{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T22:11:19Z","timestamp":1773871879618,"version":"3.50.1"},"reference-count":44,"publisher":"American Physiological Society","issue":"1","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Cell Physiology"],"published-print":{"date-parts":[[2014,1,1]]},"abstract":"<jats:p> Chronic myeloid leukemia (CML) is a hematopoietic stem\/progenitor cell disorder in which Bcr-Abl oncoprotein inhibits cell differentiation. Differentiation induction is considered an alternative strategy for treating CML. Activin A, a member of the transforming growth factor-\u03b2 superfamily, induces erythroid differentiation of CML cells through the p38 MAPK pathway. In this study, treatment of the K562 CML stem\/progenitor cell line with activin A followed by a subtoxic concentration of the Bcr-Abl inhibitor imatinib strongly induced growth inhibition and apoptosis compared with simultaneous treatment with activin A and imatinib. Imatinib-induced growth inhibition and apoptosis following activin A pretreatment were dose- and time-dependent. Imatinib-induced growth inhibition and apoptosis were also dependent on the pretreatment dose of activin A. More than 90% of the activin A-induced increases in glycophorin A-positive cells were sensitive to imatinib. However, only some of original glycophorin A-positive cells in the activin A treatment group were sensitive to imatinib. Sequential treatment with activin A and imatinib decreased Bcr-Abl, procaspase-3, Mcl-1, and Bcl-xL and also induced cleavage of procaspase-3\/poly(ADP-ribose)polymerase. The reduction of erythroid differentiation in p38 MAPK dominant-negative mutants or by short hairpin RNA knockdown of p38 MAPK decreased the growth inhibition and apoptosis mediated by sequential treatment with activin A and imatinib. Furthermore, the same inhibition level of multidrug resistance 1 expression was observed in cells treated with activin A alone, treated sequentially with activin A and imatinib, or treated simultaneously with activin A and imatinib. The p38 MAPK inhibitor SB-203580 can restore activin A-inhibited multidrug resistance 1 expression. Taken together, our results suggest that a subtoxic concentration of imatinib could exhibit strong cytotoxicity against erythroid-differentiated K562 CML cells. <\/jats:p>","DOI":"10.1152\/ajpcell.00130.2013","type":"journal-article","created":{"date-parts":[[2013,10,3]],"date-time":"2013-10-03T01:34:34Z","timestamp":1380764074000},"page":"C37-C44","source":"Crossref","is-referenced-by-count":8,"title":["Activin A induction of erythroid differentiation sensitizes K562 chronic myeloid leukemia cells to a subtoxic concentration of imatinib"],"prefix":"10.1152","volume":"306","author":[{"given":"Yu-Wen","family":"Huang","sequence":"first","affiliation":[{"name":"Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei-Hwa","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Pathology, Taipei Medical University-Shuang Ho Hospital, Taipei, Taiwan; and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu-Hui","family":"Tsai","sequence":"additional","affiliation":[{"name":"Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan;"},{"name":"Department of Physical Medicine and Rehabilitation, Taipei Medical University Hospital, Taipei, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huei-Mei","family":"Huang","sequence":"additional","affiliation":[{"name":"Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan;"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"24","reference":[{"key":"B1","first-page":"1328","volume":"6","author":"Ahmad I","year":"2000","journal-title":"Clin Cancer Res"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2004-02-0749"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1080\/09537100701549546"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-008-8637-6"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.249060"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.leukres.2007.11.007"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejps.2012.05.017"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-04-3553"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1093\/jb\/mvs097"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1007\/s00277-007-0394-3"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-06-1216"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1177\/153537020623100507"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1038\/sj.leu.2402912"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1007\/s11064-007-9413-y"},{"key":"B15","first-page":"757","volume":"34","author":"Das A","year":"2009","journal-title":"Int J Oncol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V96.10.3343"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/j.mce.2011.10.009"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V97.9.2596"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/0145-2126(94)90103-1"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM200104053441402"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V99.1.319"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.23.4.1278-1291.2003"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V94.6.2056"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2141.2001.02558.x"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2004.06.083"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.21627"},{"key":"B27","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1002\/jcp.22074","volume":"223","author":"Huang HM","year":"2010","journal-title":"J Cell Physiol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa040258"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1038\/sj.leu.2404609"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1038\/bjc.2011.348"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa011573"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1210587"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V45.3.321.321"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1507\/endocrj.KR-113"},{"key":"B35","first-page":"152","volume":"91","author":"Mauro MJ","year":"2006","journal-title":"Heamatologica"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1016\/S0303-7207(01)00514-7"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-04-2828"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2006-10-054098"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1097\/MOH.0b013e3283257aee"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V99.10.3530"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1007\/s10495-006-9529-6"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1634\/stemcells.2005-0299"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M211093200"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1210\/en.2002-220089"}],"container-title":["American Journal of Physiology-Cell Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.physiology.org\/doi\/pdf\/10.1152\/ajpcell.00130.2013","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,6,17]],"date-time":"2024-06-17T16:38:34Z","timestamp":1718642314000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.physiology.org\/doi\/10.1152\/ajpcell.00130.2013"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,1,1]]},"references-count":44,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2014,1,1]]}},"alternative-id":["10.1152\/ajpcell.00130.2013"],"URL":"https:\/\/doi.org\/10.1152\/ajpcell.00130.2013","relation":{},"ISSN":["0363-6143","1522-1563"],"issn-type":[{"value":"0363-6143","type":"print"},{"value":"1522-1563","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,1,1]]}}}