Abstract
Oncolytic virotherapy has been an attractive drug platform for targeted therapy of cancer over the past few years. Viral vectors can be used to target and lyse cancer cells, but achieving good efficacy and specificity with this treatment approach is a major challenge. Here, we assessed the ability of a novel dual-specific anti-tumor oncolytic adenovirus, expressing the hemagglutinin-neuraminidase (HN) gene from the Newcastle disease virus under the human telomerase reverse transcriptase (hTERT) promoter (Ad-hTERTp-E1a-HN), to inhibit esophageal cancer EC-109 cells in culture and to reduce tumor burden in xenografted BALB/c nude mice. In vitro, infection with Ad-hTERT-E1a-HN could inhibit the growth of EC-109 cells significantly and also protect normal human liver cell line L02 from growth suppression in 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays. Ad-hTERT-E1a-HN also effectively and selectively decreased the sialic acid level on EC-109 cells, but not on L02 cells. Furthermore, Ad-hTERT-E1a-HN was shown to induce the apoptosis pathway via acridine orange and ethidium bromide staining (AO/EB staining), increase reactive oxygen species (ROS), reduce mitochondrial membrane potential and release cytochrome c. In vivo, xenografted BALB/c nude mice were treated via intratumoral or intravenous injections of Ad-hTERT-E1a-HN. Although both treatments showed an obvious suppression in tumor volume, only Ad-hTERT-E1a-HN delivered via intratumoral injection elicited a complete response to treatment. These results reinforced previous findings and highlighted the potential therapeutic application of Ad-hTERT-E1a-HN for treatment of esophageal cancer in clinical trials.
Highlights
Esophageal cancer is one of the most common diseases in the digestive system with early metastasis, high mortality and poor prognosis
All of the recombinant adenoviruses restrained the growth of EC-109 cells via induction of apoptosis and necrosis, these results indicated that Ad-human telomerase reverse transcriptase (hTERT)-E1a-HN had the strongest anti-tumor effect
Xiao-Ping He et al [18] previously showed that the anti-tumor effect of a conditionally replicating adenovirus (CRAd) vector modified by incorporation of an anti-angiogenesis inhibitor gene (CRAd-Cans) was even more potent than that of the replication-deficient adenovirus Ad5-Cans against pancreatic cancer both in vivo and in vitro
Summary
Esophageal cancer is one of the most common diseases in the digestive system with early metastasis, high mortality and poor prognosis. It has been shown that gene therapy can play a role as an adjuvant treatment modality for esophageal cancer [1]. Gene therapy is a mature discipline, which has the potential to treat or even cure several diseases [2]. Oncolytic viruses are replicating microorganisms that have been selected or engineered to grow inside tumor cells [4]. Arming oncolytic viruses with anti-cancer genes has been a major focus in cancer virotherapy, and exploited transgenes include tumor suppressor, pro-apoptotic, anti-angiogenic, “suicide,” RNA interference and immunomodulatory genes [5,6]
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