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

• Published in: PloS one 2011-08, Vol.6 (8), p.e23720-e23720
• Main Authors: Zhu, Jian feng, Li, Zi jian, Zhang, Guang sen, Meng, Kun, Kuang, Wen yong, Li, Jin, Zhou, Xin fu, Li, Rui juan, Peng, Hong ling, Dai, Chong wen, Shen, Jian Kai, Gong, Fan jie, Xu, Yun xiao, Liu, Su fang
• Format: Article
• Language: English
• Subjects: Abl gene; Abl protein; AKT protein; Analysis; Annexin V; Antineoplastic Agents - pharmacology; Antitumor activity; Apoptosis; BCR gene; BCR protein; BCR-ABL protein; BCR-ABL1 gene; Binding sites; Bone marrow; c-Abl protein; c-Jun protein; Cancer; CD34 antigen; Cell adhesion & migration; Cell growth; Cell proliferation; Chronic myeloid leukemia; Extracellular signal-regulated kinase; Flavonoids - pharmacology; Gene expression; Hematology; Humans; Imatinib; Immunoglobulins; Janus kinase 2; Janus Kinase 2 - metabolism; Janus Kinases - metabolism; Kinases; Leukemia; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - metabolism; Life span; MAP kinase; Medicine; Mice; Mitogen-Activated Protein Kinase Kinases - metabolism; Molecular biology; mRNA; Myeloid leukemia; Proteins; Proto-Oncogene Proteins c-akt - metabolism; Signal Transduction - drug effects; Signaling; STAT3 Transcription Factor - metabolism; Time dependence; Transcription factors; Tumor Cells, Cultured; Tumors; Western blotting
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0023720

To explore the effects of Icaritin on chronic myeloid leukemia (CML) cells and underlying mechanisms. 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. 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. 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.