title: p53 activated by AND gate genetic circuit under radiation and hypoxia for targeted cancer gene therapy.
abstract: 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 cArG6 , heat shock response elements SNF1, HSF1 and HSE4 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.
authors.affiliation: Department of Cardiology, Children Hospital, Chongqing Medical University, Chongqing, China.
authors.forename: Miao
authors.initials: M
authors.lastname: Ding
authors.affiliation: Institute of Combined Injury, State Key Laboratory of Trauma, Burns and Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Li
authors.affiliation: Department of Emergency, Children Hospital, Chongqing Medical University, Chongqing, China.
authors.forename: Rong
authors.initials: R
authors.lastname: He
authors.affiliation: Department of Emergency, Children Hospital, Chongqing Medical University, Chongqing, China.
authors.forename: Xingyong
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Cardiology, Children Hospital, Chongqing Medical University, Chongqing, China.
authors.forename: Qijian
authors.initials: Q
authors.lastname: Yi
authors.affiliation: Department of Radiation Oncology, Tumor Hospital of Sichuan, Chengdu, Sichuan, China.
authors.forename: Weidong
authors.initials: W
authors.lastname: Wang
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics*; D000077192:Adenocarcinoma of Lung; D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics*; D045744:Cell Line, Tumor; D015870:Gene Expression / Q000235:genetics; D052138:Genes, Neoplasm / Q000235:genetics; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000235:genetics; D006360:Heat-Shock Proteins / Q000235:genetics; D006801:Humans; D000860:Hypoxia / Q000235:genetics*; D008175:Lung Neoplasms / Q000235:genetics*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D011401:Promoter Regions, Genetic / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D011836:Radiation Tolerance / Q000235:genetics*; D020218:Response Elements / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D006360:Heat-Shock Proteins; D016159:Tumor Suppressor Protein p53; C071570:SNF1-related protein kinases; D017346:Protein Serine-Threonine Kinases
keywords: AND gate; cancer; hypoxia; radiation; targeted gene therapy