{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T02:46:05Z","timestamp":1789785965887,"version":"4.0.1"},"reference-count":32,"publisher":"Portland Press Ltd.","issue":"1","content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2009,5,15]]},"abstract":"<jats:p>Resistance to imatinib is commonly associated with reactivation of Bcr-Abl signalling. However, Bcr-Abl-independent signalling pathways may be activated and contributed to imatinib resistance in some CML (chronic myelogenous leukaemia) patients. We had isolated three imatinib-resistant K562\/R1, R2 and R3 variants with gradual loss of Bcr-Abl from K562 cells to develop effective therapeutic strategies for imatinib-resistant CML. Interestingly, we found that these cells became highly sensitive to TRAIL (tumour necrosis factor-related apoptosis-inducing factor) in comparison with K562 cells showing high resistance to TRAIL. Treatment of K562\/R3 cells with TRAIL resulted in activation of TRAIL receptor pathway by including caspase 8 activation, Bid cleavage, cytochrome c release and caspase 3 activation. These results were accompanied by down-regulation of c-FLIP {cellular FLICE [FADD (Fas-associated death domain)-like interleukin 1\u03b2-converting enzyme]-inhibitory protein} in imatinib-resistant K562 variants compared with K562 cells. Overexpression of c-FLIP in K562\/R3 cells acquired TRAIL resistance and conversely, c-FLIP-silenced K562 cells became sensitive to TRAIL. Moreover, Bcr-Abl-silenced K562 cells showed down-regulation of c-FLIP and the subsequent overcome of TRAIL resistance. Taken together, our results demonstrated for the first time that the loss of Bcr-Abl in imatinib-resistant cells led to the down-regulation of c-FLIP and subsequent increase of TRAIL sensitivity, suggesting that TRAIL could be an effective strategy for the treatment of imatinib-resistant CML with loss of Bcr-Abl.<\/jats:p>","DOI":"10.1042\/bj20082131","type":"journal-article","created":{"date-parts":[[2009,2,10]],"date-time":"2009-02-10T10:37:55Z","timestamp":1234262275000},"page":"73-81","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Sensitization of imatinib-resistant CML cells to TRAIL-induced apoptosis is mediated through down-regulation of Bcr-Abl as well as c-FLIP"],"prefix":"10.1042","volume":"420","author":[{"given":"Soo-Jung","family":"Park","sequence":"first","affiliation":[{"name":"Department of Biochemistry, Pusan National University School of Medicine, Yangsan 622-770, South Korea"},{"name":"Pusan National University BK21 Medical Science Education Center, Yangsan 622-770, South Korea"},{"name":"Research Center for Ischemic Tissue Regeneration, Pusan National University School of Medicine, Yangsan 622-770, South Korea"},{"name":"Division of Intractable Diseases, Center for Biomedical Sciences, National Institute of Health, Seoul 122-701, South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mi-Ju","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Pusan National University School of Medicine, Yangsan 622-770, South Korea"},{"name":"Pusan National University BK21 Medical Science Education Center, Yangsan 622-770, South Korea"},{"name":"Research Center for Ischemic Tissue Regeneration, Pusan National University School of Medicine, Yangsan 622-770, South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hak-Bong","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Pusan National University School of Medicine, Yangsan 622-770, South Korea"},{"name":"Pusan National University BK21 Medical Science Education Center, Yangsan 622-770, South Korea"},{"name":"Research Center for Ischemic Tissue Regeneration, Pusan National University School of Medicine, Yangsan 622-770, South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chi-Dug","family":"Kang","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Pusan National University School of Medicine, Yangsan 622-770, South Korea"},{"name":"Pusan National University BK21 Medical Science Education Center, Yangsan 622-770, South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sun-Hee","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Pusan National University School of Medicine, Yangsan 622-770, South Korea"},{"name":"Pusan National University BK21 Medical Science Education Center, Yangsan 622-770, South Korea"},{"name":"Research Center for Ischemic Tissue Regeneration, Pusan National University School of Medicine, Yangsan 622-770, South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2009,4,28]]},"reference":[{"key":"2021112215082363100_B1","doi-asserted-by":"crossref","first-page":"4010","DOI":"10.1182\/blood-2003-12-4111","article-title":"The biology of CML blast crisis","volume":"103","author":"Calabretta","year":"2004","journal-title":"Blood"},{"key":"2021112215082363100_B2","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1097\/00001622-200101000-00002","article-title":"Chronic myelogenous leukemia","volume":"13","author":"Mauro","year":"2001","journal-title":"Curr. 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