title: Icaritin shows potent anti-leukemia activity on chronic myeloid leukemia in vitro and in vivo by regulating MAPK/ERK/JNK and JAK2/STAT3 /AKT signalings.
abstract: OBJECTIVE
  To explore the effects of Icaritin on chronic myeloid leukemia (CML) cells and underlying mechanisms.
  
  
  METHODS
  CML cells were incubated with various concentration of Icaritin for 48 hours, the cell proliferation was analyzed by MTT and the apoptosis was assessed with Annexin V and Hoechst 33258 staining. Cell hemoglobinization was determined. Western blotting was used to evaluate the expressions of MAPK/ERK/JNK signal pathway and Jak-2/Phorpho-Stat3/Phorsph-Akt network-related protein. NOD-SCID nude mice were applied to demonstrate the anti-leukemia effect of Icaritin in vivo.
  
  
  RESULTS
  Icaritin potently inhibited proliferation of K562 cells (IC50 was 8 µM) and primary CML cells (IC50 was 13.4 µM for CML-CP and 18 µM for CML-BC), induced CML cells apoptosis and promoted the erythroid differentiation of K562 cells with time-dependent manner. Furthermore, Icaritin was able to suppress the growth of primary CD34+ leukemia cells (CML) and Imatinib-resistant cells, and to induce apoptosis. In mouse leukemia model, Icaritin could prolong lifespan of NOD-SCID nude mice inoculated with K562 cells as effective as Imatinib without suppression of bone marrow. Icaritin could up-regulate phospho-JNK or phospho-C-Jun and down-regulate phospho-ERK, phospho-P-38, Jak-2, phospho-Stat3 and phospho-Akt expression with dose- or time-dependent manner. Icaritin had no influence both on c-Abl and phospho-c-Abl protein expression and mRNA levels of Bcr/Abl.
  
  
  CONCLUSIONS
  Icaritin from Chinese herb medicine may be a potential anti-CML agent with low adverse effect. The mechanism of anti-leukemia for Icaritin is involved in the regulation of Bcr/Abl downstream signaling. Icaritin may be useful for an alternative therapeutic choice of Imatinib-resistant forms of CML.
authors: Division of Hematology, Institute of Molecular Hematology, The Second Xiang-Ya Hospital, Central South University, Changsha, Hunan, People's Republic of China.
authors: Jian feng
authors: Jf
authors: Zhu
authors: Zi jian
authors: Zj
authors: Li
authors: Guang sen
authors: Gs
authors: Zhang
authors: Kun
authors: K
authors: Meng
authors: Wen yong
authors: Wy
authors: Kuang
authors: Jin
authors: J
authors: Li
authors: Xin fu
authors: Xf
authors: Zhou
authors: Rui juan
authors: Rj
authors: Li
authors: Hong ling
authors: Hl
authors: Peng
authors: Chong wen
authors: Cw
authors: Dai
authors: Jian Kai
authors: JK
authors: Shen
authors: Fan jie
authors: Fj
authors: Gong
authors: Yun xiao
authors: Yx
authors: Xu
authors: Su fang
authors: Sf
authors: Liu
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D005419:Flavonoids / Q000494:pharmacology*; D006801:Humans; D053614:Janus Kinase 2 / Q000378:metabolism*; D053612:Janus Kinases / Q000378:metabolism; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000378:metabolism; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D005419:Flavonoids; D050796:STAT3 Transcription Factor; D053614:Janus Kinase 2; D053612:Janus Kinases; D051057:Proto-Oncogene Proteins c-akt; D020929:Mitogen-Activated Protein Kinase Kinases; C499403:icaritin