{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T21:06:32Z","timestamp":1790024792744,"version":"4.0.1"},"reference-count":60,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2023,3,20]],"date-time":"2023-03-20T00:00:00Z","timestamp":1679270400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Essen Laboratory and Science Training Program for Young Physicians","award":["ELAN 2023"],"award-info":[{"award-number":["ELAN 2023"]}]},{"name":"Essen Laboratory and Science Training Program for Young Physicians","award":["CSC 2023"],"award-info":[{"award-number":["CSC 2023"]}]},{"name":"Chinese Scholarship Fund","award":["ELAN 2023"],"award-info":[{"award-number":["ELAN 2023"]}]},{"name":"Chinese Scholarship Fund","award":["CSC 2023"],"award-info":[{"award-number":["CSC 2023"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Uveal melanoma (UM) is the most common primary cancer of the eye in adults. A new systemic therapy is needed to reduce the high metastasis and mortality rate. As \u03b2-blockers are known to have anti-tumor effects on various cancer entities, this study focuses on investigating the effect of \u03b21-selective blockers atenolol, celiprolol, bisoprolol, metoprolol, esmolol, betaxolol, and in particular, nebivolol on UM. The study was performed on 3D tumor spheroids as well as 2D cell cultures, testing tumor viability, morphological changes, long-term survival, and apoptosis. Flow cytometry revealed the presence of all three \u03b2-adrenoceptors with a dominance of \u03b22-receptors on cell surfaces. Among the blockers tested, solely nebivolol concentration-dependently decreased viability and altered 3D tumor spheroid structure. Nebivolol blocked the repopulation of cells spreading from 3D tumor spheroids, indicating a tumor control potential at a concentration of \u226520 \u00b5M. Mechanistically, nebivolol induced ATP depletion and caspase-3\/7 activity, indicating that mitochondria-dependent signaling is involved. D-nebivolol or nebivolol combined with the \u03b22-antagonist ICI 118.551 displayed the highest anti-tumor effects, suggesting a contribution of both \u03b21- and \u03b22-receptors. Thus, the present study reveals the tumor control potential of nebivolol in UM, which may offer a perspective for co-adjuvant therapy to reduce recurrence or metastasis.<\/jats:p>","DOI":"10.3390\/ijms24065894","type":"journal-article","created":{"date-parts":[[2023,3,21]],"date-time":"2023-03-21T03:15:03Z","timestamp":1679368503000},"page":"5894","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Blockade of \u00df-Adrenergic Receptors by Nebivolol Enables Tumor Control Potential for Uveal Melanoma in 3D Tumor Spheroids and 2D Cultures"],"prefix":"10.3390","volume":"24","author":[{"given":"Lina S.","family":"Farhoumand","sequence":"first","affiliation":[{"name":"Eye Research Lab, Department of Ophthalmology, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongtao","family":"Liu","sequence":"additional","affiliation":[{"name":"Eye Research Lab, Department of Ophthalmology, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theodora","family":"Tsimpaki","sequence":"additional","affiliation":[{"name":"Eye Research Lab, Department of Ophthalmology, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulrike B.","family":"Hendgen-Cotta","sequence":"additional","affiliation":[{"name":"CardioScience Labs, Department of Cardiology and Vascular Medicine, West German Heart and Vascular Center, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8001-0265","authenticated-orcid":false,"given":"Tienush","family":"Rassaf","sequence":"additional","affiliation":[{"name":"CardioScience Labs, Department of Cardiology and Vascular Medicine, West German Heart and Vascular Center, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikolaos E.","family":"Bechrakis","sequence":"additional","affiliation":[{"name":"Eye Research Lab, Department of Ophthalmology, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7868-5167","authenticated-orcid":false,"given":"Miltiadis","family":"Fiorentzis","sequence":"additional","affiliation":[{"name":"Eye Research Lab, Department of Ophthalmology, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Utta","family":"Berchner-Pfannschmidt","sequence":"additional","affiliation":[{"name":"Eye Research Lab, Department of Ophthalmology, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,3,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"22","DOI":"10.2174\/1573402114666180918102735","article-title":"Three Generations of beta-blockers: History, Class Differences and Clinical Applicability","volume":"15","author":"Ceron","year":"2019","journal-title":"Curr. Hypertens. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1201","DOI":"10.1158\/1078-0432.CCR-11-0641","article-title":"Molecular pathways: Beta-adrenergic signaling in cancer","volume":"18","author":"Cole","year":"2012","journal-title":"Clin. Cancer Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1016\/j.semcancer.2013.08.009","article-title":"beta-Adrenergic system, a backstage manipulator regulating tumour progression and drug target in cancer therapy","volume":"23","author":"Tang","year":"2013","journal-title":"Semin. Cancer Biol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"4266","DOI":"10.18632\/oncotarget.2887","article-title":"Adrenergic regulation of monocyte chemotactic protein 1 leads to enhanced macrophage recruitment and ovarian carcinoma growth","volume":"6","author":"Nagaraja","year":"2015","journal-title":"Oncotarget"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2496","DOI":"10.1111\/bph.14552","article-title":"beta-Adrenoceptors as drug targets in melanoma: Novel preclinical evidence for a role of \u03b23-adrenoceptors","volume":"176","author":"Calvani","year":"2019","journal-title":"Br. J. Pharmacol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"628","DOI":"10.18632\/oncotarget.197","article-title":"Beta-blocker drug therapy reduces secondary cancer formation in breast cancer and improves cancer specific survival","volume":"1","author":"Powe","year":"2010","journal-title":"Oncotarget"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2","DOI":"10.5070\/D3217028111","article-title":"Beta blocker treatment for infantile hemangiomas","volume":"21","author":"Rouhana","year":"2015","journal-title":"Dermatol. Online J."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"104587","DOI":"10.1016\/j.phrs.2019.104587","article-title":"beta-blockers: Their new life from hypertension to cancer and migraine","volume":"151","author":"Fumagalli","year":"2020","journal-title":"Pharmacol. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1111\/j.1751-7176.2011.00515.x","article-title":"beta-Adrenergic blockers","volume":"13","author":"Frishman","year":"2011","journal-title":"J. Clin. Hypertens."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1038\/nrd.2018.168","article-title":"Drug repurposing: Progress, challenges and recommendations","volume":"18","author":"Pushpakom","year":"2019","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1049640","DOI":"10.3389\/fphar.2022.1049640","article-title":"Screening of GPCR drugs for repurposing in breast cancer","volume":"13","author":"Abdulkareem","year":"2022","journal-title":"Front. Pharmacol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.pcad.2004.04.004","article-title":"Cardiovascular drug class specificity: Beta-blockers","volume":"47","author":"Reiter","year":"2004","journal-title":"Prog. Cardiovasc. Dis."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"853","DOI":"10.1016\/j.recesp.2019.02.023","article-title":"Beta-blockers: Historical Perspective and Mechanisms of Action","volume":"72","author":"Oliver","year":"2019","journal-title":"Rev. Esp. Cardiol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1097\/00005344-198805000-00007","article-title":"Pharmacological and hemodynamic profile of nebivolol, a chemically novel, potent, and selective beta 1-adrenergic antagonist","volume":"11","author":"Janssens","year":"1988","journal-title":"J. Cardiovasc. Pharmacol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1159\/000076677","article-title":"Comparative effects of a two-week treatment with nebivolol and nifedipine in hypertensive patients suffering from COPD","volume":"71","author":"Cazzola","year":"2004","journal-title":"Respiration"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1586\/14779072.6.4.471","article-title":"Beta-blockers in the management of hypertension: Focus on nebivolol","volume":"6","author":"Wojciechowski","year":"2008","journal-title":"Expert Rev. Cardiovasc. Ther."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1491","DOI":"10.1016\/j.jacc.2009.05.066","article-title":"Nebivolol: The somewhat-different beta-adrenergic receptor blocker","volume":"54","author":"Munzel","year":"2009","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1185\/03007990903533681","article-title":"Effects of beta-blockers on glucose and lipid metabolism","volume":"26","author":"Fonseca","year":"2010","journal-title":"Curr. Med. Res. Opin."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1349","DOI":"10.1007\/s40265-015-0435-5","article-title":"A Review of Nebivolol Pharmacology and Clinical Evidence","volume":"75","author":"Fongemie","year":"2015","journal-title":"Drugs"},{"key":"ref_20","first-page":"190","article-title":"New beta-blocker gets FDA approval","volume":"65","author":"Traynor","year":"2008","journal-title":"Am. J. Health Syst. Pharm."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"964","DOI":"10.1097\/00005344-199106000-00016","article-title":"Nebivolol induces endothelium-dependent relaxations of canine coronary arteries","volume":"17","author":"Gao","year":"1991","journal-title":"J. Cardiovasc. Pharmacol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1111\/j.1527-3466.2008.00044.x","article-title":"Different pharmacological properties of two enantiomers in a unique beta-blocker, nebivolol","volume":"26","author":"Ignarro","year":"2008","journal-title":"Cardiovasc. Ther."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"5919","DOI":"10.1038\/s41467-021-26222-x","article-title":"FBXL2 counteracts Grp94 to destabilize EGFR and inhibit EGFR-driven NSCLC growth","volume":"12","author":"Niu","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"691998","DOI":"10.3389\/fphar.2021.691998","article-title":"Adrenergic Blockade by Nebivolol to Suppress Oral Squamous Cell Carcinoma Growth via Endoplasmic Reticulum Stress and Mitochondria Dysfunction","volume":"12","author":"Chen","year":"2021","journal-title":"Front. Pharmacol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1038\/eye.2016.275","article-title":"Uveal melanoma: Relatively rare but deadly cancer","volume":"31","author":"Kaliki","year":"2017","journal-title":"Eye"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1791","DOI":"10.31557\/APJCP.2022.23.5.1791","article-title":"Global Incidence and Trend of Uveal Melanoma from 1943\u20132015: A Meta-Analysis","volume":"23","author":"Naseripoor","year":"2022","journal-title":"Asian Pac. J. Cancer Prev."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2299","DOI":"10.1002\/cncr.29727","article-title":"Uveal melanoma: From diagnosis to treatment and the science in between","volume":"122","author":"Chattopadhyay","year":"2016","journal-title":"Cancer"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1038\/s41572-020-0158-0","article-title":"Uveal melanoma","volume":"6","author":"Jager","year":"2020","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Rossi, E., Croce, M., Reggiani, F., Schinzari, G., Ambrosio, M., Gangemi, R., Tortora, G., Pfeffer, U., and Amaro, A. (2021). Uveal Melanoma Metastasis. Cancers, 13.","DOI":"10.20944\/preprints202110.0013.v1"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1111\/aos.13452","article-title":"Prognostic impact of chromosomal aberrations and GNAQ, GNA11 and BAP1 mutations in uveal melanoma","volume":"96","author":"Staby","year":"2018","journal-title":"Acta Ophthalmol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"4651","DOI":"10.1167\/iovs.03-0538","article-title":"Very long-term prognosis of patients with malignant uveal melanoma","volume":"44","author":"Kujala","year":"2003","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1758835920965852","DOI":"10.1177\/1758835920965852","article-title":"Uveal melanoma: Progress in molecular biology and therapeutics","volume":"12","author":"Li","year":"2020","journal-title":"Ther. Adv. Med. Oncol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1819","DOI":"10.1038\/s41417-022-00443-8","article-title":"New targeted and epigenetic therapeutic strategies for the treatment of uveal melanoma","volume":"29","author":"Wei","year":"2022","journal-title":"Cancer Gene Ther."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Van der Kooij, M.K., Speetjens, F.M., van der Burg, S.H., and Kapiteijn, E. (2019). Uveal Versus Cutaneous Melanoma; Same Origin, Very Distinct Tumor Types. Cancers, 11.","DOI":"10.3390\/cancers11060845"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2191","DOI":"10.1056\/NEJMoa1000584","article-title":"Mutations in GNA11 in uveal melanoma","volume":"363","author":"Griewank","year":"2010","journal-title":"N. Engl. J. Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1016\/0140-6736(92)90861-V","article-title":"Chromosomal aberrations defining uveal melanoma of poor prognosis","volume":"339","author":"Prescher","year":"1992","journal-title":"Lancet"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1222","DOI":"10.1016\/S0140-6736(96)90736-9","article-title":"Prognostic implications of monosomy 3 in uveal melanoma","volume":"347","author":"Prescher","year":"1996","journal-title":"Lancet"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1410","DOI":"10.1126\/science.1194472","article-title":"Frequent mutation of BAP1 in metastasizing uveal melanomas","volume":"330","author":"Harbour","year":"2010","journal-title":"Science"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1002\/dc.23450","article-title":"Uveal melanoma: An analysis of cellular features and comparison to monosomy 3 status","volume":"44","author":"Hamadeh","year":"2016","journal-title":"Diagn. Cytopathol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"7265","DOI":"10.1002\/cam4.2594","article-title":"Beta-blockers exert potent anti-tumor effects in cutaneous and uveal melanoma","volume":"8","author":"Bustamante","year":"2019","journal-title":"Cancer Med."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Farhoumand, L.S., Fiorentzis, M., Kraemer, M.M., Sak, A., Stuschke, M., Rassaf, T., Hendgen-Cotta, U., Bechrakis, N.E., and Berchner-Pfannschmidt, U. (2022). The Adrenergic Receptor Antagonist Carvedilol Elicits Anti-Tumor Responses in Uveal Melanoma 3D Tumor Spheroids and May Serve as Co-Adjuvant Therapy with Radiation. Cancers, 14.","DOI":"10.3390\/cancers14133097"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Fiorentzis, M., Sokolenko, E.A., Bechrakis, N.E., Ting, S., Schmid, K.W., Sak, A., Stuschke, M., Seitz, B., and Berchner-Pfannschmidt, U. (2021). Electrochemotherapy with Bleomycin Enhances Radiosensitivity of Uveal Melanomas: First In Vitro Results in 3D Cultures of Primary Uveal Melanoma Cell Lines. Cancers, 13.","DOI":"10.3390\/cancers13123086"},{"key":"ref_43","first-page":"T5","article-title":"Uveal Melanoma Cell Lines: Where do they come from? (An American Ophthalmological Society Thesis)","volume":"114","author":"Jager","year":"2016","journal-title":"Trans. Am. Ophthalmol. Soc."},{"key":"ref_44","first-page":"843","article-title":"The receptor binding profile of the new antihypertensive agent nebivolol and its stereoisomers compared with various beta-adrenergic blockers","volume":"34","author":"Pauwels","year":"1988","journal-title":"Mol. Pharmacol."},{"key":"ref_45","first-page":"4147","article-title":"Cell culture as spheroids: An approach to multicellular resistance","volume":"18","author":"Desoize","year":"1998","journal-title":"Anticancer Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1177\/1087057104265040","article-title":"The use of 3-D cultures for high-throughput screening: The multicellular spheroid model","volume":"9","author":"Freyer","year":"2004","journal-title":"J. Biomol. Screen."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1172","DOI":"10.1002\/biot.200700228","article-title":"Recent advances in three-dimensional multicellular spheroid culture for biomedical research","volume":"3","author":"Lin","year":"2008","journal-title":"Biotechnol. J."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/j.carbpol.2016.05.005","article-title":"Tumor spheroid assembly on hyaluronic acid-based structures: A review","volume":"150","author":"Carvalho","year":"2016","journal-title":"Carbohydr. Polym."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Mergener, S., Siveke, J.T., and Pena-Llopis, S. (2021). Monosomy 3 Is Linked to Resistance to MEK Inhibitors in Uveal Melanoma. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22136727"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"3606","DOI":"10.1038\/s41467-020-17384-1","article-title":"Coordinate beta-adrenergic inhibition of mitochondrial activity and angiogenesis arrest tumor growth","volume":"11","author":"Santacatterina","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1083\/jcb.144.2.281","article-title":"Ordering the cytochrome c-initiated caspase cascade: Hierarchical activation of caspases-2, -3, -6, -7, -8, and -10 in a caspase-9-dependent manner","volume":"144","author":"Slee","year":"1999","journal-title":"J. Cell Biol."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Brentnall, M., Rodriguez-Menocal, L., De Guevara, R.L., Cepero, E., and Boise, L.H. (2013). Caspase-9, caspase-3 and caspase-7 have distinct roles during intrinsic apoptosis. BMC Cell Biol., 14.","DOI":"10.1186\/1471-2121-14-32"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"2824","DOI":"10.1021\/acs.biochem.1c00459","article-title":"Caspase-9 Activation of Procaspase-3 but Not Procaspase-6 Is Based on the Local Context of Cleavage Site Motifs and on Sequence","volume":"60","author":"Soni","year":"2021","journal-title":"Biochemistry"},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Sokolenko, E.A., Berchner-Pfannschmidt, U., Ting, S.C., Schmid, K.W., Bechrakis, N.E., Seitz, B., Tsimpaki, T., Kraemer, M.M., and Fiorentzis, M. (2021). Optimisation of the Chicken Chorioallantoic Membrane Assay in Uveal Melanoma Research. Pharmaceutics, 14.","DOI":"10.3390\/pharmaceutics14010013"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1111\/j.1755-148X.2012.00971.x","article-title":"Genetic and molecular characterization of uveal melanoma cell lines","volume":"25","author":"Griewank","year":"2012","journal-title":"Pigment Cell Melanoma Res."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1002\/(SICI)1097-0215(19971114)73:4<470::AID-IJC3>3.0.CO;2-X","article-title":"Melanomas that develop within the eye inhibit lymphocyte proliferation","volume":"73","author":"Verbik","year":"1997","journal-title":"Int. J. Cancer"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"4660","DOI":"10.1167\/iovs.03-0151","article-title":"Dose fractionation effects in primary and metastatic human uveal melanoma cell lines","volume":"44","author":"Kilic","year":"2003","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1002\/ijc.2910620208","article-title":"Establishment and characterization of an uveal-melanoma cell line","volume":"62","author":"Blom","year":"1995","journal-title":"Int. J. Cancer"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1508","DOI":"10.1016\/j.molonc.2014.06.004","article-title":"Establishment of novel cell lines recapitulating the genetic landscape of uveal melanoma and preclinical validation of mTOR as a therapeutic target","volume":"8","author":"Nemati","year":"2014","journal-title":"Mol. Oncol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1159\/000201566","article-title":"Novel cell lines derived by long-term culture of primary uveal melanomas","volume":"223","author":"Nareyeck","year":"2009","journal-title":"Ophthalmologica"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/6\/5894\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:59:43Z","timestamp":1760122783000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/6\/5894"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,20]]},"references-count":60,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2023,3]]}},"alternative-id":["ijms24065894"],"URL":"https:\/\/doi.org\/10.3390\/ijms24065894","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,3,20]]}}}