- Current treatments of hepatocellular carcinoma (HCC) are ineffective and unsatisfactory in many aspects. Cancer-targeting gene virotherapy using oncolytic adenoviruses (OAds) armed with anticancer genes has shown efficacy and safety in clinical trials. Nowadays, both inhibitor of growth 4 (ING4), as a multimodal tumor suppressor gene, and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), as a potent apoptosis-inducing gene, are experiencing a renaissance in cancer gene therapy. Herein we investigated the antitumor activity and safety of mono-and combined therapy with OAds armed with ING4 (Ad-Delta B/ING4) and TRAIL (Ad-Delta B/TRAIL) gene, respectively, on preclinical models of human HCC. OAd-mediated expression of ING4 or TRAIL transgene was confirmed. Ad-Delta B/TRAIL and/or Ad-Delta B/ING4 exhibited potent killing effect on human HCC cells (HuH7 and Hep3B) but not on normal liver cells. Most importantly, systemic therapy with Ad-Delta B/ING4 plus Ad-Delta B/TRAIL elicited more eradicative effect on an orthotopic mouse model of human HCC than their monotherapy, without causing obvious overlapping toxicity. Mechanistically, Ad-Delta B/ING4 and Ad-Delta B/TRAIL were remarkably cooperated to induce antitumor apoptosis and immune response, and to repress tumor angiogenesis. This is the first study showing that concomitant therapy with Ad-Delta B/ING4 and Ad-Delta B/TRAIL may provide a potential strategy for HCC therapy and merits further investigations to realize its possible clinical translation.
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