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Arsenic Trioxide and Icariin Show Synergistic Anti-leukemic Activity

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Abstract

Although As2O3 (ATO) has been recommended as the front-line agent for treatment of acute promyelocytic leukemia (APL), particularly for relapsed or refractory APL, it has been associated with profound toxicity. Icariin is a natural compound with activity against a variety of cancers. This study was designed to investigate the effect of Icariin on APL cells and to determine whether Icariin can potentiate the antitumor activity of ATO in APL cells. Cell proliferation and apoptosis were measured using MTT assay and flow cytometry, respectively. The expression of apoptosis and proliferation-related molecules was detected by Western blotting. Reactive oxygen species (ROS) and mitochondrial membrane potential were determined with florescence staining. Icariin inhibited proliferation in a dose-dependent manner and induced apoptosis in both of the tested APL cell lines. Icariin enhanced the in vitro antitumor activity of ATO against APL. The antitumor activity of Icariin and its enhancement of the antitumor activity of ATO correlated with the increase in accumulation of intracellular ROS. Our results showed that Icariin, by increasing intracellular ROS, exhibited antitumor activity and potentiated the antitumor activity of ATO against APL. Therefore, combination treatment with Icariin and ATO might offer a novel therapeutic option for patients with APL, although further studies are needed.

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References

  1. Estey, E., & Dohner, H. (2006). Acute myeloid leukaemia. Lancet, 368(9550), 1894–1907.

    Article  PubMed  Google Scholar 

  2. Rogers, C. S., et al. (2014). Vitamin D3 potentiates the antitumorigenic effects of arsenic trioxide in human leukemia (HL-60) cells. Experimental Hematology and Oncology, 3(1), 9.

    Article  PubMed Central  PubMed  Google Scholar 

  3. Borrow, J., et al. (1990). Molecular analysis of acute promyelocytic leukemia breakpoint cluster region on chromosome 17. Science, 249(4976), 1577–1580.

    Article  CAS  PubMed  Google Scholar 

  4. de The, H., et al. (1990). The t(15;17) translocation of acute promyelocytic leukaemia fuses the retinoic acid receptor alpha gene to a novel transcribed locus. Nature, 347(6293), 558–561.

    Article  PubMed  Google Scholar 

  5. Cyranoski, D. (2007). Arsenic patent keeps drug for rare cancer out of reach of many. Nature Medicine, 13(9), 1005.

    Article  CAS  PubMed  Google Scholar 

  6. Shen, Z. X., et al. (1997). Use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia (APL): II. Clinical efficacy and pharmacokinetics in relapsed patients. Blood, 89(9), 3354–3360.

    CAS  PubMed  Google Scholar 

  7. Soignet, S. L., et al. (1998). Complete remission after treatment of acute promyelocytic leukemia with arsenic trioxide. New England Journal of Medicine, 339(19), 1341–1348.

    Article  CAS  PubMed  Google Scholar 

  8. Fox, E., et al. (2008). Phase 1 trial and pharmacokinetic study of arsenic trioxide in children and adolescents with refractory or relapsed acute leukemia, including acute promyelocytic leukemia or lymphoma. Blood, 111(2), 566–573.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Ebinger, M., et al. (2011). Long-term remission after first-line single-agent treatment with arsenic trioxide of relapsed acute promyelocytic leukemia in an 8-year-old boy. Pediatric Hematology and Oncology, 28(4), 334–337.

    Article  CAS  PubMed  Google Scholar 

  10. Douer, D., & Tallman, M. S. (2005). Arsenic trioxide: New clinical experience with an old medication in hematologic malignancies. Journal of Clinical Oncology, 23(10), 2396–2410.

    Article  CAS  PubMed  Google Scholar 

  11. Sanz, M. A., et al. (2009). Management of acute promyelocytic leukemia: Recommendations from an expert panel on behalf of the European LeukemiaNet. Blood, 113(9), 1875–1891.

    Article  CAS  PubMed  Google Scholar 

  12. Li, S., et al. (2010). Icariin, a natural flavonol glycoside, induces apoptosis in human hepatoma SMMC-7721 cells via a ROS/JNK-dependent mitochondrial pathway. Cancer Letters, 298(2), 222–230.

    Article  CAS  PubMed  Google Scholar 

  13. Lin, C. C., et al. (2004). Cytotoxic effects of Coptis chinensis and Epimedium sagittatum extracts and their major constituents (berberine, coptisine and icariin) on hepatoma and leukaemia cell growth. Clinical and Experimental Pharmacology and Physiology, 31(1–2), 65–69.

    Article  CAS  PubMed  Google Scholar 

  14. Wang, Y., et al. (2010). Icariin exterts negative effects on human gastric cancer cell invasion and migration by vasodilator-stimulated phosphoprotein via Rac1 pathway. European Journal of Pharmacology, 635(1–3), 40–48.

    Article  CAS  PubMed  Google Scholar 

  15. Zhang, D. C., et al. (2013). Icariin potentiates the antitumor activity of gemcitabine in gallbladder cancer by suppressing NF-κB. Acta Pharmacologica Sinica, 34(2), 301–308.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. Yang, L., et al. (2014). Synergistic anti-cancer effects of Icariin and temozolomide in glioblastoma. Cell Biochemistry and Biophysics. 2014. doi:10.1007/s12013-014-0360-3.

    Google Scholar 

  17. Shi, D. B., et al. (2014). Icariin-mediated inhibition of NF-κB activity enhances the in vitro and in vivo antitumour effect of 5-fluorouracil in colorectal cancer. Cell Biochemistry and Biophysics, 69(3), 523–530.

    Article  CAS  PubMed  Google Scholar 

  18. Li, W., et al. (2014). Icariin synergizes with arsenic trioxide to suppress human hepatocellular carcinoma. Cell Biochemistry and Biophysics, 68(2), 427–436.

    Article  PubMed  Google Scholar 

  19. Chou, T. C., & Talalay, P. (1984). Quantitative analysis of dose-effect relationships: The combined effects of multiple drugs or enzyme inhibitors. Advances in Enzyme Regulation, 22, 27–55.

    Article  CAS  PubMed  Google Scholar 

  20. Wang, D., et al. (2008). Two hour exposure to sodium butyrate sensitizes bladder cancer to anticancer drugs. International Journal of Urology, 15(5), 435–441.

    Article  PubMed  Google Scholar 

  21. Liou, G. Y., & Storz, P. (2010). Reactive oxygen species in cancer. Free Radical Research, 44(5), 479–496.

    Article  CAS  PubMed  Google Scholar 

  22. Chen, Y., et al. (2011). Icariin and its pharmaceutical efficacy: Research progress of molecular mechanism. Zhong Xi Yi Jie He Xue Bao, 9(11), 1179–1184.

    Article  CAS  PubMed  Google Scholar 

  23. Huang, X., Zhu, D., & Lou, Y. (2007). A novel anticancer agent, icaritin, induced cell growth inhibition, G1 arrest and mitochondrial transmembrane potential drop in human prostate carcinoma PC-3 cells. European Journal of Pharmacology, 564(1–3), 26–36.

    Article  CAS  PubMed  Google Scholar 

  24. Wang, Y., et al. (2010). Icariin exterts negative effects on human gastric cancer cell invasion and migration by vasodilator-stimulated phosphoprotein via Rac1 pathway. European Journal of Pharmacology, 635(1–3), 40–48.

    Article  CAS  PubMed  Google Scholar 

  25. Wang, Q., et al. (2011). Icariin induces apoptosis in mouse MLTC-10 Leydig tumor cells through activation of the mitochondrial pathway and down-regulation of the expression of piwil4. International Journal of Oncology, 39(4), 973–980.

    CAS  PubMed  Google Scholar 

  26. Tatham, M. H., et al. (2008). RNF4 is a poly-SUMO-specific E3 ubiquitin ligase required for arsenic-induced PML degradation. Nature Cell Biology, 10(5), 538–546.

    Article  CAS  PubMed  Google Scholar 

  27. Chen, G. Q., et al. (1997). Use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia (APL): I. As2O3 exerts dose-dependent dual effects on APL cells. Blood, 89(9), 3345–3353.

    CAS  PubMed  Google Scholar 

  28. Yang, C. H., et al. (1999). Arsenic trioxide sensitivity is associated with low level of glutathione in cancer cells. British Journal of Cancer, 81(5), 796–799.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. Chou, W. C., et al. (2004). Role of NADPH oxidase in arsenic-induced reactive oxygen species formation and cytotoxicity in myeloid leukemia cells. Proceedings of the National Academy of Sciences of the United States of America, 101(13), 4578–4583.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. Fan, Y., et al. (2014). Arsenic trioxide and resveratrol show synergistic anti-leukemia activity and neutralized cardiotoxicity. PLoS ONE, 9(8), e105890.

    Article  PubMed Central  PubMed  Google Scholar 

  31. Benbijja, M., Mellouk, A., & Bobe, P. (2014). Sensitivity of leukemic T-cell lines to arsenic trioxide cytotoxicity is dependent on the induction of phosphatase B220/CD45R expression at the cell surface. Molecular Cancer, 13, 251.

    Article  PubMed Central  PubMed  Google Scholar 

  32. Wo, Y. B., et al. (2008). Reactive oxygen species involved in prenylflavonoids, icariin and icaritin, initiating cardiac differentiation of mouse embryonic stem cells. Journal of Cellular Biochemistry, 103(5), 1536–1550.

    Article  CAS  PubMed  Google Scholar 

  33. Ding, L., et al. (2008). Involvement of p38MAPK and reactive oxygen species in icariin-induced cardiomyocyte differentiation of murine embryonic stem cells in vitro. Stem Cells and Development, 17(4), 751–760.

    Article  CAS  PubMed  Google Scholar 

  34. Zeng, K. W., et al. (2010). Icariin attenuates lipopolysaccharide-induced microglial activation and resultant death of neurons by inhibiting TAK1/IKK/NF-κB and JNK/p38 MAPK pathways. International Immunopharmacology, 10(6), 668–678.

    Article  CAS  PubMed  Google Scholar 

  35. Xiao-Hong, D., et al. (2013). Icariin delays homocysteine-induced endothelial cellular senescence involving activation of the PI3K/AKT-eNOS signaling pathway. Pharmaceutical Biology, 51(4), 433–440.

    Article  PubMed  Google Scholar 

  36. Zhou, H., et al. (2014). Icariin attenuates angiotensin II-induced hypertrophy and apoptosis in H9c2 cardiomyocytes by inhibiting reactive oxygen species-dependent JNK and p38 pathways. Experimental and Therapeutic Medicine, 7(5), 1116–1122.

    PubMed Central  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Pharmacy, The Affiliated Hospital of Medical College Qingdao University, Qingdao, 266003, China

    Zhi Wang, Hong Zhang, Liling Dai, Ping Li, Yali Liu & Luning Wang

  2. Emergency Department of Qingdao Emergency Center, Qingdao, 266035, China

    Tongguo Song

Authors
  1. Zhi Wang
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  2. Hong Zhang
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  3. Liling Dai
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  4. Tongguo Song
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  5. Ping Li
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  6. Yali Liu
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  7. Luning Wang
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Correspondence to Liling Dai.

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Wang, Z., Zhang, H., Dai, L. et al. Arsenic Trioxide and Icariin Show Synergistic Anti-leukemic Activity. Cell Biochem Biophys 73, 213–219 (2015). https://doi.org/10.1007/s12013-015-0660-2

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  • DOI: https://doi.org/10.1007/s12013-015-0660-2

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