Azacytidine enhances sensitivity response to Imatinib In BCR/ABL positive CML cell line
Purpose: Azacytidine (5-Aza) is a chemotherapeutic drug used for DNA-de-methylation resulting in re-expression of silenced tumor suppressor genes (TSG). Epigenetic silencing of TSG such as involved in the development and progression of cancers. Re-expression of SHP1 is inversely propo...
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Main Authors: | , , |
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Format: | Article |
Language: | English |
Published: |
2017
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Subjects: | |
Online Access: | http://eprints.unisza.edu.my/5728/1/FH02-ICODE-18-12779.pdf http://eprints.unisza.edu.my/5728/ |
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Summary: | Purpose: Azacytidine (5-Aza) is a chemotherapeutic drug used for DNA-de-methylation
resulting in re-expression of silenced tumor suppressor genes (TSG). Epigenetic silencing of
TSG such as involved in the development and progression of cancers. Re-expression of SHP1 is inversely proportionate with STAT3 signaling pathways. Majority of CML patients
treated with imatinib, a BCR/ABL inhibitor would develop resistance under prolonged
therapy. Here we evaluated the expression of SHP-1 gene and its methylation status with
sensitivity response of resistant CML cells to imatinib before and after treatment with 5-Aza.
Methods: BCR/ABL positive CML cell lines, K562 and K562-R, an imatinib resistant cell lines
were treated with 5-Aza. Cytotoxicity of imatinib and apoptosis were determined by MTS
and annexin-V, respectively. Gene expression analysis was detected by real time-PCR; STATs
activity was examined using Western blot and methylation status of SHP-1gene was
determined by pyrosequencing analysis. Results: There was a significant higher in the
expression of SHP-1 in K562-R+5-Aza cells compared to K562 and K562-R (p=0.001).
Methylation of SHP-1 gene was significantly decreased in K562-R+5-Aza cells compared to
others (p=0.003). STAT3 was inactivated in K562-R+5-Aza cell lines which showed higher
sensitivity to imatinib. Conslusion: In conclusion, 5-Aza could enhances efficacy of imatinib
on BCR/ABL CML cells through re-expression of SHP-1 gene and inhibition of STAT3
signaling. |
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