Dual Inhibition of Bcr-Abl and Hsp90 by C086 Potently Inhibits the Proliferation of Imatinib-Resistant CML Cells

doi:10.1158/1078-0432.CCR-13-3317

	Dual Inhibition of Bcr-Abl and Hsp90 by C086 Potently Inhibits the Proliferation of Imatinib-Resistant CML Cells
	Wu, Lixian 2,3,4; Yu, Jing 5; Chen, Ruijia 2,3; Liu, Yang 1,3,4; Lou, Liguang6 ; Wu, Ying 3,4; Huang, Lisen 2; Fan, Yingjuan 3; Gao, Pinzhang 2; Huang, Meijuan 7
刊名	CLINICAL CANCER RESEARCH
	2015-02-15
卷号	21 期号:4 页码:833-843
ISSN号	1078-0432
DOI	10.1158/1078-0432.CCR-13-3317
文献子类	Article
英文摘要	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. (C) 2014 AACR.
资助项目	National Natural Science Foundation of China[30901824] ; National Natural Science Foundation of China[81173096] ; National Natural Science Foundation of China[81273541] ; National Natural Science Foundation of China[30873101] ; National Natural Science Foundation of China[30472187] ; National Science and Technology Foundation of China for Key Projects of "Major New Drugs Innovation and Development"[2012ZX09103-101-028] ; Natural Science Foundation of Fujian Province of China[2011J06013]
WOS关键词	CHRONIC MYELOID-LEUKEMIA ; TYROSINE KINASE INHIBITORS ; HEMATOPOIETIC STEM-CELLS ; CLINICAL RESISTANCE ; SELECTIVE INHIBITOR ; CANCER-CELLS ; MUTANTS ; THERAPY ; HEAT-SHOCK-PROTEIN-90 ; NILOTINIB
WOS研究方向	Oncology
语种	英语
出版者	AMER ASSOC CANCER RESEARCH
WOS记录号	WOS:000349851200021
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/276637]
专题	中国科学院上海药物研究所
通讯作者	Wu, Lixian
作者单位	1.Fujian Med Univ, Sch Pharm, Dept Pharmacochem, Fuzhou 350004, Fujian, Peoples R China; 2.Fujian Med Univ, Sch Pharm, Dept Pharmacol, Fuzhou 350004, Fujian, Peoples R China; 3.Fujian Med Univ, Inst Mat Med, Fuzhou 350004, Fujian, Peoples R China; 4.Fujian Med Univ, Fuijan Key Lab Nat Med Pharmacol, Fuzhou 350004, Fujian, Peoples R China; 5.Fujian Med Univ, Sch Basic Med, Dept Pathol, Fuzhou 350004, Fujian, Peoples R China; 6.Shanghai Inst Mat Med, Shanghai, Peoples R China; 7.Fujian Med Univ, Union Hosp, Fujian Inst Hematol, Fuzhou 350004, Fujian, Peoples R China
推荐引用方式 GB/T 7714	Wu, Lixian,Yu, Jing,Chen, Ruijia,et al. Dual Inhibition of Bcr-Abl and Hsp90 by C086 Potently Inhibits the Proliferation of Imatinib-Resistant CML Cells[J]. CLINICAL CANCER RESEARCH,2015,21(4):833-843.
APA	Wu, Lixian.,Yu, Jing.,Chen, Ruijia.,Liu, Yang.,Lou, Liguang.,...&Xu, Jianhua.(2015).Dual Inhibition of Bcr-Abl and Hsp90 by C086 Potently Inhibits the Proliferation of Imatinib-Resistant CML Cells.CLINICAL CANCER RESEARCH,21(4),833-843.
MLA	Wu, Lixian,et al."Dual Inhibition of Bcr-Abl and Hsp90 by C086 Potently Inhibits the Proliferation of Imatinib-Resistant CML Cells".CLINICAL CANCER RESEARCH 21.4(2015):833-843.