{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T14:16:43Z","timestamp":1791123403944,"version":"4.1.0"},"reference-count":37,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2012,2,17]],"date-time":"2012-02-17T00:00:00Z","timestamp":1329436800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecular Oncology"],"published-print":{"date-parts":[[2012,6]]},"abstract":"<jats:p>Indirubin is the major active anti\u2010tumor component of a traditional Chinese herbal medicine used for treatment of chronic myelogenous leukemia (CML). While previous studies indicate that indirubin is a promising therapeutic agent for CML, the molecular mechanism of action of indirubin is not fully understood. We report here that indirubin derivatives (IRDs) potently inhibit Signal Transducer and Activator of Transcription 5 (Stat5) protein in CML cells. Compound E804, which is the most potent in this series of IRDs, blocked Stat5 signaling in human K562 CML cells, imatinib\u2010resistant human KCL\u201022 CML cells expressing the T315I mutant Bcr\u2010Abl (KCL\u201022M), and CD34\u2010positive primary CML cells from patients. Autophosphorylation of Src family kinases (SFKs) was strongly inhibited in K562 and KCL\u201022M cells at 5\u00a0\u03bcM E804, and in primary CML cells at 10\u00a0\u03bcM E804, although higher concentrations partially inhibited autophosphorylation of Bcr\u2010Abl. Previous studies indicate that SFKs cooperate with Bcr\u2010Abl to activate downstream Stat5 signaling. Activation of Stat5 was strongly blocked by E804 in CML cells. E804 down\u2010regulated expression of Stat5 target proteins Bcl\u2010xL and Mcl\u20101, associated with induction of apoptosis. In sum, our findings identify IRDs as potent inhibitors of the SFK\/Stat5 signaling pathway downstream of Bcr\u2010Abl, leading to apoptosis of K562, KCL\u201022M and primary CML cells. IRDs represent a promising structural class for development of new therapeutics for wild type or T315I mutant Bcr\u2010Abl\u2010positive CML patients.<\/jats:p>","DOI":"10.1016\/j.molonc.2012.02.002","type":"journal-article","created":{"date-parts":[[2012,2,17]],"date-time":"2012-02-17T20:16:23Z","timestamp":1329509783000},"page":"276-283","source":"Crossref","is-referenced-by-count":65,"title":["Indirubin derivatives induce apoptosis of chronic myelogenous leukemia cells involving inhibition of Stat5 signaling"],"prefix":"10.1002","volume":"6","author":[{"given":"Sangkil","family":"Nam","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Scuto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fan","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"WenYong","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sungman","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hwa-Seung","family":"Yoo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heiko","family":"Konig","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ravi","family":"Bhatia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinlai","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karl-Heinz","family":"Merz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerhard","family":"Eisenbrand","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Jove","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2012,2,17]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2004-02-0749"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2002-04-1204"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1208079"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)81959-5"},{"key":"e_1_2_9_6_1","first-page":"945","article-title":"Activated STAT signaling in human tumors provides novel molecular targets for therapeutic intervention","volume":"8","author":"Buettner R.","year":"2002","journal-title":"Clin. 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