Novel oxime derivatives of radicicol induce erythroid differentiation associated with preferential G1 phase accumulation against chronic myelogenous leukemia cells through destabilization of Bcr-Abl with Hsp90 complex
Novel oxime derivatives of radicicol induce erythroid differentiation associated with preferential G1 phase accumulation against chronic myelogenous leukemia cells through destabilization of Bcr-Abl with Hsp90 complex
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DOI：
10.1182/blood.v96.6.2284
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发表时间：
2000-09-15
期刊：
影响因子：
20.3
通讯作者：
Akinaga, S
中科院分区：
文献类型：
--
作者：
Shiotsu, Y;Neckers, LM;Akinaga, S
慢性粒细胞白血病(CML)是一种多能造血干细胞的克隆性疾病，其特征是嵌合的bcr-abl基因导致p210(bcr-abl)蛋白活性异常。自由基是一种大环状抗真菌抗生素，与热休克蛋白90(Hsp90)的N端结合，破坏Raf-1等Hsp90相关蛋白的稳定。本研究观察了新型自由基醇(KF25706和KF58333)的肟衍生物(KF25706和KF58333)和苯喹类阿萨霉素类抗生素赫比霉素A(HA)对人K562 CML细胞生长和分化的影响。虽然KF25706和KF58333诱导K562细胞表达血糖素A，但自由基和透明质酸可短暂地诱导红系分化。细胞周期分析显示，KF58333处理组K562细胞出现G(1)期积聚，KF58333处理组K562细胞中p210(bcr-Abl)、Raf-1和细胞酪氨酸磷酸化蛋白被耗尽，而自由基醇和HA处理组这些蛋白短暂耗竭。KF58333还下调了细胞周期依赖性蛋白4和6的表达，上调了细胞周期依赖性蛋白抑制因子p27(Kip1)的表达，而对ERK和Hsp90蛋白的表达没有影响。免疫沉淀分析表明，p210(bcr-Abl)与Hsp90形成多个复合体，有的含有p23，有的含有Hsp70；KF58333处理使p210(bcr-Abl)从Hsp90/p23分子伴侣复合体中解离出来。KF58333可诱导K562细胞发生凋亡，KF58333可延长接种K562细胞的SCID小鼠的存活时间。这些结果表明，KF58333可能具有治疗p210(bcr-Abl)诱导的细胞异常增殖的CML的潜力。(布拉德，2000；96：2284-2291)(C)2000由美国血液病学会出版。
Chronic myelogenous leukemia (CML) is a clonal disorder of a pluripotent hematopoietic stem cells characterized by a chimeric bcr-abl gene giving rise to a p210(Bcr-Abl) protein with dysregulated tyrosine kinase activity. Radicicol, a macrocyclic antifungal antibiotic, binds to the N-terminal of heat shock protein 90 (Hsp90) and destabilizes Hsp90-associated proteins such as Raf-1. This study investigated the effect of radicicol, novel oxime derivatives of radicicol (KF25706 and KF58333), and herbimycin A (HA), a benzoquinoid ansamycin antibiotic, on the growth and differentiation of human K562 CML cells. Although KF25706 and KF58333 induced the expression of glycophorin A in K562 cells, radicicol and HA caused erythroid differentiation transiently. Cell cycle analysis showed that G(1) phase accumulation was observed in K562 cells treated with KF58333, KF58333 treatment depleted p210(Bcr-Abl), Raf-1, and cellular tyrosine phosphorylated proteins in K562 cells, whereas radicicol and HA showed transient depletion of these proteins. KF58333 also down-regulated the level of cell cycle-dependent kinases 4 and 6 and up-regulated cell cycle-dependent kinase inhibitor p27(Kip1) protein without an effect on the level of Erk and Hsp90 proteins. Immunoprecipitation analysis showed that p210(Bcr-Abl) formed multiple complexes with Hsp90, some containing p23 and others Hsp70; KF58333 treatment dissociated p210(Bcr-Abl) from Hsp90/p23 chaperone complexes. Furthermore, KF58333 induced apoptosis in K562 cells and administration of KF58333 prolonged the survival time of SCID mice inoculated with K562 cells. These results suggest that KF58333 may have therapeutic potential for the treatment of CML that involves abnormal cellular proliferation induced by p210(Bcr-Abl). (Blood, 2000;96:2284-2291) (C) 2000 by The American Society of Hematology.