Open Accessp53 activated by AND gate genetic circuit under radiation and hypoxia for targeted cancer gene therapy
Author(s) -
Ding Miao,
Li Rong,
He Rong,
Wang Xingyong,
Yi Qijian,
Wang Weidong
Publication year - 2015
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.12739
Subject(s) - cancer research , genetic enhancement , radiation sensitivity , apoptosis , radiation therapy , hypoxia (environmental) , biology , cancer cell , gene , cancer , chemistry , medicine , irradiation , genetics , physics , organic chemistry , oxygen , nuclear physics
Radio‐activated gene therapy has been developed as a novel therapeutic strategy against cancer; however, expression of therapeutic gene in peritumoral tissues will result in unacceptable toxicity to normal cells. To restrict gene expression in targeted tumor mass, we used hypoxia and radiation tolerance features of tumor cells to develop a synthetic AND gate genetic circuit through connecting radiation sensitivity promoter cArG 6 , heat shock response elements SNF 1, HSF 1 and HSE 4 with retroviral vector plxsn. Their construction and dynamic activity process were identified through downstream enhanced green fluorescent protein and wtp53 expression in non‐small cell lung cancer A549 cells and in a nude mice model. The result showed that AND gate genetic circuit could be activated by lower required radiation dose (6 Gy) and after activated, AND gate could induce significant apoptosis effects and growth inhibition of cancer cells in vitro and in vivo . The radiation‐ and hypoxia‐activated AND gate genetic circuit, which could lead to more powerful target tumoricidal activity represented a promising strategy for both targeted and effective gene therapy of human lung adenocarcinoma and low dose activation character of the AND gate genetic circuit implied that this model could be further exploited to decrease side‐effects of clinical radiation therapy.