Prostate Cancer-Specific and Potent Antitumor Effect of a DD3-Controlled Oncolytic Virus Harboring the PTEN Gene

被引:20
作者
Ding, Miao [1 ]
Cao, Xin [1 ]
Xu, Hai-neng [1 ]
Fan, Jun-kai [3 ]
Huang, Hong-ling [1 ]
Yang, Dong-qin [1 ]
Li, Yu-hua [4 ]
Wang, Jian [4 ]
Li, Runsheng [4 ]
Liu, Xin-Yuan [1 ,2 ]
机构
[1] Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Biochem & Cell Biol, State Key Lab Cell Biol, Shanghai, Peoples R China
[2] Zhejiang Sci Tech Univ, Coll Biol Sci, Xinyuan Inst Med & Biotechnol, Hangzhou, Zhejiang, Peoples R China
[3] Univ Kentucky, Lucille P Markey Canc Ctr, Dept Mol & Cellular Biochem, Lexington, KY USA
[4] Shanghai Inst Planned Parenthood Res, Key Lab Contracept Drugs & Devices NPFPC, Shanghai, Peoples R China
来源
PLOS ONE | 2012年 / 7卷 / 04期
关键词
ADENOVIRUS-MEDIATED TRANSFER; INHIBITS CELL-GROWTH; REPLICATING ADENOVIRUS; GLIOBLASTOMA CELLS; IN-VITRO; EXPRESSION; THERAPY; PROMOTER; SUPPRESSION; CARCINOMA;
D O I
10.1371/journal.pone.0035153
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Prostate cancer is a major health problem for men in Western societies. Here we report a Prostate Cancer-Specific Targeting Gene-Viro-Therapy (CTGVT-PCa), in which PTEN was inserted into a DD3-controlled oncolytic viral vector (OV) to form Ad.DD3.E1A.E1B(Delta 55)-(PTEN) or, briefly, Ad.DD3.D55-PTEN. The woodchuck post-transcriptional element (WPRE) was also introduced at the downstream of the E1A coding sequence, resulting in much higher expression of the E1A gene. DD3 is one of the most prostate cancer-specific genes and has been used as a clinical bio-diagnostic marker. PTEN is frequently inactivated in primary prostate cancers, which is crucial for prostate cancer progression. Therefore, the Ad.DD3.D55-PTEN has prostate cancer specific and potent antitumor effect. The tumor growth rate was almost completely inhibited with the final tumor volume after Ad.DD3.D55-PTEN treatment less than the initial volume at the beginning of Ad.DD3.D55-PTEN treatment, which shows the powerful antitumor effect of Ad.DD3.D55-PTEN on prostate cancer tumor growth. The CTGVT-PCa construct reported here killed all of the prostate cancer cell lines tested, such as DU145, 22RV1 and CL1, but had a reduced or no killing effect on all the non-prostate cancer cell lines tested. The mechanism of action of Ad. DD3.D55-PTEN was due to the induction of apoptosis, as detected by TUNEL assays and flow cytometry. The apoptosis was mediated by mitochondria-dependent and -independent pathways, as determined by caspase assays and mitochondrial membrane potential.
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页数:11
相关论文
共 55 条
[1]  
BERKNER KL, 1992, CURR TOP MICROBIOL, V158, P39
[2]  
BERKNER KL, 1988, BIOTECHNIQUES, V6, P616
[3]   An adenovirus mutant that replicates selectively in p53-deficient human tumor cells [J].
Bischoff, JR ;
Kim, DH ;
Williams, A ;
Heise, C ;
Horn, S ;
Muna, M ;
Ng, L ;
Nye, JA ;
SampsonJohannes, A ;
Fattaey, A ;
McCormick, F .
SCIENCE, 1996, 274 (5286) :373-376
[4]  
Cheney IW, 1998, CANCER RES, V58, P2331
[5]   An oncolytic conditionally replicating adenovirus for hormone-dependent and hormone-independent prostate cancer [J].
Cheng, WS ;
Dzojic, H ;
Nilsson, B ;
Tötterman, TH ;
Essand, M .
CANCER GENE THERAPY, 2006, 13 (01) :13-20
[6]  
Davies MA, 1999, CANCER RES, V59, P2551
[7]  
Davies MA, 2002, CLIN CANCER RES, V8, P1904
[8]  
de Kok JB, 2002, CANCER RES, V62, P2695
[9]   Development of prostate cancer treatment: The good news [J].
Denmeade, SR ;
Isaacs, JT .
PROSTATE, 2004, 58 (03) :211-224
[10]   Recent deal highlights hopes for cancer-killing viruses [J].
Evans, Jon .
NATURE MEDICINE, 2011, 17 (03) :268-269