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Transfer of Manipulated Tumor-associated Neutrophils into Tumor-Bearing Mice to Study their Angiogenic Potential In Vivo
Published on: July 20, 2019
Vorinostat increases expression of functional norepinephrine transporter in neuroblastoma in vitro and in vivo model
Swati S More1, Melissa Itsara, Xiaodong Yang
1Departments of Bioengineering and Therapeutic Sciences, UCSF School of Medicine and UCSF Benioff Children's Hospital, San Francisco, California 94158, USA.
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 microCi/(mg tissue-dose injected)] vs. -untreated mice [0.022 ± 0.003 microCi/(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.
Insights
Vorinostat, a histone deacetylase inhibitor, increases norepinephrine transporter (NET) expression in neuroblastoma (NB) cells. This enhances the uptake of (131)I-meta-iodobenzylguanidine (MIBG), suggesting improved NB therapy.
Area of Science:
- Pharmacology and Therapeutics
- Oncology
- Molecular Biology
Background:
- Histone deacetylase (HDAC) inhibition modulates gene expression, potentially affecting drug biodistribution.
- Neuroblastoma (NB) is a pediatric cancer where targeted therapies are crucial.
- The norepinephrine transporter (NET) is a key uptake mechanism for radiopharmaceuticals like (131)I-MIBG.
Purpose of the Study:
- To investigate if vorinostat, an HDAC inhibitor, enhances the accumulation of (131)I-MIBG in neuroblastoma tumors.
- To determine if vorinostat upregulates the human norepinephrine transporter (NET) expression in NB.
Main Methods:
- In vitro studies using human NB cell lines (Kelly, SH-SY-5Y) treated with vorinostat.
- In vivo studies using NB1691-luc mouse xenografts treated with vorinostat.
- Assessment of NET mRNA and protein levels, and (123)I-MIBG uptake in response to vorinostat.
Main Results:
- Vorinostat treatment caused a dose-dependent increase in NET mRNA and protein in NB cell lines.
- MIBG uptake increased significantly (4-fold in Kelly, 2.5-fold in SH-SY-5Y) after vorinostat pretreatment.
- NB xenografts showed increased NET expression and enhanced (123)I-MIBG tumor uptake in vorinostat-treated mice compared to controls.
Conclusions:
- Preclinical data indicate that vorinostat effectively upregulates NET expression in neuroblastoma.
- Vorinostat pretreatment enhances the tumor-specific uptake of (131)I-MIBG in neuroblastoma models.
- This combination therapy holds promise for improving neuroblastoma treatment outcomes.
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