title: Vorinostat increases expression of functional norepinephrine transporter in neuroblastoma in vitro and in vivo model systems.
abstract: OBJECTIVE
  Histone deacetylase (HDAC) inhibition causes transcriptional activation or repression of several genes that in turn can influence the biodistribution of other chemotherapeutic agents. Here, we hypothesize that the combination of vorinostat, a HDAC inhibitor, with (131)I-meta-iodobenzylguanidine (MIBG) would lead to preferential accumulation of the latter in neuroblastoma (NB) tumors via increased expression of the human norepinephrine transporter (NET).
  
  
  METHODS
  In vitro and in vivo experiments examined the effect of vorinostat on the expression of NET, an uptake transporter for (131)I-MIBG. Human NB cell lines (Kelly and SH-SY-5Y) and NB1691-luc mouse xenografts were employed. The upregulated NET protein was characterized for its effect on (123)I-MIBG biodistribution.
  
  
  RESULTS
  Preincubation of NB cell lines, Kelly, and SH-SY-5Y, with vorinostat caused dose-dependent increases in NET mRNA and protein levels. Accompanying this was a corresponding dose-dependent increase in MIBG uptake in NB cell lines. Four- and 2.5-fold increases were observed in Kelly and SH-SY-5Y cells, respectively, pretreated with vorinostat in comparison to untreated cells. Similarly, NB xenografts, created by intravenous tail vein injection of NB1691-luc, and harvested from nude mice livers treated with vorinostat (150 mg/kg i.p.) showed substantial increases in NET protein expression. Maximal effect of vorinostat pretreatment in NB xenografts on (123)I-MIBG biodistribution was observed in tumors that exhibited enhanced uptake in vorinostat-treated [0.062 ± 0.011 μCi/(mg tissue-dose injected)] vs. -untreated mice [0.022 ± 0.003 μCi/(mg tissue-dose injected); P < 0.05].
  
  
  CONCLUSIONS
  The results of our study provide preclinical evidence that vorinostat treatment can enhance NB therapy with (131)I-MIBG.
authors.affiliation: Departments of Bioengineering and Therapeutic Sciences, UCSF School of Medicine and UCSF Benioff Children's Hospital, San Francisco, California 94158, USA.
authors.forename: Swati S
authors.initials: SS
authors.lastname: More
authors.forename: Melissa
authors.initials: M
authors.lastname: Itsara
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Yang
authors.forename: Ethan G
authors.initials: EG
authors.lastname: Geier
authors.forename: Michelle K
authors.initials: MK
authors.lastname: Tadano
authors.forename: Youngho
authors.initials: Y
authors.lastname: Seo
authors.forename: Henry F
authors.initials: HF
authors.lastname: Vanbrocklin
authors.forename: William A
authors.initials: WA
authors.lastname: Weiss
authors.forename: Sabine
authors.initials: S
authors.lastname: Mueller
authors.forename: Daphne A
authors.initials: DA
authors.lastname: Haas-Kogan
authors.forename: Steven G
authors.initials: SG
authors.lastname: Dubois
authors.forename: Katherine K
authors.initials: KK
authors.lastname: Matthay
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Giacomini
mesh_terms: D019797:3-Iodobenzylguanidine / Q000378:metabolism* / Q000493:pharmacokinetics; D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D057809:HEK293 Cells; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009447:Neuroblastoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D019275:Radiopharmaceuticals / Q000378:metabolism / Q000493:pharmacokinetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014018:Tissue Distribution / Q000187:drug effects; D014183:Transplantation, Heterologous; D000077337:Vorinostat
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D050484:Norepinephrine Plasma Membrane Transport Proteins; D019275:Radiopharmaceuticals; D019797:3-Iodobenzylguanidine; D000077337:Vorinostat