{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,7]],"date-time":"2026-02-07T08:56:15Z","timestamp":1770454575039,"version":"3.49.0"},"reference-count":58,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2018,10,24]],"date-time":"2018-10-24T00:00:00Z","timestamp":1540339200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000402","name":"Kay Kendall Leukaemia Fund","doi-asserted-by":"publisher","award":["KKL982"],"award-info":[{"award-number":["KKL982"]}],"id":[{"id":"10.13039\/501100000402","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000402","name":"Kay Kendall Leukaemia Fund","doi-asserted-by":"publisher","award":["KKL999"],"award-info":[{"award-number":["KKL999"]}],"id":[{"id":"10.13039\/501100000402","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J Cellular Molecular Medi"],"published-print":{"date-parts":[[2019,1]]},"abstract":"Abstract<\/jats:title>CUDC<\/jats:styled-content>\u2010907, a dual PI<\/jats:styled-content>3K\/HDAC<\/jats:styled-content> inhibitor, has been proposed to have therapeutic potential in hematopoietic malignancies. However, the molecular mechanisms of its effects in chronic lymphocytic leukaemia (CLL<\/jats:styled-content>) remain elusive. We show that CLL<\/jats:styled-content> cells are sensitive to CUDC<\/jats:styled-content>\u2010907, even under conditions similar to the protective microenvironment of proliferation centres. CUDC<\/jats:styled-content>\u2010907 inhibited PI<\/jats:styled-content>3K\/AKT<\/jats:styled-content> and HDAC<\/jats:styled-content> activity, as expected, but also suppressed RAF<\/jats:styled-content>\/MEK<\/jats:styled-content>\/ERK<\/jats:styled-content> and STAT<\/jats:styled-content>3 signalling and reduced the expression of anti\u2010apoptotic BCL<\/jats:styled-content>\u20102 family proteins BCL<\/jats:styled-content>\u20102, BCL<\/jats:styled-content>\u2010xL<\/jats:styled-content>, and MCL<\/jats:styled-content>\u20101. Moreover, CUDC<\/jats:styled-content>\u2010907 downregulated cytokines BAFF<\/jats:styled-content> and APRIL<\/jats:styled-content> and their receptors BAFFR<\/jats:styled-content>, TACI<\/jats:styled-content>, and BCMA<\/jats:styled-content>, thus blocking BAFF<\/jats:styled-content>\u2010induced NF<\/jats:styled-content>\u2010\u03baB signalling. T cell chemokines CCL<\/jats:styled-content>3\/4\/17\/22 and phosphorylation of CXCR<\/jats:styled-content>4 were also reduced by CUDC<\/jats:styled-content>\u2010907. These data indicated that CUDC<\/jats:styled-content>\u2010907 abrogates different protective signals and suggested that it might sensitize CLL<\/jats:styled-content> cells to other drugs. Indeed, combinations of low concentrations of CUDC<\/jats:styled-content>\u2010907 with inhibitors of BCL<\/jats:styled-content>2, BTK<\/jats:styled-content>, or the NF<\/jats:styled-content>\u2010\u03baB pathway showed a potent synergistic effect. Our data indicate that, apart from its known functions, CUDC<\/jats:styled-content>\u2010907 blocks multiple pro\u2010survival pathways to overcome microenvironment protection in CLL<\/jats:styled-content> cells. This provides a rationale to evaluate the clinical relevance of CUDC<\/jats:styled-content>\u2010907 in combination therapies with other targeted inhibitors.<\/jats:p>","DOI":"10.1111\/jcmm.13935","type":"journal-article","created":{"date-parts":[[2018,10,24]],"date-time":"2018-10-24T10:20:27Z","timestamp":1540376427000},"page":"340-348","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["CUDC<\/scp>\u2010907 blocks multiple pro\u2010survival signals and abrogates microenvironment protection in CLL<\/scp>"],"prefix":"10.1111","volume":"23","author":[{"given":"Yixiang","family":"Chen","sequence":"first","affiliation":[{"name":"Mechanisms of Cancer and Ageing Laboratory Department of Molecular and Cell Biology University of Leicester Leicester UK"},{"name":"Ernest and Helen Scott Haematological Research Institute University of Leicester Leicester UK"},{"name":"Medical College Henan University of Science and Technology Luoyang China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chlo\u00e9","family":"Peubez","sequence":"additional","affiliation":[{"name":"Mechanisms of Cancer and Ageing Laboratory Department of Molecular and Cell Biology University of Leicester Leicester UK"},{"name":"Ernest and Helen Scott Haematological Research Institute University of Leicester Leicester UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Victoria","family":"Smith","sequence":"additional","affiliation":[{"name":"Mechanisms of Cancer and Ageing Laboratory Department of Molecular and Cell Biology University of Leicester Leicester UK"},{"name":"Ernest and Helen Scott Haematological Research Institute University of Leicester Leicester UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shiqiu","family":"Xiong","sequence":"additional","affiliation":[{"name":"Ernest and Helen Scott Haematological Research Institute University of Leicester Leicester UK"},{"name":"Department of Cancer Studies University of Leicester Leicester UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gabriella","family":"Kocsis\u2010Fodor","sequence":"additional","affiliation":[{"name":"Mechanisms of Cancer and Ageing Laboratory Department of Molecular and Cell Biology University of Leicester Leicester UK"},{"name":"Ernest and Helen Scott Haematological Research Institute University of Leicester Leicester UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ben","family":"Kennedy","sequence":"additional","affiliation":[{"name":"Department of Haematology University Hospitals of Leicester Leicester UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Simon","family":"Wagner","sequence":"additional","affiliation":[{"name":"Department of Haematology University Hospitals of Leicester Leicester UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Constantine","family":"Balotis","sequence":"additional","affiliation":[{"name":"Department of Haematology University Hospitals of Leicester Leicester UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sandrine","family":"Jayne","sequence":"additional","affiliation":[{"name":"Ernest and Helen Scott Haematological Research Institute University of Leicester Leicester UK"},{"name":"Department of Cancer Studies University of Leicester Leicester UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martin J. S.","family":"Dyer","sequence":"additional","affiliation":[{"name":"Ernest and Helen Scott Haematological Research Institute University of Leicester Leicester UK"},{"name":"Department of Cancer Studies University of Leicester Leicester UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1963-8840","authenticated-orcid":false,"given":"Salvador","family":"Macip","sequence":"additional","affiliation":[{"name":"Mechanisms of Cancer and Ageing Laboratory Department of Molecular and Cell Biology University of Leicester Leicester UK"},{"name":"Ernest and Helen Scott Haematological Research Institute University of Leicester Leicester UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2018,10,24]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra041720"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.2119\/molmed.2012.00303"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-07-2223"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrclinonc.2009.72"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2009-06-225326"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamcr.2015.07.009"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2010-05-284984"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2567.2006.02377.x"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2003-02-0540"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcancer.2010.09.005"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.184.3.1101"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V94.11.3658"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/382833a0"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.leu.2403398"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.164.4.2200"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2007-11-125278"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1111\/bjh.14285"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V99.8.2969"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2002-02-0539"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2010-03-275305"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1315226"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1111\/bjh.12219"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1210620"},{"key":"e_1_2_7_25_1","first-page":"166","article-title":"Histone deacetylase inhibitors: molecular mechanisms of action and clinical trials as anti\u2010cancer drugs","volume":"3","author":"Kim HJ","year":"2011","journal-title":"Am J Transl Res"},{"key":"e_1_2_7_26_1","first-page":"462","article-title":"Histone deacetylase inhibitors in the treatment of lymphoma","volume":"10","author":"Lemoine M","year":"2010","journal-title":"Discov Med"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2009-05-220889"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-07-4306"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-12-0055"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(15)00584-7"},{"key":"e_1_2_7_31_1","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2017.172882"},{"key":"e_1_2_7_32_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2007-06-093906"},{"key":"e_1_2_7_33_1","doi-asserted-by":"publisher","DOI":"10.1006\/meth.2001.1262"},{"key":"e_1_2_7_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0145-2126(98)00154-4"},{"key":"e_1_2_7_35_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1004594107"},{"key":"e_1_2_7_36_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1215637"},{"key":"e_1_2_7_37_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3048"},{"key":"e_1_2_7_38_1","doi-asserted-by":"publisher","DOI":"10.1038\/bcj.2011.9"},{"key":"e_1_2_7_39_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V80.12.3173.3173"},{"key":"e_1_2_7_40_1","doi-asserted-by":"publisher","DOI":"10.1080\/10428190701447353"},{"key":"e_1_2_7_41_1","doi-asserted-by":"publisher","DOI":"10.1038\/cdd.2009.48"},{"key":"e_1_2_7_42_1","doi-asserted-by":"publisher","DOI":"10.3109\/10428199809092690"},{"key":"e_1_2_7_43_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V91.9.3379"},{"key":"e_1_2_7_44_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2008-08-173310"},{"key":"e_1_2_7_45_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.290.5493.989"},{"key":"e_1_2_7_46_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2006-06-027755"},{"key":"e_1_2_7_47_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2008-07-170415"},{"key":"e_1_2_7_48_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI40645"},{"key":"e_1_2_7_49_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.162.8.4455"},{"key":"e_1_2_7_50_1","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2015.316"},{"key":"e_1_2_7_51_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V96.8.2655"},{"key":"e_1_2_7_52_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2013-11-535047"},{"key":"e_1_2_7_53_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2013-11-538546"},{"key":"e_1_2_7_54_1","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2015.105"},{"key":"e_1_2_7_55_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2141.2007.06717.x"},{"key":"e_1_2_7_56_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2007-05-089037"},{"key":"e_1_2_7_57_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.leu.2402107"},{"key":"e_1_2_7_58_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.leu.2401602"},{"key":"e_1_2_7_59_1","doi-asserted-by":"publisher","DOI":"10.1111\/bjh.14880"}],"container-title":["Journal of Cellular and Molecular Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fjcmm.13935","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/jcmm.13935","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,15]],"date-time":"2023-09-15T20:27:10Z","timestamp":1694809630000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/jcmm.13935"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,10,24]]},"references-count":58,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2019,1]]}},"alternative-id":["10.1111\/jcmm.13935"],"URL":"https:\/\/doi.org\/10.1111\/jcmm.13935","archive":["Portico"],"relation":{},"ISSN":["1582-1838","1582-4934"],"issn-type":[{"value":"1582-1838","type":"print"},{"value":"1582-4934","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,10,24]]},"assertion":[{"value":"2018-07-03","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-09-03","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-10-24","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}