{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,14]],"date-time":"2026-02-14T13:13:36Z","timestamp":1771074816918,"version":"3.50.1"},"reference-count":42,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2011,12,21]],"date-time":"2011-12-21T00:00:00Z","timestamp":1324425600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American J Hematol"],"published-print":{"date-parts":[[2012,3]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Non\u2010Hodgkin lymphoma (NHL) represents a heterogenous group of neoplasias originating from lymphoid cells. Increased angiogenesis and expression of Vascular Endothelial Growth Factor (VEGF) and its receptors (VEGFR) have been found to be associated with NHL disease progression. Increase in VEGF and other cytokines stimulate signaling cascades, including the Ras\/Raf\/Mek\/Erk pathway, resulting in increased proliferation and decreased apoptosis. Here, we report the in vitro antilymphoma activity of sorafenib, an inhibitor of VEGFR and Raf kinase. Sorafenib induced potent cytotoxicity in NHL cell lines and patient samples. This induction of cytotoxicity was associated with a corresponding increase in apoptotic cell death. Mechanism of action of sorafenib was investigated in follicular (DoHH2) and Burkitt lymphoma (Raji) cell lines. pStat3, pAkt, Mcl1, and Xiap were downregulated in both cell lines, whereas pErk decreased in Raji but not in DoHH2 cells following sorafenib treatment. IL6 was unable to prevent sorafenib induced repression of pStat3, pAkt, Mcl1, and Bcl\u2010Xl. Sorafenib in combination with an mTORC1 inhibitor rapamycin demonstrated synergy in inducing cytotoxicity in NHL cells. Sorafenib\/rapamycin combination resulted in downregulation of pAkt, pmTOR, p\u2010p70S6K, p4EBP1, pGSK3\u03b2, Mcl1, and Bcl\u2010Xl. On the basis of our results, a clinical trial is underway using sorafenib with everolimus in NHL patients., 2012. \u00a9 2011 Wiley Periodicals, Inc.<\/jats:p>","DOI":"10.1002\/ajh.22263","type":"journal-article","created":{"date-parts":[[2011,11,23]],"date-time":"2011-11-23T15:13:52Z","timestamp":1322061232000},"page":"277-283","source":"Crossref","is-referenced-by-count":25,"title":["Sorafenib, a multikinase inhibitor, is effective in vitro against non\u2010hodgkin lymphoma and synergizes with the mTOR inhibitor rapamycin"],"prefix":"10.1002","volume":"87","author":[{"given":"Vijay","family":"Ramakrishnan","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Timm","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jessica L.","family":"Haug","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Teresa K.","family":"Kimlinger","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Timothy","family":"Halling","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Linda E.","family":"Wellik","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas E.","family":"Witzig","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"S.","family":"Vincent Rajkumar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alex A.","family":"Adjei","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shaji","family":"Kumar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2011,12,21]]},"reference":[{"key":"e_1_2_6_2_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM197111182852108"},{"key":"e_1_2_6_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrd2115"},{"key":"e_1_2_6_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjc.6690154"},{"key":"e_1_2_6_5_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2003-11-3811"},{"key":"e_1_2_6_6_2","first-page":"3111","article-title":"Prognostic value of bone marrow angiogenesis in multiple myeloma","volume":"6","author":"Rajkumar SV","year":"2000","journal-title":"Clin Cancer Res"},{"key":"e_1_2_6_7_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V96.6.2240"},{"key":"e_1_2_6_8_2","first-page":"15","article-title":"Vascular endothelial growth factor and the regulation of angiogenesis","volume":"55","author":"Ferrara N","year":"2000","journal-title":"Recent Prog Horm Res"},{"key":"e_1_2_6_9_2","doi-asserted-by":"publisher","DOI":"10.1006\/scbi.1998.0091"},{"key":"e_1_2_6_10_2","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdn666"},{"key":"e_1_2_6_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/labinvest.3700697"},{"key":"e_1_2_6_12_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF02896156"},{"key":"e_1_2_6_13_2","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1096-9896(199709)183:1<44::AID-PATH1103>3.0.CO;2-I"},{"key":"e_1_2_6_14_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2004-01-0226"},{"key":"e_1_2_6_15_2","doi-asserted-by":"publisher","DOI":"10.1080\/10428190902856808"},{"key":"e_1_2_6_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.leukres.2007.01.006"},{"key":"e_1_2_6_17_2","first-page":"577","article-title":"v\u2010myc and v\u2010raf act synergistically to induce B\u2010cell tumors in pristane\u2010primed adult BALBC mice","volume":"5","author":"Kurie JM","year":"1990","journal-title":"Oncogene"},{"key":"e_1_2_6_18_2","doi-asserted-by":"publisher","DOI":"10.1159\/000083373"},{"key":"e_1_2_6_19_2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2005.06.124"},{"key":"e_1_2_6_20_2","doi-asserted-by":"publisher","DOI":"10.1358\/dot.2005.41.12.937959"},{"key":"e_1_2_6_21_2","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2009.403"},{"key":"e_1_2_6_22_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-04-1443"},{"key":"e_1_2_6_23_2","doi-asserted-by":"publisher","DOI":"10.1002\/ajh.21785"},{"key":"e_1_2_6_24_2","article-title":"MRK003, a gamma\u2010secretase inhibitor exhibits promising in vitro pre\u2010clinical activity in multiple myeloma and non\u2010Hodgkin\/s lymphoma","author":"Ramakrishnan V","journal-title":"Leukemia"},{"key":"e_1_2_6_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/0065-2571(84)90007-4"},{"key":"e_1_2_6_26_2","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2010.226"},{"key":"e_1_2_6_27_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2009-05-220889"},{"key":"e_1_2_6_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(04)00215-6"},{"key":"e_1_2_6_29_2","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.21753"},{"key":"e_1_2_6_30_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1208841"},{"key":"e_1_2_6_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2010.02.146"},{"key":"e_1_2_6_32_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0408381102"},{"key":"e_1_2_6_33_2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2005.01.3441"},{"key":"e_1_2_6_34_2","doi-asserted-by":"publisher","DOI":"10.1186\/1741-7015-7-41"},{"key":"e_1_2_6_35_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-04-4180"},{"key":"e_1_2_6_36_2","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdi113"},{"key":"e_1_2_6_37_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-05-2925"},{"key":"e_1_2_6_38_2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2007.14.5482"},{"key":"e_1_2_6_39_2","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdp347"},{"key":"e_1_2_6_40_2","doi-asserted-by":"publisher","DOI":"10.1038\/370527a0"},{"key":"e_1_2_6_41_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2005.02.031"},{"key":"e_1_2_6_42_2","first-page":"3065","article-title":"Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K\u2010dependent feedback loop in human cancer","volume":"118","author":"Carracedo A","year":"2008","journal-title":"J Clin Invest"},{"key":"e_1_2_6_43_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1582-4934.2009.00692.x"}],"container-title":["American Journal of Hematology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fajh.22263","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ajh.22263","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,21]],"date-time":"2023-11-21T13:35:42Z","timestamp":1700573742000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ajh.22263"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2011,12,21]]},"references-count":42,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2012,3]]}},"alternative-id":["10.1002\/ajh.22263"],"URL":"https:\/\/doi.org\/10.1002\/ajh.22263","archive":["Portico"],"relation":{},"ISSN":["0361-8609","1096-8652"],"issn-type":[{"value":"0361-8609","type":"print"},{"value":"1096-8652","type":"electronic"}],"subject":[],"published":{"date-parts":[[2011,12,21]]}}}