罗斯科维汀体外诱导白血病细胞凋亡的多种途径

Hairong Song, Å. Sidén, Z. Hassan
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摘要

罗斯科维汀是一种有效的细胞周期蛋白依赖性激酶(CDKs)抑制剂,与激酶的ATP结合袋竞争。罗斯科维汀已被证明对体外癌细胞系和体内肿瘤异种移植具有细胞毒性作用。与常规细胞抑制剂联合使用在体外癌细胞系中有很强的协同作用。本研究探讨了罗斯科维汀诱导人白血病细胞株HL-60、Jurkat和K562细胞死亡的机制。用罗斯科维汀(0.5 ~ 200 mol/L)孵育细胞24小时,分别用瑞祖脲和h -胸腺嘧啶掺入法研究细胞活力和增殖。流式细胞术检测细胞周期和线粒体膜电位,Giemsa染色检测细胞凋亡,Western blot检测细胞凋亡通路。在所有细胞系中,活性和增殖均以浓度依赖性的方式受到抑制。HL-60、Jurkat和K562的IC50分别为17、24和47 mol/L。三种细胞系均出现线粒体膜电位丧失、细胞色素c释放、caspase-3活性片段和PARP断裂。在HL-60和Jurkat细胞中均观察到caspase-2和-8的断裂片段,且出现顺序不同,而在K562细胞中未观察到这些片段。因此,罗斯科维汀是一种有效的白血病细胞凋亡诱导剂,并且根据不同的细胞系,凋亡通过不同的途径介导。
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Multiple Pathways of Apoptosis Induced by Roscovitine in Leukemic Cell Lines In Vitro
Roscovitine is a potent inhibitor of cyclin-dependent kinases (CDKs) that competes with the ATP binding pocket of kinases. Roscovitine has been shown to have cytotoxic effect on cancer cell lines in vitro and also in tumor xenografts in vivo. A strong synergistic effect in combination with conventional cytostatics has been reported in cancer cell lines in vitro. In this study, the mechanisms of roscovitineinduced cell death were investigated in human leukemic cell lines HL-60, Jurkat and K562. Cells were incubated with roscovitine (0.5-200 mol/L) up to 24 hours and cell viability and proliferation were studied using resazurin and H-thymidine incorporation assays, respectively. Cell cycle and mitochondrial membrane potential were analyzed using flow cytometry, apoptosis was assessed using morphological criteria in Giemsa staining and apoptotic pathways using Western blot analysis. Both viability and proliferation were inhibited in a concentration-dependent manner in all cell lines. Estimated IC50 was 17, 24 and 47 mol/L for HL-60, Jurkat and K562, respectively. Loss of mitochondrial membrane potential, release of cytochrome c, active fragment of caspase-3 and cleaved PARP were observed in all three cell lines. The cleaved fragments of caspase-2 and -8 were observed in HL-60 and Jurkat cells and the order of appearance differed between these two cell lines, while none of these fragments was observed in K562 cells. Thus, roscovitine is a potent inducer of apoptosis in leukemic cells and apoptosis has been mediated through different pathways depending on the cell line.
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