Dual Inhibition of Bcr-Abl and Hsp90 by C086 Potently Inhibits the Proliferation of Imatinib-Resistant CML Cells
Dual Inhibition of Bcr-Abl and Hsp90 by C086 Potently Inhibits the Proliferation of Imatinib-Resistant CML Cells
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C086 对 Bcr-Abl 和 Hsp90 的双重抑制可有效抑制伊马替尼耐药 CML 细胞的增殖
DOI：
10.1158/1078-0432.ccr-13-3317
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发表时间：
2014-12
期刊：
影响因子：
--
通讯作者：
Jianhua Xu
中科院分区：
文献类型：
--
作者：
Meijuan Huang;Yong Wu;Yuanzhong Chen;Jianhua Xu
目的：虽然酪氨酸激酶抑制剂（TKI），如伊马替尼提供了一种有效的治疗慢性髓细胞性白血病（CML）患者的成熟细胞中的Bcr-Abl激酶活性，TKI可能无法根除白血病干细胞（LSC）群体。因此，需要替代疗法来靶向具有野生型（WT）或突变Bcr-Abl的成熟CML细胞和LSC。为研究姜黄素衍生物C 086对伊马替尼耐药细胞的作用，探讨其抑制Bcr-Abl激酶和热休克蛋白90（Hsp 90）功能的机制。实验设计：生化分析用于测试ABL激酶活性;荧光测量使用重组NHsp 90，Hsp 90 ATP酶测定，免疫沉淀，免疫印迹法用于检查Hsp 90的功能。采用集落形成单位、长期培养起始细胞（LTC-IC）和流式细胞术检测CML祖细胞和干细胞。结果如下：用纯化的重组Abl激酶进行的生化测定证实C 086可以直接抑制Abl的激酶活性，包括WT和Q252 H、Y253 F和T315 I突变。此外，我们确定了C 086作为一种新的Hsp 90抑制剂，能够破坏CML细胞中的Hsp 90分子伴侣功能。因此，它抑制伊马替尼敏感和耐药CML细胞的生长。有趣的是，C 086有能力抑制LTC-IC，并在体外诱导CD 34 + CD 38+和CD 34 + CD 38 −细胞凋亡。此外，C 086可降低CML NOD-SCID小鼠中CD 45+、CD 45 + CD 34 + CD 38+和CD 45 + CD 34 + CD 38 −细胞的数量。结论：C 086对Abl激酶活性和Hsp 90分子伴侣功能的双重抑制为治疗Bcr-Abl诱导的对TKI耐药的白血病提供了一种新的治疗策略。Clin Cancer Res; 21（4）; 833-43.©2014 AACR.
Purpose: Although tyrosine kinase inhibitors (TKI) such as imatinib provide an effective treatment against Bcr-Abl kinase activity in the mature cells of patients with chronic myelogenous leukemia (CML), TKIs probably cannot eradicate the leukemia stem cell (LSC) population. Therefore, alternative therapies are required to target both mature CML cells with wild-type (WT) or mutant Bcr-Abl and LSCs. To investigate the effect of C086, a derivative of curcumin, on imatinib-resistant cells, we explored its underlying mechanisms of Bcr-Abl kinase and heat shock protein 90 (Hsp90) function inhibition. Experimental Design: Biochemical assays were used to test ABL kinase activity; fluorescence measurements using recombinant NHsp90, Hsp90 ATPase assay, immunoprecipitation, and immunoblotting were applied to examine Hsp90 function. Colony-forming unit, long-term culture-initiating cells (LTC-IC), and flow cytometry were used to test CML progenitor and stem cells. Results: Biochemical assays with purified recombinant Abl kinase confirmed that C086 can directly inhibit the kinase activity of Abl, including WT and the Q252H, Y253F, and T315I mutations. Furthermore, we identified C086 as a novel Hsp90 inhibitor with the capacity to disrupt the Hsp90 chaperone function in CML cells. Consequently, it inhibited the growth of both imatinib-sensitive and -resistant CML cells. Interestingly, C086 has the capacity to inhibit LTC-ICs and to induce apoptosis in both CD34+CD38+ and CD34+CD38− cells in vitro. Moreover, C086 could decrease the number of CD45+, CD45+CD34+CD38+, and CD45+CD34+CD38− cells in CML NOD-SCID mice. Conclusions: Dual suppression of Abl kinase activity and Hsp90 chaperone function by C086 provides a new therapeutic strategy for treating Bcr-Abl–induced leukemia resistant to TKIs. Clin Cancer Res; 21(4); 833–43. ©2014 AACR.
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影响因子：
11.4
作者：
Blagosklonny, MV;Fojo, T;Neckers, LM
通讯作者：
Neckers, LM
影响因子：
50.3
作者：
Weisberg, E;Manley, PW;Griffin, JD
通讯作者：
Griffin, JD
DOI：
10.1158/1078-0432.ccr-11-1000
发表时间：
2012-01-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Neckers L;Workman P
通讯作者：
Workman P
BCR-ABL 激酶已死亡；
DOI：
10.1172/jci43605
发表时间：
2011
期刊：
The Journal of clinical investigation
影响因子：
--
作者：
Perl,Alexander;Carroll,Martin
通讯作者：
Carroll,Martin
影响因子：
3.6
作者：
Chen, Chun;Liu, Yang;Xu, Jianhua
通讯作者：
Xu, Jianhua