{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,25]],"date-time":"2026-07-25T05:10:01Z","timestamp":1784956201937,"version":"3.55.0"},"reference-count":51,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2021,8,22]],"date-time":"2021-08-22T00:00:00Z","timestamp":1629590400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100016017","name":"Duke-NUS Medical School","doi-asserted-by":"publisher","award":["start-up"],"award-info":[{"award-number":["start-up"]}],"id":[{"id":"10.13039\/100016017","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Singapore National Medical Research Council","award":["DYNAMO NMRC\/OFLCG\/001\/2017"],"award-info":[{"award-number":["DYNAMO NMRC\/OFLCG\/001\/2017"]}]},{"name":"Singapore National Medical Research Council","award":["TAPP NMRC\/OFLCG\/004\/2018"],"award-info":[{"award-number":["TAPP NMRC\/OFLCG\/004\/2018"]}]},{"name":"DEBBIE AND SYLVIA DESANTIS CHAIR IN NATURAL PRODUCTS DRUG DISCOVERY AND DEVELOPMENT","award":["Debbie and Sylvia DeSantis professorship"],"award-info":[{"award-number":["Debbie and Sylvia DeSantis professorship"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Marine Drugs"],"abstract":"<jats:p>Ocular angiogenic diseases, characterized by abnormal blood vessel formation in the eye, are the leading cause of blindness. Although Anti-VEGF therapy is the first-line treatment in the market, a substantial number of patients are refractory to it or may develop resistance over time. As uncontrolled proliferation of vascular endothelial cells is one of the characteristic features of pathological neovascularization, we aimed to investigate the role of the class I histone deacetylase (HDAC) inhibitor Largazole, a cyclodepsipeptide from a marine cyanobacterium, in ocular angiogenesis. Our study showed that Largazole strongly inhibits retinal vascular endothelial cell viability, proliferation, and the ability to form tube-like structures. Largazole strongly inhibits the vessel outgrowth from choroidal explants in choroid sprouting assay while it does not affect the quiescent choroidal vasculature. Largazole also inhibits vessel outgrowth from metatarsal bones in metatarsal sprouting assay without affecting pericytes coverage. We further demonstrated a cooperative effect between Largazole and an approved anti-VEGF drug, Alflibercept. Mechanistically, Largazole strongly inhibits the expression of VEGFR2 and leads to an increased expression of cell cycle inhibitor, p21. Taken together, our study provides compelling evidence on the anti-angiogenic role of Largazole that exerts its function through mediating different signaling pathways.<\/jats:p>","DOI":"10.3390\/md19080471","type":"journal-article","created":{"date-parts":[[2021,8,22]],"date-time":"2021-08-22T21:47:52Z","timestamp":1629668872000},"page":"471","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Largazole Inhibits Ocular Angiogenesis by Modulating the Expression of VEGFR2 and p21"],"prefix":"10.3390","volume":"19","author":[{"given":"Beiying","family":"Qiu","sequence":"first","affiliation":[{"name":"Centre for Vision Research, Duke NUS Medical School, 8 College Road, Singapore 169857, Singapore"},{"name":"Singapore Eye Research Institute (SERI), The Academia, 20 College Road, Level 6 Discovery Tower, Singapore 169856, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alison","family":"Tan","sequence":"additional","affiliation":[{"name":"Centre for Vision Research, Duke NUS Medical School, 8 College Road, Singapore 169857, Singapore"},{"name":"Singapore Eye Research Institute (SERI), The Academia, 20 College Road, Level 6 Discovery Tower, Singapore 169856, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5036-2451","authenticated-orcid":false,"given":"Yu Zhi","family":"Tan","sequence":"additional","affiliation":[{"name":"Lee Kong Chian School of Medicine, Nanyang Technological University, 11 Mandalay Road, Singapore 308232, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi-Yin","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry and Center for Natural Products, Drug Discovery and Development (CNPD3), University of Florida, 1345 Center Drive, Gainesville, FL 32610, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4091-7492","authenticated-orcid":false,"given":"Hendrik","family":"Luesch","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry and Center for Natural Products, Drug Discovery and Development (CNPD3), University of Florida, 1345 Center Drive, Gainesville, FL 32610, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaomeng","family":"Wang","sequence":"additional","affiliation":[{"name":"Centre for Vision Research, Duke NUS Medical School, 8 College Road, Singapore 169857, Singapore"},{"name":"Singapore Eye Research Institute (SERI), The Academia, 20 College Road, Level 6 Discovery Tower, Singapore 169856, Singapore"},{"name":"Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Proteos, 61 Biopolis Dr, Singapore 138673, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,8,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"892043","DOI":"10.1155\/2015\/892043","article-title":"Ocular Angiogenesis","volume":"2015","author":"Dreyfuss","year":"2015","journal-title":"J. Ophthalmol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1835","DOI":"10.1016\/S0140-6736(08)61759-6","article-title":"Age-related macular degeneration","volume":"372","author":"Coleman","year":"2008","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1900","DOI":"10.1001\/jama.291.15.1900","article-title":"Age-Related Macular Degeneration Is the Leading Cause of Blindness","volume":"291","author":"Bressler","year":"2004","journal-title":"JAMA"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"e106","DOI":"10.1016\/S2214-109X(13)70145-1","article-title":"Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: A systematic review and meta-analysis","volume":"2","author":"Wong","year":"2014","journal-title":"Lancet Glob. Health"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1629","DOI":"10.1056\/NEJMra1909637","article-title":"Evaluation and Care of Patients with Diabetic Retinopathy","volume":"382","author":"Jampol","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"16012","DOI":"10.1038\/nrdp.2016.12","article-title":"Diabetic retinopathy","volume":"2","author":"Wong","year":"2016","journal-title":"Nat. Rev. Dis. Prim."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"S84","DOI":"10.2337\/diacare.27.2007.S84","article-title":"Retinopathy in Diabetes","volume":"27","author":"Fong","year":"2003","journal-title":"Diabetes Care"},{"key":"ref_8","first-page":"302","article-title":"Prevalence of diabetic retinopathy, proliferative diabetic retinopathy and non-proliferative diabetic retinopathy in Asian T2DM patients: A systematic review and Meta-analysis","volume":"12","author":"Yang","year":"2019","journal-title":"Int. J. Ophthalmol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1124\/pr.56.4.3","article-title":"Vascular Endothelial Growth Factor and Angiogenesis","volume":"56","author":"Hoeben","year":"2004","journal-title":"Pharmacol. Rev."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Writing Committee for the Diabetic Retinopathy Clinical Research (2015). Panretinal Photocoagulation vs Intravitreous Ranibizumab for Proliferative Diabetic Retinopathy: A Randomized Clinical Trial. JAMA, 314, 2137\u20132146.","DOI":"10.1001\/jama.2015.15217"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1145","DOI":"10.1001\/archophthalmol.2012.1043","article-title":"Long-term Effects of Ranibizumab on Diabetic Retinopathy Severity and Progression","volume":"130","author":"Ip","year":"2012","journal-title":"Arch. Ophthalmol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1147","DOI":"10.1016\/S0140-6736(18)31550-2","article-title":"Age-related macular degeneration","volume":"392","author":"Mitchell","year":"2018","journal-title":"Lancet"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Wang, W., and Lo, A.C.Y. (2018). Diabetic Retinopathy: Pathophysiology and Treatments. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19061816"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"4213","DOI":"10.1172\/JCI65157","article-title":"Targeted deletion of Vegfa in adult mice induces vision loss","volume":"122","author":"Kurihara","year":"2012","journal-title":"J. Clin. Investig."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Diabetic Retinopathy Clinical Research (2015). Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema. N. Engl. J. Med., 372, 1193\u20131203.","DOI":"10.1056\/NEJMoa1414264"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1292","DOI":"10.1097\/IAE.0000000000000876","article-title":"Ranibizumab for diabetic macular edema refractory to multiple prior treatments","volume":"36","author":"Ciulla","year":"2016","journal-title":"Retinoids"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1056","DOI":"10.3390\/md9061056","article-title":"Marine Bioactives as Functional Food Ingredients: Potential to Reduce the Incidence of Chronic Diseases","volume":"9","author":"Lordan","year":"2011","journal-title":"Mar. Drugs"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1039\/C5NP00156K","article-title":"Marine natural products","volume":"33","author":"Blunt","year":"2016","journal-title":"Nat. Prod. Rep."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3254","DOI":"10.1167\/iovs.19-26936","article-title":"Apratoxin S4 Inspired by a Marine Natural Product, a New Treatment Option for Ocular Angiogenic Diseases","volume":"60","author":"Qiu","year":"2019","journal-title":"Investig. Opthalmology Vis. Sci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1806","DOI":"10.1021\/ja7110064","article-title":"Structure and activity of largazole, a potent antiproliferative agent from the Floridian marine cyanobacterium Symploca sp.","volume":"130","author":"Taori","year":"2008","journal-title":"J. Am. Chem. Soc."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"8455","DOI":"10.1021\/ja8013727","article-title":"Total Synthesis and Molecular Target of Largazole, a Histone Deacetylase Inhibitor","volume":"130","author":"Ying","year":"2008","journal-title":"J. Am. Chem. Soc."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1039\/c2np00066k","article-title":"Largazole: From discovery to broad-spectrum therapy","volume":"29","author":"Hong","year":"2012","journal-title":"Nat. Prod. Rep."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1937","DOI":"10.1021\/acschemneuro.0c00093","article-title":"Largazole is a Brain-Penetrant Class I HDAC Inhibitor with Extended Applicability to Glioblastoma and CNS Diseases","volume":"11","author":"Lilibeth","year":"2020","journal-title":"ACS Chem. Neurosci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1124\/jpet.110.172387","article-title":"Anticolon Cancer Activity of Largazole, a Marine-Derived Tunable Histone Deacetylase Inhibitor","volume":"335","author":"Liu","year":"2010","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1097\/BCR.0b013e3181c7ed82","article-title":"Molecular Mediators of Angiogenesis","volume":"31","author":"Ucuzian","year":"2010","journal-title":"J. Burn. Care Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1016\/j.ejphar.2014.06.019","article-title":"Largazole, an inhibitor of class I histone deacetylases, attenuates inflammatory corneal neovascularization","volume":"740","author":"Zhou","year":"2014","journal-title":"Eur. J. Pharmacol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1322","DOI":"10.1021\/acschembio.5b00860","article-title":"Multidimensional Screening Platform for Simultaneously Targeting Oncogenic KRAS and Hypoxia-Inducible Factors Pathways in Colorectal Cancer","volume":"11","author":"Bousquet","year":"2016","journal-title":"ACS Chem. Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1016\/j.cell.2011.08.039","article-title":"Basic and Therapeutic Aspects of Angiogenesis","volume":"146","author":"Potente","year":"2011","journal-title":"Cell"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1023\/A:1012218401036","article-title":"Comparison of three in vitro human angiogenesis assays with capillaries formed in vivo","volume":"4","author":"Donovan","year":"2001","journal-title":"Angiogenesis"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"295","DOI":"10.3129\/i08-049","article-title":"Ocular blood flow in diabetes and age-related macular degeneration","volume":"43","author":"Pemp","year":"2008","journal-title":"Can. J. Ophthalmol."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Hidayat, A.A., and Fine, B.S. (1985). Diabetic choroidopathy. Light and electron microscopic observations of seven cases. Ophthalmology, 92.","DOI":"10.1016\/S0161-6420(85)34013-7"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Shao, Z., Friedlander, M., Hurst, C.G., Cui, Z., Pei, D.T., Evans, L.P., Juan, A.M., Tahir, H., Duhamel, F., and Chen, J. (2013). Choroid sprouting assay: An ex vivo model of microvascular angiogenesis. PLoS ONE, 8.","DOI":"10.1371\/annotation\/c6b85ec4-996d-4daf-863a-44260a888470"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1459","DOI":"10.1038\/nprot.2015.097","article-title":"The fetal mouse metatarsal bone explant as a model of angiogenesis","volume":"10","author":"Song","year":"2015","journal-title":"Nat. Protoc."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s40942-017-0084-9","article-title":"Retinal and choroidal angiogenesis: A review of new targets","volume":"3","author":"Cabral","year":"2017","journal-title":"Int. J. Retin. Vitr."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1368","DOI":"10.1021\/ol100308a","article-title":"Total Synthesis and Biological Evaluation of Largazole and Derivatives with Promising Selectivity for Cancers Cells","volume":"12","author":"Zeng","year":"2010","journal-title":"Org. Lett."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1316","DOI":"10.1038\/onc.2012.138","article-title":"Glucocorticoids and histone deacetylase inhibitors cooperate to block the invasiveness of basal-like breast cancer cells through novel mechanisms","volume":"32","author":"Law","year":"2012","journal-title":"Oncogene"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1111\/liv.12034","article-title":"A histone deacetylase inhibitor, largazole, decreases liver fibrosis and angiogenesis by inhibiting transforming growth factor-beta and vascular endothelial growth factor signalling","volume":"33","author":"Liu","year":"2013","journal-title":"Liver Int."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"903","DOI":"10.3390\/md11030903","article-title":"Marine-Derived Angiogenesis Inhibitors for Cancer Therapy","volume":"11","author":"Wang","year":"2013","journal-title":"Mar. Drugs"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Shoda, C., Miwa, Y., Nimura, K., Okamoto, K., Yamagami, S., Tsubota, K., and Kurihara, T. (2020). Hypoxia-Inducible Factor Inhibitors Derived from Marine Products Suppress a Murine Model of Neovascular Retinopathy. Nutrition, 12.","DOI":"10.3390\/nu12041055"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1021\/np500931q","article-title":"Targeted Natural Products Discovery from Marine Cyanobacteria Using Combined Phylogenetic and Mass Spectrometric Evaluation","volume":"78","author":"Engene","year":"2015","journal-title":"J. Nat. Prod."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"670","DOI":"10.1111\/jpy.12309","article-title":"Caldora penicillata gen. nov., comb. nov. (cyanobacteria), a pantropical marine species with biomedical relevance","volume":"51","author":"Engene","year":"2015","journal-title":"J. Phycol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1016\/j.celrep.2019.08.073","article-title":"A Small-Molecule Pan-Id Antagonist Inhibits Pathologic Ocular Neovascularization","volume":"29","author":"Wojnarowicz","year":"2019","journal-title":"Cell Rep."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"25509","DOI":"10.1038\/srep25509","article-title":"A novel small molecule ameliorates ocular neovascularisation and synergises with anti-VEGF therapy","volume":"6","author":"Sulaiman","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"4021","DOI":"10.1021\/ol801532s","article-title":"Synthesis and Activity of Largazole Analogues with Linker and Macrocycle Modification","volume":"10","author":"Ying","year":"2008","journal-title":"Org. Lett."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"DeMay, J., Bernard, C., Reinhardt, A., and Marie, B. (2019). Natural Products from Cyanobacteria: Focus on Beneficial Activities. Mar. Drugs, 17.","DOI":"10.20944\/preprints201904.0192.v1"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1419","DOI":"10.1056\/NEJMoa054481","article-title":"Ranibizumab for Neovascular Age-Related Macular Degeneration","volume":"355","author":"Rosenfeld","year":"2006","journal-title":"N. Engl. J. Med."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1432","DOI":"10.1056\/NEJMoa062655","article-title":"Ranibizumab versus Verteporfin for Neovascular Age-Related Macular Degeneration","volume":"355","author":"Brown","year":"2006","journal-title":"N. Engl. J. Med."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1186","DOI":"10.1136\/bjophthalmol-2013-304670","article-title":"Predictive factors for non-response to intravitreal ranibizumab treatment in age-related macular degeneration","volume":"98","author":"Suzuki","year":"2014","journal-title":"Br. J. Ophthalmol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1318","DOI":"10.1136\/bjo.2006.113902","article-title":"Non-responders to bevacizumab (Avastin) therapy of choroidal neovascular lesions","volume":"91","author":"Lux","year":"2007","journal-title":"Br. J. Ophthalmol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1038\/eye.2013.107","article-title":"Adverse events and complications associated with intravitreal injection of anti-VEGF agents: A review of literature","volume":"27","author":"Falavarjani","year":"2013","journal-title":"Eye"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1021\/acs.oprd.7b00352","article-title":"Process Development and Scale-up Total Synthesis of Largazole, a Potent Class I Histone Deacetylase Inhibitor","volume":"22","author":"Chen","year":"2018","journal-title":"Org. Process. Res. Dev."}],"container-title":["Marine Drugs"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1660-3397\/19\/8\/471\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:49:16Z","timestamp":1760165356000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1660-3397\/19\/8\/471"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,22]]},"references-count":51,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2021,8]]}},"alternative-id":["md19080471"],"URL":"https:\/\/doi.org\/10.3390\/md19080471","relation":{},"ISSN":["1660-3397"],"issn-type":[{"value":"1660-3397","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8,22]]}}}