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

• Authors: Yao-Hui Wu , Yong You , Zhi-Chao Chen , Ping Zou
• Languages of publication: EN

Abstracts

EN

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.

Keywords

EN

chemotherapeutic resistance; Survivin; acute myeloid leukemia; shRNA; apoptosis

• Publisher: Polish Biochemical Society
• Journal: Acta Biochimica Polonica
• Year: 2008
• Volume: 55
• Issue: 4
• Pages: 673-680

Dates

published

2008

received

2008-06-30

revised

2008-10-03

accepted

2008-12-02

(unknown)

2008-12-18

Contributors

author

Yao-Hui Wu

• Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

author

Yong You

• Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

author

Zhi-Chao Chen

• Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

author

Ping Zou

• Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

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