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Genetic blockade of insulin‐like growth factor‐1 receptor via recombinant adenovirus in lung cancer can be enhanced by the histone deacetylase inhibitor, vorinostat
Author(s) -
Park MiYoung,
Kim Dal Rae,
Eo Eun Young,
Lim Hyo Jeong,
Park Jong Sun,
Cho YoungJae,
Yoon HoIl,
Lee Jae Ho,
Lee ChoonTaek
Publication year - 2013
Publication title -
the journal of gene medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.689
H-Index - 91
eISSN - 1521-2254
pISSN - 1099-498X
DOI - 10.1002/jgm.2699
Subject(s) - vorinostat , histone deacetylase inhibitor , biology , histone deacetylase , cancer research , insulin like growth factor , signal transduction , growth factor , microbiology and biotechnology , receptor , histone , biochemistry , gene
Abstract Background Many approaches have been suggested as anti‐tumor therapy for targeting insulin‐like growth factor 1 receptor (IGF‐1R), such as monoclonal antibodies and tyrosine kinase inhibitor. We introduced recombinant adenoviruses expressing antisense, dominant negative or short hairpin RNA to IGF‐1R. Moreover, we demonstrated that histone deacetylase inhibitor (vorinostat) can increase the transduction efficiency of adenoviruses by increasing CAR‐induced transduction and by enhancing the transcription of the adenoviral transgene. In the present study, we showed that the combination of ad‐sh (short hairpin) IGF‐1R with vorinostat leads to a synergistic enhancement of IGF‐1R blockade. Methods We measured the change in IGF‐1R upon cotreatment with vorinostat and ad‐shIGF‐1R. Changes in transduction efficiency of ad‐shIGF‐1R were measured by fluorescent microscopy. Changes in apoptotic proportion and cell survival after the cotreatment were measured by the sub‐G1 assay and cell counts. The effect of nuclear factor (NF)‐κB activation was also measured by NF‐κB p65 activation enzyme‐linked immunosorbent assay. Drug interactions were analyzed upon cotreatment with ad‐shIGF‐1R, vorinostat and cisplatin. Results Combined treatment of ad‐shIGF‐1R and vorinostat synergistically suppressed the IGF‐1R expression in lung cancer cell lines and also increased the transduction efficiency of ad‐shIGF‐1R. Ad‐shIGF‐1R and vorinostat cotreatment increased apoptotic cell death and synergistically suppressed cell growth compared to ad‐shIGF‐1R or vorinostat treatment alone. Vorinostat suppressed NF‐κB activation, which was activated by ad‐shIGF‐1R. Moreover, triple combination of ad‐shIGF‐1R, vorinostat and cisplatin demonstrated synergistic cytotoxicity on lung cancer cells. Conclusions Vorinostat enhanced the blocking capability of ad‐shIGF‐1R. The combined treatment of vorinostat and ad‐sh‐IGF‐1R appears to have promising potential as a new therapeutic approach for lung cancer. Copyright © 2013 John Wiley & Sons, Ltd.