title: Combination of vorinostat and adenovirus-TRAIL exhibits a synergistic antitumor effect by increasing transduction and transcription of TRAIL in lung cancer cells.
abstract: Soluble TRAIL and adenovirus (ad)-TRAIL exhibit a strong antitumor effect by inducing apoptosis. Vorinostat is the histone deacetylase (HDAC) inhibitor that induces cell death in cancer cell lines and regulates the expression of epigenetically silenced genes, such as Coxackie adenoviral receptor (CAR), the receptor for adenoviral entry. We propose a new strategy in which vorinostat will induce high expression of ad-TRAIL and a strong antitumor response, and investigated the mechanism involved. The effect of vorinostat on transcription and expression of TRAIL from ad-TRAIL-transduced lung cancer cells were confirmed by reverse transciption-PCR (RT-PCR), quantitative real time-PCR and western blot assay. Anti-tumor effects were measured after cotreatment of vorinostat and ad-TRAIL, and the drug interactions were analyzed. After combined treatment of vorinostat and ad-TRAIL, apoptosis and western blot assays for Akt, Bcl-2 and caspase were performed. Vorinostat increased the expression of CAR in lung cancer cell lines and increased the expression of luciferase (luc) from ad-luc-transduced cells and TRAIL from ad-TRAIL-transduced cells. RT-PCR and quantitative real time-PCR, after sequential vorinostat treatment, revealed that vorinostat may enhance TRAIL expression from ad-TRAIL by increasing transduction through enhanced CAR expression and increasing adenoviral transgene transcription. Combined vorinostat and ad-TRAIL treatment showed the synergistic anti-tumor effect in lung cancer cell lines. Combined vorinostat and ad-TRAIL induced stronger apoptosis induction, suppression of NF-κB activation and breakdown of the anti-apoptotic molecule Bcl-2. In conclusion, the vorinostat synergistically enhanced the anti-tumor effect of ad-TRAIL by (1) increasing adenoviral transduction through the increased expression of CAR and (2) increasing adenoviral transgene (TRAIL) transcription in lung cancer cell lines.
authors: Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.
authors: D R
authors: DR
authors: Kim
authors: M-Y
authors: MY
authors: Park
authors: C-S
authors: CS
authors: Lee
authors: S-H
authors: SH
authors: Shim
authors: H-I
authors: HI
authors: Yoon
authors: J H
authors: JH
authors: Lee
authors: M-W
authors: MW
authors: Sung
authors: Y-S
authors: YS
authors: Kim
authors: C-T
authors: CT
authors: Lee
mesh_terms: D000256:Adenoviridae / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D015153:Blotting, Western; D005434:Flow Cytometry; D006801:Humans; D006877:Hydroxamic Acids / Q000627:therapeutic use*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000628:therapy*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism*; D000077337:Vorinostat; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D006877:Hydroxamic Acids; D053221:TNF-Related Apoptosis-Inducing Ligand; D000077337:Vorinostat