Arginine deiminase expressed in vivo, driven by human telomerase reverse transcriptase promoter, displays high hepatoma targeting and oncolytic efficiency
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Hui Jiang1,*, Song Guo2,*, Dan Xiao3,*, Xuzhao Bian1, Jie Wang1, Ying Wang1, Huiting Zhou1, Jun Cai4 and Zhongliang Zheng1
1State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China
2Department of Orthopedic, Wuhan Puai Hospital, Wuhan 430034, China
3Department of Gastroenterology, Jianghan University Affiliated Hospital, Wuhan 430000, China
4Hubei Collaborative Innovation Center for Industrial Fermentation, College of Biotechnology, Hubei University of Technology, Wuhan 430068, China
*These authors have contributed equally to this work
Zhongliang Zheng, email: [email protected]
Keywords: arginine deiminase, ADI, arginine starvation, cancer-targeting therapy, hTERT promoter
Received: September 13, 2016 Accepted: March 21, 2017 Published: April 11, 2017
Arginine starvation has the potential to selectively treat both primary tumor and (micro) metastatic tissue with very low side effects. Arginine deiminase (ADI; EC 220.127.116.11), an arginine-degrading enzyme, has been studied as a potential anti-tumor drug for the treatment of arginine-auxotrophic tumors. Though ADI-PEG20 (pegylated ADI by PEG 20,000) already passed the phase I/II clinical trials , it is just used as adjuvant therapy because of its low efficiency and less targeting. Then, this paper discussed the efficiency of arginine starvation mediated by ADI expressed in cytoplasm for liver cancers. In order to guarantee the tumor targeting, human telomerase reverse transcriptase (hTERT) promoter was used to drive the expression of ADI in vivo. To access the anti-tumor efficiency of ADI, p53 gene was used as the positive control. Thus, ADI displayed obvious cytotoxicity to BEL7402 and HUH7 cell lines in cytoplasm. The apoptosis rates rose from 15% to nearly 60% after changing the expression vectors from pcDNA4 plasmid to adenovirus. Compared with p53-adenovirus, ADI-adenovirus showed the higher oncolytic activity in the intratumoral injection model of mice. Tumor disappeared after the treatment of ADI-adenovirus for two weeks, and the mice pulled through all. Therefore, ADI is an ideal anti-tumor gene for caner targeting therapy with the help of hTERT promoter.
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