Curcumin derivative C817 inhibits proliferation of imatinib-resistant chronic myeloid leukemia cells with wild-type or mutant Bcr-Abl in vitro
Curcumin derivative C817 inhibits proliferation of imatinib-resistant chronic myeloid leukemia cells with wild-type or mutant Bcr-Abl in vitro
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姜黄素衍生物C817体外抑制野生型或突变型Bcr-Abl对伊马替尼耐药的慢性粒细胞白血病细胞的增殖
DOI：
10.1038/aps.2013.180
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发表时间：
2014-02
影响因子：
8.2
通讯作者：
Jian-hua XU
中科院分区：
文献类型：
--
作者：
Li-guang LOU;Zhi-hong ZHENG;Yuan-zhong CHEN;Jian-hua XU
目的：寻找新的激酶抑制剂，克服伊马替尼耐药的治疗慢性粒细胞白血病（CML），我们合成了C817，一种新的姜黄素衍生物，并测试其对野生型（WT）和伊马替尼耐药突变型Abl激酶，以及在体外伊马替尼敏感和耐药CML cells中的活性。方法：32 D细胞携带野生型或突变型Abl激酶（核苷酸结合P-loop突变体Q252 H，Y253 F，和伊马替尼接触残基突变体T315 I），以及K562/G 01细胞（与整个Bcr-Abl基因扩增）进行了测试。使用Kinase-Glo发光激酶测定平台在重组WT和突变体（Q252 H、Y253 F和T315 I）Abl激酶中测量激酶活性。MTT法检测细胞增殖活性，流式细胞仪检测细胞凋亡。Western blotting检测Bcr-Abl启动的信号蛋白磷酸化水平。结果：C817以非ATP竞争性方式抑制野生型和突变型（Q252 H、Y253 F和T315 I）Abl激酶活性，IC 50值在低纳摩尔水平。与上述结果一致，C817抑制伊马替尼敏感和耐药CML细胞的生长，包括野生型K562、K562/G 01、32 D-T315 I、32 D-Q252 H和32 D-Y253 F细胞，IC 50值为低微摩尔水平。C817（0.5或1 μmol/L）可剂量依赖性地抑制伊马替尼耐药K562/G 01细胞Bcr-Abl及其下游蛋白STAT-5和CrkL的磷酸化。结论：C817是治疗Bcr-Abl激酶结构域突变导致伊马替尼耐药的CML患者的有效药物。
Aim:To find new kinase inhibitors that overcome the imatinib resistance in treatment of chronic myeloid leukemia (CML), we synthesized C817, a novel derivative of curcumin, and tested its activities against wild-type (WT) and imatinib-resistant mutant Abl kinases, as well as in imatinib-sensitive and resistant CML cells in vitro.Methods:32D cells harboring WT or mutant Abl kinases (nucleotide binding P-loop mutants Q252H, Y253F, and imatinib contact residue mutant T315I), as well as K562/G01 cells (with whole Bcr-Abl gene amplication) were tested. Kinase activity was measured using Kinase-Glo Luminescent Kinase Assay Platform in recombinant WT and mutant (Q252H, Y253F, and T315I) Abl kinases. Cell proliferation and apoptosis were examined using MTT assay and flow cytometry, respectively. The phosphorylation levels of Bcr-Abl initiated signaling proteins were analyzed using Western blotting. Colony forming units (CFU) growth and long term culture-initiating cells (LTC-ICs) were used to test the effects of C817 on human leukemia progenitor/stem cells.Results:C817 potently inhibited both WT and mutant (Q252H, Y253F, and T315I) Abl kinase activities in a non-ATP competitive manner with the values of IC 50 at low nanomole levels. In consistent with above results, C817 suppressed the growth of both imatinib-sensitive and resistant CML cells, including wild-type K562, K562/G01, 32D-T315I, 32D-Q252H, and 32D-Y253F cells with the values of IC 50 at low micromole levels. C817 (0.5 or 1 μmol/L) dose-dependently inhibited the phosphorylation of Bcr-Abl and downstream proteins STAT-5 and CrkL in imatinib-resistant K562/G01 cells. Furthermore, C817 significantly suppressed CFU growth and LTC-ICs, implicating that C817 could eradiate human leukemia progenitor/stem cells.Conclusion:C817 is a promising compound for treatment of CML patients with Bcr-Abl kinase domain mutations that confer imatinib resistance.
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影响因子：
3.5
作者：
Adams, BK;Ferstl, EM;Shoji, M
通讯作者：
Shoji, M
影响因子：
--
作者：
R. van Os;B. Dethmers-Ausema;G. de Haan
通讯作者：
R. van Os;B. Dethmers-Ausema;G. de Haan
影响因子：
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作者：
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A. Lau;C. Li;A. Santos;M. Warso;T. Gupta;R. Yu;T. Kong
影响因子：
7.2
作者：
Tretiakova, Irina;Blaesius, Dagmar;Werz, Oliver
通讯作者：
Werz, Oliver
影响因子：
4.3
作者：
A. Quamrul Hassan;Sreenath V. Sharma;M. Warmuth
通讯作者：
A. Quamrul Hassan;Sreenath V. Sharma;M. Warmuth