Indirubin derivatives induce apoptosis of chronic myelogenous leukemia cells via inhibition of Stat5

来源 :2009上海中药与天然药物国际大会 | 被引量 : 0次 | 上传用户:wuheman
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  Src family kinases (SFKs) are constitutively activated in numerous human cancer cell lines and tumor tissues of patients,resulting in cell proliferation,tumorigenesis and metastasis.SFKs phosphorylate and thereby activate Signal Transducer and Activator of Transcription (STAT) proteins.Constitutive activation of STAT modulates cell growth and survival of human cancer cells.SFKs/STAT signaling is currently being investigated as new molecular targets for human cancer treatments.Indirubin is the active antitumor component of a traditional Chinese herbal medicine mixture used for chronic myelogenous leukemia (CML).Clinical trial studies indicated that indirubin is a promising therapeutic agent for CML and chronic granulocytic leukemia treatment.However,the molecular mechanism of action of indirubin in human CML is not fully understood.We report that indirubin derivatives (IRDs)potently inhibited constitutively-activated Stat5 in CML cells.In particular,E804,which is the most potent in this series of IRDs,blocked Stat5 signaling in K562 human CML cells and CD34+-positive primary CML cells from patients.Autophosphorylation of SFKs was inhibited in K562 CML cells at 5 μM or in primary cells at 10 μM 4 h after E804 treatment.E804 displayed an IC50 =8.7 μM in Abl kinase assays in vitro,reducing levels of p-Bcr-Abl at higher concentrations.Tyrosyl phosphorylation of Stat5,which is a substrate of SFKs,was blocked by E804,followed by suppression of Stat5 DNA-binding activities in CML cells.Consistently,E804 down-regulated expression of Stat5 downstream proteins such as Bcl-xL and Mcl-1,associated with induction of apoptosis.In sum,we identify that IRDs inhibit the Bcr-Abl/SFKs/Stat5 signaling in CML cells,providing a mechanism of action for treatment of CML.Moreover,E804 has potential as an anti-tumor therapeutic agent for human CML treatment.
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