{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T15:16:39Z","timestamp":1789917399405,"version":"4.0.1"},"reference-count":63,"publisher":"Wiley","issue":"18","license":[{"start":{"date-parts":[[2017,8,11]],"date-time":"2017-08-11T00:00:00Z","timestamp":1502409600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100003500","name":"Universit\u00e0 degli Studi di Padova","doi-asserted-by":"publisher","award":["60A04\u20100220\/12"],"award-info":[{"award-number":["60A04\u20100220\/12"]}],"id":[{"id":"10.13039\/501100003500","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003500","name":"Universit\u00e0 degli Studi di Padova","doi-asserted-by":"publisher","award":["60A04\u20100443\/13 CPDA121973"],"award-info":[{"award-number":["60A04\u20100443\/13 CPDA121973"]}],"id":[{"id":"10.13039\/501100003500","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003500","name":"Universit\u00e0 degli Studi di Padova","doi-asserted-by":"publisher","award":["60A04\u20109153\/15"],"award-info":[{"award-number":["60A04\u20109153\/15"]}],"id":[{"id":"10.13039\/501100003500","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005010","name":"Associazione Italiana per la Ricerca sul Cancro","doi-asserted-by":"publisher","award":["IG 18803"],"award-info":[{"award-number":["IG 18803"]}],"id":[{"id":"10.13039\/501100005010","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2017,9]]},"abstract":"<jats:sec><jats:title>Background and Purpose<\/jats:title><jats:p>Cardiac glycosides are Na<jats:sup>+<\/jats:sup>\/K<jats:sup>+<\/jats:sup>\u2010ATPases inhibitors used to treat congestive heart failure and cardiac arrhythmias. Epidemiological studies indicate that patients on digitalis therapy are more protected from cancer. Evidence of a selective cytotoxicity against cancer cells has suggested their potential use as anticancer drugs. The effect on angiogenesis of clinically used cardiac glycosides has not been extensively explored.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>We studied the effect of digoxin, digitoxin and ouabain on early events of the angiogenic process in HUVECs. We determined HUVEC viability, proliferation, migration and differentiation into capillary tube\u2010like structures. We also tested drug activity using an <jats:italic>in vivo<\/jats:italic> angiogenesis model. Activation of protein tyrosine kinase 2 (FAK) and signalling proteins associated with the Na<jats:sup>+<\/jats:sup>\/K<jats:sup>+<\/jats:sup>\u2010ATPase signalosome was determined by Western blotting.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>Digitoxin and ouabain (1\u2013100\u00a0nM) inhibited HUVEC migration, concentration\u2010dependently, without affecting cell viability, while digoxin induced apoptosis at the same concentrations. Digitoxin antagonized growth factor\u2010induced migration and tubularization at concentrations (1\u201325\u00a0nM) within its plasma therapeutic range. The anti\u2010angiogenic effect of digitoxin was confirmed also by <jats:italic>in vivo<\/jats:italic> studies. Digitoxin induced Src, Akt and ERK1\/2 phosphorylation but did not affect FAK autophosphorylation at Tyr<jats:sup>397<\/jats:sup>. However, it significantly inhibited growth factor\u2010induced FAK phosphorylation at Tyr<jats:sup>576\/577<\/jats:sup>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Implications<\/jats:title><jats:p>Therapeutic concentrations of digitoxin inhibited angiogenesis and FAK activation by several pro\u2010angiogenic stimuli. These novel findings suggest a potential repositioning of digitoxin as a broad\u2010spectrum anti\u2010angiogenic drug for diseases where pathological angiogenesis is involved.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.13944","type":"journal-article","created":{"date-parts":[[2017,7,8]],"date-time":"2017-07-08T07:46:46Z","timestamp":1499500006000},"page":"3094-3106","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":40,"title":["Therapeutic concentrations of digitoxin inhibit endothelial focal adhesion kinase and angiogenesis induced by different growth factors"],"prefix":"10.1111","volume":"174","author":[{"given":"Annalisa","family":"Trenti","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical and Pharmacological Sciences University of Padova  Padova Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabetta","family":"Zulato","sequence":"additional","affiliation":[{"name":"Istituto Oncologico Veneto IOV \u2013 IRCCS  Padova Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorenza","family":"Pasqualini","sequence":"additional","affiliation":[{"name":"Istituto Oncologico Veneto IOV \u2013 IRCCS  Padova Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"Indraccolo","sequence":"additional","affiliation":[{"name":"Istituto Oncologico Veneto IOV \u2013 IRCCS  Padova Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Bolego","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical and Pharmacological Sciences University of Padova  Padova Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5008-9240","authenticated-orcid":false,"given":"Lucia","family":"Trevisi","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical and Pharmacological Sciences University of Padova  Padova Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2017,8,11]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1097\/00002030-199409000-00004"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.13354"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.13353"},{"issue":"2","key":"e_1_2_10_5_1","first-page":"10","article-title":"Treatment of congestive heart failure\u2011current status of use of digitoxin","volume":"31","author":"Belz GG","year":"2001","journal-title":"Eur J Clin Invest"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature04478"},{"key":"e_1_2_10_7_1","first-page":"198","volume-title":"4th ImageJ User and Developer Conference Proceedings","author":"Carpentier G","year":"2012"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mito.2012.06.003"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/tox.20769"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.12856"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1097\/HPC.0b013e318221e7dd"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200109079"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamem.2006.09.006"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1742-1241.2010.02395.x"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1752-8062.2011.00376.x"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mvr.2003.11.002"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.2741\/1114"},{"key":"e_1_2_10_18_1","first-page":"2157","article-title":"Focal adhesion kinase is expressed in the angiogenic blood vessels of malignant astrocytic tumors in vivo and promotes capillary tube formation of brain microvascular endothelial cells","volume":"9","author":"Haskell H","year":"2003","journal-title":"Clin Cancer Res"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2407-1-11"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/377539a0"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.2010.00872.x"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1202680"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1124\/mol.104.007302"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000259593.07661.1e"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0024-3205(96)00602-9"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2012.01.023"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ctrv.2013.11.009"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1517\/14728222.11.8.1043"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biochi.2014.08.013"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1021\/cb500665r"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.12955"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc1647"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.4161\/onci.23082"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1002\/path.2172"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm1549"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-11-0242"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1124\/mi.8.1.8"},{"key":"e_1_2_10_38_1","first-page":"519","article-title":"A simple, quantitative method for assessing angiogenesis and antiangiogenic agents using reconstituted basement membrane, heparin, and fibroblast growth factor","volume":"67","author":"Passaniti A","year":"1992","journal-title":"Lab Invest"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi048680w"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1385\/CBB:46:3:303"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8274.CD-10-0020"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcb.240550113"},{"key":"e_1_2_10_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2011.08.039"},{"key":"e_1_2_10_44_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrd2682"},{"key":"e_1_2_10_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbapap.2008.07.006"},{"key":"e_1_2_10_46_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.14-252684"},{"key":"e_1_2_10_47_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00098.2007"},{"key":"e_1_2_10_48_1","doi-asserted-by":"publisher","DOI":"10.7150\/ijbs.9224"},{"key":"e_1_2_10_49_1","doi-asserted-by":"publisher","DOI":"10.1038\/35010517"},{"key":"e_1_2_10_50_1","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-12-394305-7.00002-1"},{"key":"e_1_2_10_51_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM198802113180606"},{"key":"e_1_2_10_52_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkv1037"},{"key":"e_1_2_10_53_1","first-page":"493","article-title":"Is digitalis a therapy for breast carcinoma?","volume":"6","author":"Stenkvist B","year":"1999","journal-title":"Oncol Rep"},{"key":"e_1_2_10_54_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM198202253060813"},{"key":"e_1_2_10_55_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc3792"},{"key":"e_1_2_10_56_1","doi-asserted-by":"publisher","DOI":"10.1002\/emmm.201000106"},{"key":"e_1_2_10_57_1","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.E05-08-0735"},{"key":"e_1_2_10_58_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2014.02.021"},{"key":"e_1_2_10_59_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2004.07.027"},{"key":"e_1_2_10_60_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2003.09.007"},{"key":"e_1_2_10_61_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2537"},{"key":"e_1_2_10_62_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.09-145664"},{"key":"e_1_2_10_63_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0809763105"},{"key":"e_1_2_10_64_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.addr.2010.11.001"}],"container-title":["British Journal of Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fbph.13944","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/bph.13944","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,3]],"date-time":"2023-10-03T19:50:25Z","timestamp":1696362625000},"score":1,"resource":{"primary":{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/10.1111\/bph.13944"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,8,11]]},"references-count":63,"journal-issue":{"issue":"18","published-print":{"date-parts":[[2017,9]]}},"alternative-id":["10.1111\/bph.13944"],"URL":"https:\/\/doi.org\/10.1111\/bph.13944","archive":["Portico"],"relation":{},"ISSN":["0007-1188","1476-5381"],"issn-type":[{"value":"0007-1188","type":"print"},{"value":"1476-5381","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,8,11]]},"assertion":[{"value":"2017-02-28","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2017-06-27","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2017-08-11","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}