title: Genetic blockade of insulin-like growth factor-1 receptor via recombinant adenovirus in lung cancer can be enhanced by the histone deacetylase inhibitor, vorinostat.
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.
authors: Department of Internal Medicine, Respiratory Center, Seoul National University Bundang Hospital, Seongnam, Korea.
authors: Mi-Young
authors: MY
authors: Park
authors: Dal Rae
authors: DR
authors: Kim
authors: Eun Young
authors: EY
authors: Eo
authors: Hyo Jeong
authors: HJ
authors: Lim
authors: Jong Sun
authors: JS
authors: Park
authors: Young-Jae
authors: YJ
authors: Cho
authors: Ho-Il
authors: HI
authors: Yoon
authors: Jae Ho
authors: JH
authors: Lee
authors: Choon-Taek
authors: CT
authors: Lee
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000971:Antineoplastic Combined Chemotherapy Protocols; D017209:Apoptosis / Q000187:drug effects; D002452:Cell Count; D045744:Cell Line, Tumor; D004274:DNA, Recombinant / Q000235:genetics / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015967:Gene Expression Regulation, Viral / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000188:drug therapy*; D008856:Microscopy, Fluorescence; D034741:RNA, Small Interfering / Q000235:genetics; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000235:genetics*; D051996:Transcription Factor RelA / Q000378:metabolism; D014161:Transduction, Genetic / Q000379:methods; D000077337:Vorinostat
chemical_list: D004274:DNA, Recombinant; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D034741:RNA, Small Interfering; D051996:Transcription Factor RelA; D000077337:Vorinostat; D017526:Receptor, IGF Type 1