کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
8453406 | 1547883 | 2018 | 7 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Chk1 inhibitors overcome imatinib resistance in chronic myeloid leukemia cells
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کلمات کلیدی
موضوعات مرتبط
علوم زیستی و بیوفناوری
بیوشیمی، ژنتیک و زیست شناسی مولکولی
تحقیقات سرطان
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
Drug resistance to tyrosine kinase inhibitors (TKIs) is currently a clinical problem of chronic myelogenous leukemia (CML). Bcr-Abl protein depletion is considered as a way to overcome drug resistance to TKIs. In our study, Chk1 inhibitors, AZD7762 and MK-8776, had strong antitumor effects on CML cell line KBM5 and imatinib-resistant form KBM5T315I. Moreover, Chk1 inhibitors showed a strong cytotoxic effect on leukemia cells from primary CML and imatinib-resistance CML patients, but low cytotoxic effect on normal human mononuclear cells. Then, we found that Chk1 inhibitors induced apoptosis and increased DNA damage in CML cell lines with the degradation of the Bcr-Abl protein. Using the proteasome inhibitor and an immunoprecipitation assay, we found that Chk1 inhibitors triggered the degradation of Bcr-Abl through ubiquitination, which is depending on E3 ubiquitin ligase CHIP. At last, MK-8776 showed a significant tumor-suppressive effect of KBM5T315I cell in xenograft tumor models. Taking together, these findings suggest that targeting Chk1 may overcome TKIs resistance for the treatment of CML.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Leukemia Research - Volume 64, January 2018, Pages 17-23
Journal: Leukemia Research - Volume 64, January 2018, Pages 17-23
نویسندگان
Hu Lei, Jin Jin, Meng Liu, Xiangyun Li, Hao Luo, Li Yang, Hanzhang Xu, Yingli Wu,