Preferences help
enabled [disable] Abstract
Number of results
2008 | 55 | 4 | 673-680
Article title

Reversal of drug resistance by silencing Survivin gene expression in acute myeloid leukemia cells

Title variants
Languages of publication
The role of Survivin in the pathogenesis of leukemia was explored in order to discover the effective avenues for gene therapy. Most primary leukemia cells isolated from patients as well as three leukemia cell lines (HL-60, K562, and U937) all expressed Survivin gene. To investigate the relationship between Survivin and chemotherapeutic resistance, HL-60 cells were treated with daunorubicin (DNR), mitoxantrone (MIT) or arsenious oxide (As2O3), and it was found that after 24 h the level of Survivin mRNA was decreased by 9.7%, 41.0% and 27.5%, respectively. At 72 h, the level of Survivin mRNA was increased by 21.2% and 65.2% in HL-60 cells treated with DNR or MIT, but decreased by 33.2% in those treated with As2O3 as compared with that in the cells treated for 24 h. These results showed that DNR and MIT could initally decrease the expression of Survivin and then increase it, but As2O3 could decrease the Survivin expression continually. Furthermore, shRNA plasmids targeting the Survivin gene (pEGFP-Survivin), which can silence the expression of Survivin with a high specificity, were constructed. pEGFP-Survivin and pEGFP-H1 were transfected into HL-60 cells via electroporation and selected by G418, and HL-60/Survivin and HL-60/EGFP cells were obtained. After treatment with DNR, the cell survival rate and IC50 of DNR in HL-60/Survivin cells were decreased substantially as compared with those of HL-60/EGFP and HL-60 cells (IC50 of DNR: 18.3 ± 2.45 vs 40.8 ± 6.37 and 39.2 ± 5.91 ng/ml, respectively), and the apoptosis rate was elevated ((84.3 ± 19.7)% vs (45.8 ± 13.8)% and (50.9 ± 12.4)%, respectively). These results suggest that shRNA can down-regulate the expression of Survivin in HL-60 cells substantially and improve their sensitivity to DNR. They also further explain the pathogenesis of leukemia drug resistance and provide new theory in the design of clinical therapies.
Physical description
  • Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
  • Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
  • Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
  • Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
  • Adida C, Haioun C, Gaulard P (2000) Prognostic significance of Survivin expression in diffuse large B-cell lymphomas. Blood 96: 1921-1925.
  • Adida C, Recher C, Raffoux E (2000) Expression and prognostic significance of Survivin in de novo acute myeloid leukaemia. Br J Haematol 111: 196-203.
  • Ai Z, Yin L, Zhou X, Zhu Y, Zhu D, Yu Y, Feng Y (2006) Inhibition of survivin reduces cell proliferation and induces apoptosis in human endometrial cancer. Cancer 107: 746-756.
  • Altieri DC (2003) Survivin, versatile modulation of cell division and apoptosis in cancer. Oncogene 22: 8581-8589.
  • Bhardwaj A, Sethi G, Vadhan-Raj S, Bueso-Ramos C, Takada Y, Gaur U, Nair AS, Shishodia S, Aggarwal BB (2007) Resveratrol inhibits proliferation, induces apoptosis, and overcomes chemoresistance through down-regulation of STAT3 and nuclear factor-kappaB-regulated antiapoptotic and cell survival gene products in human multiple myeloma cells. Blood 109: 2293-2302.
  • Brummelkamp TR, Bernards R, Agami R (2002) A system for stable expression of short interfering RNAs in mammalian cells. Science 296: 550-553.
  • Carter BZ, Milella M, Altieri DC, Andreeff M (2001) Cytokine-regulated expression of Survivin in myeloid leukemia. Blood 97: 2784-2790.
  • Elbashir SM, Harborth J, Lendeckel W, Yalcin A, Weber K, Tuschl T (2001) Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature 411: 494-498.
  • Greiner J, Bullinger L, Guinn BA, Döhner H, Schmitt M (2008) Leukemia-associated antigens are critical for the proliferation of acute myeloid leukemia cells. Clin Cancer Res 14: 7161-7166.
  • Hannon GJ (2002) RNA interference. Nature 418: 244-251.
  • Hannon GJ, Rossi JJ (2004) Unlocking the potential of the human genome with RNA interference. Nature 431: 371-378.
  • Ikeguchi M, Liu J, Kaibara N (2002) Expression of Survivin mRNA and protein in gastric cancer cell line (MKN-45) during cisplatin treatment. Apoptosis 7: 23-29.
  • Jakubowska J, Stasiak M, Szulawska A, Bednarek A, Czyz M (2007) Combined effects of doxorubicin and STI571 on growth, differentiation and apoptosis of CML cell line K562. Acta Biochim Polon 54: 839-846.
  • Jing Y, Wang L, Xia L (2001) Combined effect of all-trans retinoic acid and arsenic trioxide in acute promyelocytic leukemia cells in vitro and in vivo. Blood 97: 264-269.
  • Mita AC, Mita MM, Nawrocki ST, Giles FJ (2008) Survivin: key regulator of mitosis and apoptosis and novel target for cancer therapeutics. Clin Cancer Res 14: 5000-5005.
  • Norgaard JM, Jensen PD, Bendix K, Clausen N, Palshof T (1999) Relevance of in vitro leukemia cell survival to short- and long-term clinical outcome in AML. Leuk Lymphoma 32: 327-337.
  • Olie RA, Simoes-Wust AP, Baumann B (2000) A novel antisense oligonucleotide targeting Survivin expression induce apoptosis sensitizes lung cancer cells to chemotherapy. Cancer Res 60: 2805-2809.
  • Sarela AI, Macadam RC, Farmery SM, Markham AF, Guillou PJ (2000) Expression of the antiapoptosis gene, Survivin, predicts death from recurrent colorectal carcinoma. Gut 46: 645-650.
  • Tamm I, Segall H, Kitada S (2000) Expression and prognostic significance of IAP-family genes in human cancers and myeloid leukemias. Clin Cancer Res 6: 1796-1803.
  • Tazzari PL, Tabellini G, Ricci F, Papa V, Bortul R, Chiarini F, Evangelisti C, Martinelli G, Bontadini A, Cocco L, McCubrey JA, Martelli AM (2008) Synergistic proapoptotic activity of recombinant TRAIL plus the akt inhibitor perifosine in acute myelogenous leukemia cells. Cancer Res 68: 9394-9403.
  • Zaffaroni N, Pennati M, Daidone MG (2005) Survivin as a target for new anticancer interventions. J Cell Mol Med 9: 360-372.
Document Type
Publication order reference
YADDA identifier
JavaScript is turned off in your web browser. Turn it on to take full advantage of this site, then refresh the page.