{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T22:19:36Z","timestamp":1790720376166,"version":"4.1.0"},"reference-count":23,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2022,1,12]],"date-time":"2022-01-12T00:00:00Z","timestamp":1641945600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Erasmus MC grant","award":["2017"],"award-info":[{"award-number":["2017"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background: To improve peptide receptor radionuclide therapy (PRRT), we aimed to enhance the expression of somatostatin type-2 receptors (SSTR2) in vitro and in vivo, using valproic acid (VPA). Methods: Human NCI-H69 small-cell lung carcinoma cells were treated with VPA, followed by [111In]In-DOTATATE uptake studies, RT-qPCR and immunohistochemistry analysis. Furthermore, NCI-H69 xenografted mice were treated with VPA or vehicle, followed by [177Lu]Lu-DOTATATE injection. Biodistribution studies were performed, and tissues were collected for further analysis. Results: VPA significantly increased SSTR2 expression in vitro. In animals, a statistically significant increased [177Lu]Lu-DOTATATE tumoral uptake was observed when VPA was administered eight hours before [177Lu]Lu-DOTATATE administration, but increased tumor SSTR2 expression levels were lacking. The animals also presented significantly higher [177Lu]Lu-DOTATATE blood levels, as well as an elevated renal tubular damage score. This suggests that the enhanced tumor uptake was presumably a consequence of the increased radiotracer circulation and the induced kidney damage. Conclusions: VPA increases SSTR2 expression in vitro. In vivo, the observed increase in tumoral [177Lu]Lu-DOTATATE uptake is not caused by SSTR2 upregulation, but rather by other mechanisms, e.g., an increased [177Lu]Lu-DOTATATE circulation time and renal toxicity. However, since both drugs are safely used in humans, the potential of VPA to improve PRRT remains open for investigation.<\/jats:p>","DOI":"10.3390\/pharmaceutics14010173","type":"journal-article","created":{"date-parts":[[2022,1,12]],"date-time":"2022-01-12T09:10:36Z","timestamp":1641978636000},"page":"173","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["The Effect of VPA Treatment on Radiolabeled DOTATATE Uptake: Differences Observed In Vitro and In Vivo"],"prefix":"10.3390","volume":"14","author":[{"given":"Maria","family":"Klomp","sequence":"first","affiliation":[{"name":"Department of Radiology and Nuclear Medicine, Erasmus MC, 3015 GD Rotterdam, The Netherlands"},{"name":"Department of Internal Medicine, Division of Endocrinology, Erasmus MC, 3015 GD Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leo","family":"Hofland","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Endocrinology, Erasmus MC, 3015 GD Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lilian","family":"van den Brink","sequence":"additional","affiliation":[{"name":"Department of Radiology and Nuclear Medicine, Erasmus MC, 3015 GD Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"van Koetsveld","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Endocrinology, Erasmus MC, 3015 GD Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fadime","family":"Dogan","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Endocrinology, Erasmus MC, 3015 GD Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Corrina","family":"de Ridder","sequence":"additional","affiliation":[{"name":"Department of Radiology and Nuclear Medicine, Erasmus MC, 3015 GD Rotterdam, The Netherlands"},{"name":"Department of Experimental Urology, Erasmus MC, 3015 GD Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Debra","family":"Stuurman","sequence":"additional","affiliation":[{"name":"Department of Radiology and Nuclear Medicine, Erasmus MC, 3015 GD Rotterdam, The Netherlands"},{"name":"Department of Experimental Urology, Erasmus MC, 3015 GD Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marian","family":"Clahsen-van Groningen","sequence":"additional","affiliation":[{"name":"Department of Pathology, Erasmus MC, 3015 GD Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marion","family":"de Jong","sequence":"additional","affiliation":[{"name":"Department of Radiology and Nuclear Medicine, Erasmus MC, 3015 GD Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simone","family":"Dalm","sequence":"additional","affiliation":[{"name":"Department of Radiology and Nuclear Medicine, Erasmus MC, 3015 GD Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,1,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1056\/NEJMoa1607427","article-title":"Phase 3 Trial of (177)Lu-Dotatate for Midgut Neuro-endocrine Tumors","volume":"376","author":"Strosberg","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"4617","DOI":"10.1158\/1078-0432.CCR-16-2743","article-title":"Long-Term Efficacy, Survival, and Safety of [177Lu-DOTA0,Tyr3]octreotate in Patients with Gastroenteropancreatic and Bronchial Neuroendocrine Tumors","volume":"23","author":"Brabander","year":"2017","journal-title":"Clin. Cancer Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1805","DOI":"10.2967\/jnumed.115.165092","article-title":"Upregulation of Key Molecules for Targeted Imaging and Therapy","volume":"57","author":"Taelman","year":"2016","journal-title":"J. Nucl. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/j.surg.2019.05.092","article-title":"Overexpression of somatostatin receptor type 2 in neuroendocrine tumors for improved Ga68-DOTATATE imaging and treatment","volume":"167","author":"Guenter","year":"2020","journal-title":"Surgery"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"767","DOI":"10.3390\/cancers11060767","article-title":"Pulmonary Carcinoid Surface Receptor Modulation Using Histone Deacetylase Inhibitors","volume":"11","author":"Guenter","year":"2019","journal-title":"Cancers"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"4905","DOI":"10.3390\/cancers13194905","article-title":"Comparing the Effect of Multiple Histone Deacetylase Inhibitors on SSTR2 Expression and [111In]In-DOTATATE Uptake in NET Cells","volume":"13","author":"Klomp","year":"2021","journal-title":"Cancers"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"14791","DOI":"10.18632\/oncotarget.9462","article-title":"Epidrug-induced upregulation of functional somatostatin type 2 receptors in human pancreatic neuroendocrine tumor cells","volume":"9","author":"Veenstra","year":"2016","journal-title":"Oncotarget"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1240","DOI":"10.2967\/jnumed.118.224048","article-title":"Combination of 5-Fluorouracil with Epigenetic Modifiers Induces Radiosensitization, Somatostatin Receptor 2 Expression, and Radioligand Binding in Neuroendocrine Tumor Cells In Vitro","volume":"60","author":"Jin","year":"2019","journal-title":"J. Nucl. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3128","DOI":"10.3390\/ijms19103128","article-title":"Pharmacological Inhibition of Class IIA HDACs by LMK-235 in Pancreatic Neuroendocrine Tumor Cells","volume":"19","author":"Wanek","year":"2018","journal-title":"Int. J. Mol. Sci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"3137","DOI":"10.1210\/en.2007-1525","article-title":"Identification of an Upstream Promoter of the Human Somatostatin Receptor, hSSTR2, Which Is Controlled by Epigenetic Modifications","volume":"149","author":"Torrisani","year":"2008","journal-title":"Endocrinology"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1159\/000441849","article-title":"Cytotoxic Effects of Valproic Acid on Neuroendocrine Tumour Cells","volume":"103","author":"Arvidsson","year":"2015","journal-title":"Neuroendocrinology"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"169","DOI":"10.3109\/1061186X.2015.1066794","article-title":"Valproic acid induces NET cell growth arrest and enhances tumor suppression of the receptor-targeted peptide\u2013drug conjugate via activating somatostatin receptor type II","volume":"24","author":"Sun","year":"2016","journal-title":"J. Drug Target."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1323","DOI":"10.1016\/j.clinbiochem.2013.06.012","article-title":"Adverse drug reactions induced by valproic acid","volume":"46","author":"Nanau","year":"2013","journal-title":"Clin. Biochem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/j.apradiso.2013.10.023","article-title":"Application of single-vial ready-for-use formulation of 111In- or 177Lu-labelled somatostatin analogs","volume":"85","author":"Chan","year":"2014","journal-title":"Appl. Radiat. Isot."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1016\/j.exphem.2008.12.002","article-title":"Valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, diminishes lymphoproliferation in the Fas -deficient MRL\/lpr\u2212\/\u2212 murine model of autoimmune lymphoproliferative syndrome (ALPS)","volume":"37","author":"Dowdell","year":"2009","journal-title":"Exp. Hematol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"5535","DOI":"10.1523\/JNEUROSCI.1139-07.2007","article-title":"Sodium valproate exerts neuro-protective effects in vivo through CREB-binding protein-dependent mechanisms but does not improve survival in an amyo-trophic lateral sclerosis mouse model","volume":"27","author":"Rouaux","year":"2007","journal-title":"J. Neurosci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"435","DOI":"10.4196\/kjpp.2010.14.6.435","article-title":"Neuroprotection by Valproic Acid in Mouse Models of Permanent and Transient Focal Cerebral Ischemia","volume":"14","author":"Qian","year":"2010","journal-title":"Korean J. Physiol. Pharmacol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"756","DOI":"10.1016\/j.nucmedbio.2012.02.003","article-title":"Nephrotoxicity profiles and threshold dose values for [177Lu]-DOTATATE in nude mice","volume":"39","author":"Svensson","year":"2012","journal-title":"Nucl. Med. Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1007\/s00709-015-0796-3","article-title":"Vitamin U has a protective effect on valproic ac-id-induced renal damage due to its anti-oxidant, anti-inflammatory, and anti-fibrotic properties","volume":"253","author":"Turkyilmaz","year":"2016","journal-title":"Protoplasma"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1006\/phrs.1997.0134","article-title":"Biochemical basis of sodium valproate hepatotoxicity and renal tubular disorder time dependence of peroxidative injury","volume":"35","author":"Raza","year":"1997","journal-title":"Pharmacol. Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1111\/nep.13012","article-title":"Mechanism of valproic acid-induced Fanconi syndrome in-volves mitochondrial dysfunction and oxidative stress in rat kidney","volume":"23","author":"Heidari","year":"2018","journal-title":"Nephrology"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1002\/bdd.2510030405","article-title":"Pharmacokinetics of valproic acid and metabolites in mouse plasma and brain following constant-rate application of the drug and its unsaturated metabolite with an osmotic delivery system","volume":"3","author":"Nau","year":"1982","journal-title":"Biopharm. Drug Dispos."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/j.seizure.2020.02.006","article-title":"Managing the patient with epilepsy and renal impairment","volume":"76","author":"Mahmoud","year":"2020","journal-title":"Seizure"}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/14\/1\/173\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T14:14:59Z","timestamp":1760364899000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/14\/1\/173"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,12]]},"references-count":23,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2022,1]]}},"alternative-id":["pharmaceutics14010173"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics14010173","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1,12]]}}}