Angelica Sinensis Polysaccharide Induces Erythroid Differentiation of Human Chronic Myelogenous Leukemia K562 Cells

  • Wang, Lu (Laboratory of Stem Cell and Tissue Engineering, Department of Histology and Embryology, Chongqing Medical University) ;
  • Jiang, Rong (Laboratory of Stem Cell and Tissue Engineering, Department of Histology and Embryology, Chongqing Medical University) ;
  • Song, Shu-Dan (The First Affiliated Hospital of Chongqing Medical University) ;
  • Hua, Zi-Sen (Laboratory of Stem Cell and Tissue Engineering, Department of Histology and Embryology, Chongqing Medical University) ;
  • Wang, Jian-Wei (Laboratory of Stem Cell and Tissue Engineering, Department of Histology and Embryology, Chongqing Medical University) ;
  • Wang, Ya-Ping (Laboratory of Stem Cell and Tissue Engineering, Department of Histology and Embryology, Chongqing Medical University)
  • 발행 : 2015.05.18


Leukemia is a clonal disorder with blocked normal differentiation and cell death of hematopoietic progenitor cells. Traditional modalities with most used radiation and chemotherapy are nonspecific and toxic which cause adverse effects on normal cells. Differentiation inducing therapy forcing malignant cells to undergo terminal differentiation has been proven to be a promising strategy. However, there is still scarce of potent differentiation inducing agents. We show here that Angelica sinensis polysaccharide (ASP), a major active component in Dong quai (Chinese Angelica sinensis), has potential differentiation inducing activity in human chronic erythro-megakaryoblastic leukemia K562 cells. MTT assays and flow cytometric analysis demonstrated that ASP inhibited K562 cell proliferation and arrested the cell cycle at the G0/G1 phase. ASP also triggered K562 cells to undergo erythroid differentiaton as revealed by morphological changes, intensive benzidine staining and hemoglobin colorimetric reaction, as well as increased expression of glycophorin A (GPA) protein. ASP induced redistribution of STAT5 protein from the cytoplasm to the nucleus. Western blotting analysis further identified that ASP markedly sensitized K562 cells to exogenous erythropoietin (EPO) by activating EPO-induced JAK2/STAT5 tyrosine phosphorylation, thus augmenting the EPO-mediated JAK2/STAT5 signaling pathway. On the basis of these findings, we propose that ASP might be developed as a potential candidate for chronic myelogenous leukemia inducing differentiation treatment.


  1. Armstrong TS, Gilbert MR (2008). Use of complementary and alternative medical therapy by patients with primary brain tumors. Curr Neurol Neurosci Rep, 8, 264-8.
  2. Bradley HL, Hawley TS, Bunting KD (2002). Cell intrinsic defects in cytokine responsiveness of STAT5-deficient hematopoietic stem cells. Blood, 100, 1383-89.
  3. Bunel V, Anotoine MH, Nortier J, et al (2014). Potential nephroprotective effects of the Chinese herb Angelica sinensis against cisplatin tubulotoxicity. Pharm Biol, 11, 1-10.
  4. Bunting KD (2007). STAT5 signaling in normal and pathologic hematopoiesis. Front Biosci, 12, 2807-20.
  5. Cao W, Li XQ, Wang X, et al (2010). A novel polysaccharide, isolated from Angelica sinensis (Oliv.) Diels induces the apoptosis of cervical cancer Hela cells through an intrinsic apoptotic pathway. Phytomedicine, 17, 598-605.
  6. Cao W, Li XQ, Wang X, et al (2010). Characterizations and anti-tumor activities of three acidic polysaccharides from Angelica sinensis (Oliv.) Diels. Int J Biol Macromol, 46, 115-22.
  7. Chen Y, Duan JA, Qian D, et al (2010). Assessment and comparison of immunoregulatory activity of four hydrosoluble fractions of Anglica sinensis in vitro on the peritoneal macrophages in ICR mice. Int Immunopharmacol, 10, 422-30.
  8. Ferbeyre G, Morigg R (2011). The role of Stat5 transcription factors as tumor suppressors or oncogenes. Biochim Biophys Acta, 1815, 104-14,.
  9. Gao M, Zhang JH, Zhou FX, et al (2012). Angelica sinensis suppresses human lung adenocarcinoma A549 cell metastasis by regulating MMPs/TIMPs and TGF-${\beta}$1. Oncol Rep, 27, 585-93.
  10. Grebien F, Kerenyi MA, Kovacic B, et al (2008). Stat5 activation enables erythropoiesis in the absence of EpoR and Jak2. Blood, 111, 4511-22.
  11. Han L, Wierenga ATJ, Rozenveld-Geugien MK, et al (2009). Single-cell STAT5 signal transduction profiling in normal and leukemic stem and progenitor cell populations reveals highly distinct cytokine responses. Plos One, 4, 7989.
  12. Hsu JW, Huang HC, Chen ST, et al (2009). Ganoderma lucidum Polysaccharides induce macrophage-like differentiation in human leukemia THP-1 cells via caspase and p53 activation. Evid Based Complement Alternat Med, 2011, 1-13.
  13. Huang YC, Chao DK, Chao KSC, et al (2009). Oral small-molecule tyrosine kinase inhibitor midostaurin (PKC412) inhibits growth and induces megakaryocytic differentiation in human leukemia cells. Toxicol In Vitro, 23, 979-85.
  14. Hui MK, Wu WK, Shin VY, et al (2006). Polysaccharides from the root of Angelica sinensis protect bone marrow and gastrointestinal tissues against the cytotoxicity of cyclophosphamide in mice. Int J Med Sci, 3, 1-6.
  15. Jerke U, Tkachuk S, Kiyanl J, et al (2009). Stat1 nuclear translocation by nucleolin upon monocyte differentiation. Plos One, 4, 8302.
  16. Jin M, Zhao K, Huang Q, et al (2012). Isolation, structure and bioactivities of the polysaccharides from Angelica sinensis (Oliv.) Diels. Carbohydr Polym, 89, 713-22.
  17. Kawashima T, Murata K, Akira S, et al (2001). STAT5 induces macrophage differentiation of M1 leukemia cells through activation of IL-6 production mediated by NF-kappaB p65. J Immunol, 167, 3652-60.
  18. Kieslinger M, Woldman I, Moriggl R, et al (2000). Antiapoptotic activity of Stat5 required during terminal stages of myeloid differentiation. Genes Dev, 14, 232-44,.
  19. Lee JG, Hsieh WT, Bradley RR, et al (1999). Hematopoietic effect of Radix Angelica sinensis in a hemodialysis patient. Am J Kidney Dis, 34, 349-34.
  20. Lee JG, Hsieh WT, Chen SU, et al (2012). Hematopoietic and myeloprotective activities of an acidic Angelica sinensis polysaccharide on human CD34+ stem cells. J Ethnopharmacol, 139, 739-45.
  21. Lee WH, Jin JS, Tsai WC, et al (2006). Biological inhibitory effects of the Chinese herb danggui on brain astrocytoma. Pathobiology, 73, 141-8.
  22. Lewis RS and Ward ACC (2008). Stat5 as a diagnostic marker for leukemia. Expert Rev Mol Diagn, 8, 73-82.
  23. Li J, Wei Q, Zuo GW, et al (2014). Ginsenoside Rg1 induces apoptosis through inhibition of the EpoR-mediated JAK2/STAT5 signaling pathway in the TF-1/Epo human leukemia cell line. Asian Pac J Cancer Prev, 15, 2453-9.
  24. Liu J, Xu CY, Cai SZ, et al (2013). Senescence effects of Angelica sinensis polysaccharide on human acute myelogenous leukemia stem and progenitor cells. Asian Pac J Cancer Prev, 14, 1-8.
  25. Marchwicka A, Cebrat M, Sampath P, et al (2014). Perspectives of differentiation therapies of acute myeloid leukemia: the search for the molecular basis of patients' variable responses to 1, 25-dihydroxyvitamin d and vitamin a analogs. Front Oncol, 4, 125.
  26. Metcalf D (2008). Hematopoietic cytokines. Blood, 111, 485-90.
  27. Olthof SG, Fatrai S, Drayer AL, et al (2008). Downregulation of signal transducer and activator of transcription 5 (STAT5) in CD34+ cells promotes megakaryocytic development, whereas activation of STAT5 drives erythropoiesis. Stem Cell, 26, 1732-42.
  28. Peller S, Tabach Y, Rotschild M, et al (2009). Identification of gene networks associated with erythroid differentiation. Blood Cells Mol Dis, 43, 74-80.
  29. Schuringa JJ, Chung KY, Morrone G, et al (2004). Constitutive activation of STAT5A promotes human hematopoietic stem cell self-renewal and erythroid differentiation. J Exp Med, 5, 623-35.
  30. Sexauer A, Peri A, Yang X, et al (2012). Terminal myeloid differentiation in vivo is induced by FLT3 inhibition in FLT3/ITD AML. Blood, 120, 4205-14.
  31. Shang P, Qian AR, Yang TH, et al (2003). Experimental study of anti-tumor effects of polysaccharides from Angelica sinensis. World J. Gastroenterol, 9, 1963-1967.
  32. Skavland J, Jorgensen KM, Hadziavdic K, et al (2011). Specific cellular signal-transduction responses to in vivo combination therapy with ATRA, valproic acid and theophylline in acute myeloid leukemia. Blood Cancer J, 1, 4.
  33. Socolovsky M, Fallon AEJ, Brugnara S, et al (1999). Fetal anemia and apoptosis of red cell progenitors in Stat5a-/-/5b-/- mice: a direct role for Stat5 in Bcl-XL induction. Cell, 98, 181-91.
  34. Socolovsky M, Nam MDH, Fleming VH, et al (2001). Ineffective erythropoiesis in Stat5a-/-/5b-/- mice due to decreased survival of early erythroblasts. Blood, 98, 3261-73.
  35. Takahashi H, Hatta Y, Iriyama N, et al (2014). Induced differentiation of human myeloid leukemia cells into M2 macrophages by combined treatment with retinoic acid and 1${\alpha}$, 25-dihydroxyvitamin D3. Plos One, 9, 113722.
  36. Testa U (2004). Apoptotic mechanisms in the control of erythropoiesis. Leukemia, 18, 1176-99.
  37. Tsai NM, Lin SZ, Lee CC, et al (2005). The antitumor effects of Angelica sinensis on malignant brain tumors in vitro and in vivo. Clin Cancer Res, 11, 3475-84.
  38. Tsiftsoglou AS, Bonovolias ID, Tsiftsoglou SA (2009). Multilevel targeting of hematopoietic stem cell self-renewal, differentiation and apoptosis for leukemia therapy. Pharmacol Ther, 122, 264-280.
  39. Wang PP, Zhang Y, Wang KP, et al (2008). Effects of Angelica sinensis polysaccharide-iron complex on hemolytic anemia and bone marrow injury in mice. J Chinese Pharm Sci, 17, 197-202.
  40. Wierenga AT, Vellenga E, Schuringa JJ, et al (2008). Maximal STAT5-induced proliferation and self-renewal at intermediate STAT5 activity levels. Mol Cell Biol, 28, 6668-80.
  41. Wu XZ and Xie GR (2008). Induced differentiation of hepatocellular carcinoma by natural products. Afr J Tradit Comp Altern Med, 5, 325-31.
  42. Yamashita T, Wakao H, Miyajima A, et al (1998). Differentiation inducers modulate cytokine signaling pathways in a murine erythroleukemia cell line. Cancer Res, 58, 556-61.
  43. Yang XB, Zhao Y, Wang QW, et al (2005). Analysis of the monosaccharide components in Angelica polysaccharides by high performance liquid chromatography. Anal Sci, 21, 1177-80.
  44. Yang XB, Zhao Y, Zhou YJ, et al (2007). Component and antioxidant properties of polysaccharide fractions isolated from Angelica sinensis (Oliv). Diels Biol Pharm Bull, 30, 1884-90.
  45. Zhao LM, Han LN, Ren FZ, et al (2012). An ester extract of Cochinchina momordica seeds induces differentiation of melanoma B16F1 cells via MAPKs signaling. Asian Pac J Cancer Prev, 13, 3795-802.
  46. Zhuang SR, Chui HF, Chen SL, et al (2012). Effects of a Chinese medical herbs complex on cellular immunity and toxicity-related conditions of breast cancer patients. Br J Nutr, 107, 712-18.

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