{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T15:40:19Z","timestamp":1781106019077,"version":"3.54.1"},"reference-count":53,"publisher":"National Academy of Sciences","issue":"51","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2012,12,18]]},"abstract":"<jats:p>The endogenous metabolite of estradiol, 2-Methoxyestradiol (2ME2), is an antimitotic and antiangiogenic cancer drug candidate that also exhibits disease-modifying activity in animal models of rheumatoid arthritis (RA). We found that 2ME2 dramatically suppresses development of mouse experimental autoimmune encephalomyelitis (EAE), a rodent model of multiple sclerosis (MS). 2ME2 inhibits in vitro lymphocyte activation, cytokine production, and proliferation in a dose-dependent fashion. 2ME2 treatment of lymphocytes specifically reduced the nuclear translocation and transcriptional activity of nuclear factor of activated T-cells (NFAT) c1, whereas NF-\u03baB and activator protein 1 (AP-1) activation were not adversely affected. We therefore propose that 2ME2 attenuates EAE through disruption of the NFAT pathway and subsequent lymphocyte activation. By extension, our findings provide a molecular rationale for the use of 2ME2 as a tolerable oral immunomodulatory agent for the treatment of autoimmune disorders such as MS in humans.<\/jats:p>","DOI":"10.1073\/pnas.1215558110","type":"journal-article","created":{"date-parts":[[2012,12,4]],"date-time":"2012-12-04T10:41:27Z","timestamp":1354617687000},"page":"21034-21039","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":46,"title":["2-Methoxyestradiol inhibits experimental autoimmune encephalomyelitis through suppression of immune cell activation"],"prefix":"10.1073","volume":"109","author":[{"given":"Gordon S.","family":"Duncan","sequence":"first","affiliation":[{"name":"Campbell Family Institute for Breast Cancer Research, University Health Network, Toronto, ON, Canada M5G 2C1;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dirk","family":"Brenner","sequence":"additional","affiliation":[{"name":"Campbell Family Institute for Breast Cancer Research, University Health Network, Toronto, ON, Canada M5G 2C1;"},{"name":"Institut f\u00fcr Klinische Chemie und Pathobiochemie, Klinikum rechts der Isar, Technische Universit\u00e4t M\u00fcnchen, 81675 Munich, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael W.","family":"Tusche","sequence":"additional","affiliation":[{"name":"Campbell Family Institute for Breast Cancer Research, University Health Network, Toronto, ON, Canada M5G 2C1;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Br\u00fcstle","sequence":"additional","affiliation":[{"name":"Campbell Family Institute for Breast Cancer Research, University Health Network, Toronto, ON, Canada M5G 2C1;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christiane B.","family":"Knobbe","sequence":"additional","affiliation":[{"name":"Campbell Family Institute for Breast Cancer Research, University Health Network, Toronto, ON, Canada M5G 2C1;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew J.","family":"Elia","sequence":"additional","affiliation":[{"name":"Campbell Family Institute for Breast Cancer Research, University Health Network, Toronto, ON, Canada M5G 2C1;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Mock","sequence":"additional","affiliation":[{"name":"Division of Immunogenetics, Tumorimmunology Program, German Cancer Research Center, D-69120 Heidelberg, Germany; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark R.","family":"Bray","sequence":"additional","affiliation":[{"name":"Campbell Family Institute for Breast Cancer Research, University Health Network, Toronto, ON, Canada M5G 2C1;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter H.","family":"Krammer","sequence":"additional","affiliation":[{"name":"Division of Immunogenetics, Tumorimmunology Program, German Cancer Research Center, D-69120 Heidelberg, Germany; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tak W.","family":"Mak","sequence":"additional","affiliation":[{"name":"Campbell Family Institute for Breast Cancer Research, University Health Network, Toronto, ON, Canada M5G 2C1;"},{"name":"Departments of Immunology and Medical Biophysics, University of Toronto, Toronto, ON, Canada M5S 1A8"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2012,12,3]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-3083.2011.02536.x"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra052130"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2006.285"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0463.2011.02794.x"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00109-011-0841-4"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2011.02.007"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1177\/135245859900500206"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1002\/ana.21652"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0802221"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0903614"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.177.1.566"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/ni1261"},{"key":"e_1_3_3_13_2","first-page":"3691","article-title":"2-Methoxyestradiol inhibits proliferation and induces apoptosis independently of estrogen receptors alpha and beta","volume":"62","author":"LaVallee TM","year":"2002","unstructured":"TM LaVallee, et al., 2-Methoxyestradiol inhibits proliferation and induces apoptosis independently of estrogen receptors alpha and beta. Cancer Res 62, 3691\u20133697 (2002).","journal-title":"Cancer Res"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1023\/A:1026543018478"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.drudis.2007.05.005"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-05-0088"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1535-6108(03)00077-1"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-04-4095"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1002\/art.1780400120"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2474-10-46"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2008.01.016"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1530\/acta.0.1030282"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1210\/en.2006-0964"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00281-007-0072-5"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1196\/annals.1386.021"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00281-009-0189-9"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.immunol.021908.132710"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ygyno.2009.05.042"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.coi.2011.08.005"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1074-7613(00)80142-9"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.175.1.91"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneuroim.2009.06.023"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.2174\/1871522211108040262"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2172-11-20"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.coi.2008.04.004"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-06-0678"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-09-1270"},{"key":"e_1_3_3_38_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.91.9.3964"},{"key":"e_1_3_3_39_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000106900.66354.30"},{"key":"e_1_3_3_40_2","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.110.174854"},{"key":"e_1_3_3_41_2","doi-asserted-by":"publisher","DOI":"10.1021\/mp100190f"},{"key":"e_1_3_3_42_2","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-08-0107"},{"key":"e_1_3_3_43_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-08-1599"},{"key":"e_1_3_3_44_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00280-010-1478-7"},{"key":"e_1_3_3_45_2","doi-asserted-by":"publisher","DOI":"10.1096\/fj.07-9574LSF"},{"key":"e_1_3_3_46_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1102703"},{"key":"e_1_3_3_47_2","doi-asserted-by":"publisher","DOI":"10.1042\/bj3130909"},{"key":"e_1_3_3_48_2","doi-asserted-by":"publisher","DOI":"10.1002\/eji.1830251203"},{"key":"e_1_3_3_49_2","doi-asserted-by":"publisher","DOI":"10.1002\/1521-4141(200211)32:11<3108::AID-IMMU3108>3.0.CO;2-D"},{"key":"e_1_3_3_50_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1204386"},{"key":"e_1_3_3_51_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.192.4.581"},{"key":"e_1_3_3_52_2","doi-asserted-by":"publisher","DOI":"10.1093\/carcin\/24.2.209"},{"key":"e_1_3_3_53_2","doi-asserted-by":"publisher","DOI":"10.3899\/jrheum.080302"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.1215558110","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,4,12]],"date-time":"2022-04-12T21:45:46Z","timestamp":1649799946000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.1215558110"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2012,12,3]]},"references-count":53,"journal-issue":{"issue":"51","published-print":{"date-parts":[[2012,12,18]]}},"alternative-id":["10.1073\/pnas.1215558110"],"URL":"https:\/\/doi.org\/10.1073\/pnas.1215558110","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2012,12,3]]},"assertion":[{"value":"2012-12-03","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}