Therapeutic efficacy of an hTERT promoter-driven oncolytic adenovirus that expresses apoptin in gastric carcinoma

Liu,Lei; Wu,Wenbin; Zhu,Guangze; Liu,Liming; Guan,Guofang; Li,Xiao; Jin,Ningyi; Chi,Baorong

doi:10.3892/ijmm.2012.1077

Therapeutic efficacy of an hTERT promoter-driven oncolytic adenovirus that expresses apoptin in gastric carcinoma

Authors:
- Lei Liu
- Wenbin Wu
- Guangze Zhu
- Liming Liu
- Guofang Guan
- Xiao Li
- Ningyi Jin
- Baorong Chi
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Affiliations: Department of Gastroenterology, The First Hospital of Jilin University, Changchun 130021, P.R. China, Genetic Engineering Laboratory of PLA, Academy of Military Medical Sciences of PLA, Changchun 130122, P.R. China
Published online on: July 25, 2012 https://doi.org/10.3892/ijmm.2012.1077
Pages: 747-754

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Abstract

The efficacy and specificity of treatment are the major challenges for cancer gene therapy. Oncolytic virotherapy is an attractive drug delivery platform of cancer gene therapy. Previous studies have determined that apoptin is a p53-independent, Bcl-2-insensitive apoptotic protein that has the ability to induce apoptosis specifically in tumor cells. In this study, we show that the administration of a dual cancer-specific oncolytic adenovirus construct, Ad-hTERT-E1a-apoptin [in which the adenovirus early region 1a (E1a) gene is driven by the cancer-specific promoter of human telomerase reverse transcriptase (hTERT) and that expresses apoptin simultaneously], suppresses tumor growth in gastric carcinoma cells in vitro and reduces the tumor burden in vivo in xenografted nude mice. The observation that infection with the Ad-hTERT-E1a-apoptin construct significantly inhibited the growth of gastric cancer cells and protected normal human gastric epithelium from growth inhibition confirmed the induction of cancer cell-selective adenovirus replication, growth inhibition and apoptosis by this therapeutic approach. In vivo assays were performed using BALB/c nude mice that had established primary tumors. Subcutaneous primary tumor volume was reduced not only in the intratumoral injection group but also in the systemic delivery mice following treatment with Ad-hTERT-E1a-apoptin. Furthermore, treatment of primary models with Ad-hTERT-E1a-apoptin increased the mouse survival time. These data reinforce previous research and highlight the potential therapeutic application of Ad-hTERT-E1a-apoptin for the treatment of neoplastic diseases in clinical trials.

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1.	Y XuZ LiuH KongCo-expression of interleukin 12 enhances antitumor effects of a novel chimeric promoter-mediated suicide gene therapy in an immunocompetent mouse modelBiochem Biophys Res Commun412763768201110.1016/j.bbrc.2011.08.07721875574
2.	R AlemanyCancer selective adenovirusesMol Aspects Med284258200710.1016/j.mam.2006.12.002
3.	YS HavivDT CurielConditional gene targeting for cancer gene therapyAdv Drug Deliv Rev53135154200110.1016/S0169-409X(01)00225-311731024
4.	X LiY LiuZ WenPotent antitumor effects of a dual specific oncolytic adenovirus expressing apoptin in vitro and in vivoMol Cancer910201010.1186/1476-4598-9-1020085660
5.	D SarkarZZ SuN VozhillaES ParkP GuptaPB FisherDual cancer-specific targeting strategy cures primary and distant breast carcinomas in nude miceProc Natl Acad Sci USA1021403414039200510.1073/pnas.050683710216172403
6.	DE PostEM SandbergMM KyleTargeted cancer gene therapy using a hypoxia inducible factor dependent oncolytic adenovirus armed with interleukin-4Cancer Res6768726881200710.1158/0008-5472.CAN-06-324417638898
7.	OA KovalenkoJ KaplunovU HerbigS DetoledoEI AzzamJH SantosExpression of (NES-)hTERT in cancer cells delays cell cycle progression and increases sensitivity to genotoxic stressPLoS One5e10812201010.1371/journal.pone.001081220520826
8.	JM WojciakMA Martinez-YamoutHJ DysonPE WrightStructural basis for recruitment of CBP/p300 coactivators by STAT1 and STAT2 transactivation domainsEMBO J28948958200910.1038/emboj.2009.3019214187
9.	N HotiWH ChowdhuryS MustafaArmoring CRAds with p21/Waf-1 shRNAs: the next generation of oncolytic adenovirusesCancer Gene Ther17585597201010.1038/cgt.2010.1520448671
10.	AA Danen-Van OorschotDF FischerJM GrimbergenApoptin induces apoptosis in human transformed and malignant cells but not in normal cellsProc Natl Acad Sci USA945843584719979159162
11.	C BackendorfAE VisserAG de BoerApoptin: therapeutic potential of an early sensor of carcinogenic transformationAnnu Rev Pharmacol Toxicol48143169200810.1146/annurev.pharmtox.48.121806.15491017848136
12.	RA SchoopRJ Baatenburg de JongMH NotebornApoptin induces apoptosis in an oral cancer mouse modelCancer Biol Ther713681373200810.4161/cbt.7.9.641918708764
13.	M LosS PanigrahiI RashediApoptin, a tumor-selective killerBiochim Biophys Acta179313351342200910.1016/j.bbamcr.2009.04.00219374922
14.	JL RohnMH NotebornThe viral death effector Apoptin reveals tumor-specific processesApoptosis9315322200410.1023/B:APPT.0000025808.48885.9c15258463
15.	YH ZhangSR LeliveldK KooistraRecombinant Apoptin multimers kill tumor cells but are nontoxic and epitope-shielded in a normal-cell-specific fashionExp Cell Res2893646200310.1016/S0014-4827(03)00188-512941602
16.	X LiN JinZ MiAntitumor effects of a recombinant fowlpox virus expressing Apoptin in vivo and in vitroInt J Cancer11929482957200610.1002/ijc.2221517036330
17.	H LianN JinX LiInduction of an effective antitumor immune response and tumor regression by combined administration of IL-18 and ApoptinCancer Immunol Immunother56181192200710.1007/s00262-006-0178-y16767432
18.	Q LiJ ZhuF SunL LiuX LiuY YueOncostatin M promotes proliferation of ovarian cancer cells through signal transducer and activator of transcription 3Int J Mol Med28101108201121399864
19.	SH Zainal AriffinWH Wan OmarZ Zainal AriffinMF SafianS SenafiR Megat Abdul WahabIntrinsic anticarcinogenic effects of Piper sarmentosum ethanolic extract on a human hepatoma cell lineCancer Cell Int96200919257877
20.	E CandalR AnadonWJ DeGripI Rodriguez-MoldesPatterns of cell proliferation and cell death in the developing retina and optic tectum of the brown troutBrain Res Dev Brain Res154101119200510.1016/j.devbrainres.2004.10.00815617760
21.	F PatrascuA CroitoruI GramaticuM AndreiA TeiutanuM DiculescuLocally advanced or metastatic gastric cancer - new therapeutic solutionsRev Med Chir Soc Med Nat Iasi11520262011(In Romanian)
22.	AN MilneF CarneiroC O’MorainGJ OfferhausNature meets nurture: molecular genetics of gastric cancerHum Genet126615628200910.1007/s00439-009-0722-x19657673
23.	CL WuGS ShiehCC ChangTumor-selective replication of an oncolytic adenovirus carrying oct-3/4 response elements in murine metastatic bladder cancer modelsClin Cancer Res1412281238200810.1158/1078-0432.CCR-07-104718281558
24.	DH KirnF McCormickReplicating viruses as selective cancer therapeuticsMol Med Today2519527199610.1016/S1357-4310(97)81456-69015793
25.	J ShislerP Duerksen-HughesTM HermistonWS WoldLR GoodingInduction of susceptibility to tumor necrosis factor by E1A is dependent on binding to either p300 or p105-Rb and induction of DNA synthesisJ Virol70687719968523594
26.	U FischerK Schulze-OsthoffNew approaches and therapeutics targeting apoptosis in diseasePharmacol Rev57187215200510.1124/pr.57.2.615914467
27.	C OroDA JansThe tumour specific pro-apoptotic factor apoptin (Vp3) from chicken anaemia virusCurr Drug Targets5179190200410.2174/138945004349063115011951
28.	L GuelenH PatersonJ GakenM MeyersF FarzanehM TavassoliTAT-apoptin is efficiently delivered and induces apoptosis in cancer cellsOncogene2311531165200410.1038/sj.onc.120722414691460
29.	SM ZhuangA ShvartsH van OrmondtAG JochemsenAJ van der EbMH NotebornApoptin, a protein derived from chicken anemia virus, induces p53-independent apoptosis in human osteosarcoma cellsCancer Res5548648919957834613
30.	MH NotebornProteins selectively killing tumor cellsEur J Pharmacol625165173200910.1016/j.ejphar.2009.06.06819836376
31.	V PavetMM PortalJC MoulinR HerbrechtH GronemeyerTowards novel paradigms for cancer therapyOncogene30120201110.1038/onc.2010.46020935674
32.	I ChowdhuryB TharakanGK BhatCaspases - an updateComp Biochem Physiol B Biochem Mol Biol1511027200810.1016/j.cbpb.2008.05.01018602321