Inhibition of renal cancer cell growth by oncolytic adenovirus armed short hairpin RNA targeting hTERT gene

Abstract

RNA interference (RNAi) has been proved to be a powerful tool for gene knockdown purpose and holds a great promise for the treatment of cancer. Our previous study demonstrated that the reduction of hTERT expression by means of chemically synthesized siRNAs and shRNAs expressed from plasmid resulted in proliferation inhibition in human renal carcinoma cells. In this study, we constructed a novel oncolytic adenovirus-based shRNA expression system, ZD55-hTERT, and to explore ZD55-hTERT-mediated RNAi for hTERT gene silencing. Our results showed that ZD55-hTERT could induce silencing of hTERT gene effectively, allow for efficient tumor-specific viral replication and induce the apoptosis of tumor cells effectively in vitro and in nude mice. We conclude that combining shRNA gene therapy and oncolytic virotherapy can enhance antitumor efficacy as a result of synergism between CRAd oncolysis and shRNA antitumor responses.

Progression of O6-methylguanine-DNA methyltransferase and temozolomide resistance in cancer research

“…Recently, Zheng et al [59,60] focused on several constructs using an oncolytic virus to carry siRNA. Examples include a siRNA against Ki67, and a siRNA against human telomerase reverse transcriptase (hTERT), which acts as an antiproliferative and apoptosis inducer in cancer cells.…”

Oncolytic-adenovirus-expressed RNA interference for cancer therapy

“…ZD55, an E1B 55 kDa-deficient oncolytic adenovirus that is similar to ONYX-015 was constructed by Liu [84]. His collaborator Chu constructed ZD55-siApollon, ZD55 containing the U6 promoter to express shRNA directed against Apollon, a membrane-associated inhibitor of apoptosis protein [58].…”

“…Comparing the antitumor activity of ZD55, ZD55 expressing Ki67 shRNA (ZD55-Ki67) and a non-replicating adenoviral vectors expressing Ki67 shRNA (AD-Ki67), we found ZD55-Ki67 had more potent antitumor effects both in vitro and in vivo. In another study [84], we constructed a ZD55-based shRNA expression system targeting human telomerase reverse transcriptase (hTERT), ZD55-hTERT, to explore its hTERT gene silencing and antitumor outcomes. The study revealed that ZD55-hTERT could induce silencing of the hTERT gene, and is effective in suppressing telomerase activity, and inducing the apoptosis of tumor cells in vitro and in nude mice.…”

“…Renal carcinoma [86] ZD55 hTERT Renal carcinoma [84] ZD55 XIAP Hepatocellular carcinoma [50] H101 Bcl2…”

Potentiation of oncolytic virotherapy with armed shRNA

“…18 Like ONYX-015, ZD55 is defective in the E1B gene. The authors compared the antitumor activity of ZD55 expressing GFP (ZD55-EGFP), ZD55 expressing hTERT shRNA (ZD55-hTERT), and a conventional E1-deleted adenovector expressing hTERT shRNA (AD-hTERT) and found that compared with ZD55-EGFP or AD-hTERT, ZD55-hTERT had more potent antitumor effects, both in vitro and in vivo.…”