Vorinostat increases expression of functional norepinephrine transporter in neuroblastoma in vitro and in vivo model systems.

Abstract

PURPOSE:

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).

EXPERIMENTAL DESIGN:

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: Swati S More, Melissa Itsara, Xiaodong Yang, Ethan G Geier, Michelle K Tadano, Youngho Seo, Henry F Vanbrocklin, William A Weiss, Sabine Mueller, Daphne A Haas-Kogan, Steven G Dubois, Katherine K Matthay, Kathleen M Giacomini
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 17 Issue 8 Pg. 2339-49 (Apr 15 2011) ISSN: 1557-3265 [Electronic] United States
• PMID: 21421857 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2011 AACR.

Chemical References

• Histone Deacetylase Inhibitors
• Hydroxamic Acids
• Norepinephrine Plasma Membrane Transport Proteins
• Radiopharmaceuticals
• 3-Iodobenzylguanidine
• Vorinostat

Topics

• 3-Iodobenzylguanidine (metabolism, pharmacokinetics)
• Animals
• Blotting, Western
• Cell Line, Tumor
• Cell Survival (drug effects)
• Dose-Response Relationship, Drug
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• HEK293 Cells
• Histone Deacetylase Inhibitors (pharmacology)
• Humans
• Hydroxamic Acids (pharmacology)
• Mice
• Mice, Nude
• Neoplasms, Experimental (genetics, metabolism, pathology)
• Neuroblastoma (genetics, metabolism, pathology)
• Norepinephrine Plasma Membrane Transport Proteins (genetics, metabolism)
• Radiopharmaceuticals (metabolism, pharmacokinetics)
• Reverse Transcriptase Polymerase Chain Reaction
• Tissue Distribution (drug effects)
• Transplantation, Heterologous
• Vorinostat