Uptake of mIBG and catecholamines in noradrenaline- and organic cation transporter-expressing cells: potential use of corticosterone for a preferred uptake in neuroblastoma- and pheochromocytoma cells

Bayer, Melanie; Kuçi, Zyrafete; Schömig, Edgar; Gründemann, Dirk; Dittmann, Helmut; Handgretinger, Rupert; Bruchelt, Gernot

doi:10.1016/j.nucmedbio.2008.12.010

Cited by 34 publications

(19 citation statements)

References 28 publications

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“…11 We confirmed the uptake of MIBG by NET in our in vitro model using HEK293 cells stably transfected with human NET transporter (HEK-hNET). Due to its ease of handling and shorter half life, we used 123 I-labeled MIBG instead of 131 I-labeled MIBG in our in vitro and in vivo studies.…”

Section: Resultssupporting

confidence: 68%

Vorinostat Increases Expression of Functional Norepinephrine Transporter in Neuroblastoma In Vitro and In Vivo Model Systems

Itsara

Yang

et al. 2011

Clinical Cancer Research

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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 131I-metaiodobenzylguanidine (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 131I-MIBG. Human NB cell lines (Kelly and SH-SY-5Y) and NB1691luc mouse xenografts were employed. The upregulated NET protein was characterized for its effect on 123I-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-fold and 2.5 fold increases were observed in Kelly and SH-SY-5Y cells, respectively, pre-treated 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 123I-MIBG biodistribution was observed in tumors that exhibited enhanced uptake in vorinostat treated (0.062 ± 0.011 μCi/(mg tissue-dose injected)) versus 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 131I-MIBG.

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Section: Resultssupporting

confidence: 68%

Vorinostat Increases Expression of Functional Norepinephrine Transporter in Neuroblastoma In Vitro and In Vivo Model Systems

Itsara

Yang

et al. 2011

Clinical Cancer Research

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“…It is possible that tumors with low NET protein expression may accumulate MIBG via other transporters. Candidate transporters include OCTs and VMATs as these transporters have been implicated in MIBG uptake in other neuroendocrine tumors [18–20]. Our evaluation of OCT and VMAT mRNA expression did not reveal any statistically significant associations with MIBG avidity, including subset analysis focusing only on patients with low NET protein expression and MIBG avid tumors (data not shown).…”

Section: Discussionmentioning

confidence: 76%

“…Moreover, a range of cells that do not typically accumulate MIBG can be engineered to do so by transfection of the NET gene [9–17]. Additional studies in neuroblastoma and other neuroendocrine tumors have suggested that vesicular monoamine transporters (VMATs) and organic cation transporters (OCTs) may also play a role in mediating uptake of MIBG [18–20]. …”

Section: Introductionmentioning

confidence: 99%

Evaluation of Norepinephrine Transporter Expression and Metaiodobenzylguanidine Avidity in Neuroblastoma: A Report from the Children's Oncology Group

DuBois

Geier

Batra

et al. 2012

International Journal of Molecular Imaging

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Purpose. 123I-metaiodobenzylguanidine (MIBG) is used for the diagnostic evaluation of neuroblastoma. We evaluated the relationship between norepinephrine transporter (NET) expression and clinical MIBG uptake. Methods. Quantitative reverse transcription PCR (N = 82) and immunohistochemistry (IHC; N = 61) were performed for neuroblastoma NET mRNA and protein expression and correlated with MIBG avidity on diagnostic scans. The correlation of NET expression with clinical features was also performed. Results. Median NET mRNA expression level for the 19 MIBG avid patients was 12.9% (range 1.6–73.7%) versus 5.9% (range 0.6–110.0%) for the 8 nonavid patients (P = 0.31). Median percent NET protein expression was 50% (range 0–100%) in MIBG avid patients compared to 10% (range 0–80%) in nonavid patients (P = 0.027). MYCN amplified tumors had lower NET protein expression compared to nonamplified tumors (10% versus 50%; P = 0.0002). Conclusions. NET protein expression in neuroblastoma correlates with MIBG avidity. MYCN amplified tumors have lower NET protein expression.

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“…OCT1 may also be critical for therapeutic concentrations of certain cationic antineoplastic drugs, such as mitoxantrone, to be reached in tumor cells [7]. Similarly, intracellular concentrations of m-iodobenzylguanidine radiolabeled with iodine-123 (for imaging purposes) or with iodine-131 (a therapeutic radiopharmaceutical) [96] are dependent on OCT1 expression/function. Another antineoplastic drug taken up by cancer cells through OCT1 is sepantronium bromide or YM 155, a novel survivin suppressant that exhibits potent antitumor activity against solid human tumors and lymphoma cells [97].…”

Section: Role Of Oct1 In Drug Transportmentioning

confidence: 99%

Role of the Plasma Membrane Transporter of Organic Cations OCT1 and Its Genetic Variants in Modern Liver Pharmacology

Lozano

Herráez

Briz

et al. 2013

BioMed Research International

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Changes in the uptake of many drugs by the target cells may dramatically affect the pharmacological response. Thus, downregulation of SLC22A1, which encodes the organic cation transporter type 1 (OCT1), may affect the response of healthy hepatocytes and liver cancer cells to cationic drugs, such as metformin and sorafenib, respectively. Moreover, the overall picture may be modified to a considerable extent by the preexistence or the appearance during the pathogenic process of genetic variants. Some rare OCT1 variants enhance transport activity, whereas other more frequent variants impair protein maturation, plasma membrane targeting or the function of this carrier, hence reducing intracellular active drug concentrations. Here, we review current knowledge of the role of OCT1 in modern liver pharmacology, which includes the use of cationic drugs to treat several diseases, some of them of great clinical relevance such as diabetes and primary liver cancer (cholangiocarcinoma and hepatocellular carcinoma). We conclude that modern pharmacology must consider the individual evaluation of OCT1 expression/function in the healthy liver and in the target tissue, particularly if this is a tumor, in order to predict the lack of response to cationic drugs and to be able to design individualized pharmacological treatments with the highest chances of success.

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Uptake of mIBG and catecholamines in noradrenaline- and organic cation transporter-expressing cells: potential use of corticosterone for a preferred uptake in neuroblastoma- and pheochromocytoma cells

Cited by 34 publications

References 28 publications

Vorinostat Increases Expression of Functional Norepinephrine Transporter in Neuroblastoma In Vitro and In Vivo Model Systems

Vorinostat Increases Expression of Functional Norepinephrine Transporter in Neuroblastoma In Vitro and In Vivo Model Systems

Evaluation of Norepinephrine Transporter Expression and Metaiodobenzylguanidine Avidity in Neuroblastoma: A Report from the Children's Oncology Group

Role of the Plasma Membrane Transporter of Organic Cations OCT1 and Its Genetic Variants in Modern Liver Pharmacology

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