Cyclin-dependent kinase inhibitor Roscovitine induces apoptosis in chronic lymphocytic leukemia cells
Cyclin-dependent kinase inhibitor Roscovitine induces apoptosis in chronic lymphocytic leukemia cells
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DOI：
10.1038/sj.leu.2403295
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发表时间：
2004-04-01
期刊：
影响因子：
11.4
通讯作者：
Decker, T
中科院分区：
文献类型：
--
作者：
Hahntow, IN;Schneller, F;Decker, T
一种新的细胞周期抑制剂目前正在进入临床试验。这些药物通过抑制细胞周期蛋白依赖性激酶（cdk）发挥其活性，诱导癌细胞的细胞周期阻滞和凋亡。Roscovitine是一种cdk 2抑制剂，正在进行临床前评价，在对正常人B细胞无细胞毒性的剂量下诱导B-CLL细胞凋亡。在20 μ M时，Roscovitine在28个B-CLL样品中的21个中诱导细胞凋亡，并且在zap-70阳性或阴性样品中同样有效。在暴露于Roscovitine的B-CLL细胞中，半胱天冬酶-3被切割，并且泛半胱天冬酶抑制剂z.VAD. fmk阻断了Roscovitine诱导的细胞凋亡。促凋亡蛋白巴克的表达增加，Bax裂解和构象变化观察到Roscovitine处理的B-CLL细胞。抗凋亡蛋白Mcl-1和XIAP表达下调，但Bcl-2的表达保持不变。与先前在癌细胞系中的报道相反，Roscovitine治疗不伴随p53的核积累。Cyc 202（R-Roscovitine）正在癌症患者中进行早期临床试验。鉴于其对zap-70阳性和阴性B-CLL细胞的强大作用，而不是对正常淋巴细胞，Roscovitine可能是一种有吸引力的药物，可用于这种不治之症的测试。
A new class of cell cycle inhibitors is currently entering clinical trials. These drugs exert their activity by inhibition of cyclin-dependent kinases (cdk) and induce cell cycle arrest and apoptosis in cancer cells. Roscovitine, a cdk2-inhibitor that is in preclinical evaluation, induced apoptosis in B-CLL cells at doses that were not cytotoxic for normal human B cells. At 20 muM, Roscovitine induced apoptosis in 21 of 28 B-CLL samples and was equally effective in zap-70-positive or -negative samples. Caspase-3 was cleaved in B-CLL cells exposed to Roscovitine and the pancaspase inhibitor z.VAD.fmk-blocked Roscovitine-induced apoptosis. Expression of the proapoptotic protein Bak was increased and Bax cleavage and conformational change was observed in Roscovitine-treated B-CLL cells. Antiapoptotic proteins Mcl-1 and XIAP were downregulated, but the expression of Bcl-2 remained unchanged. In contrast to previous reports in cancer cell lines, Roscovitine treatment was not accompanied by nuclear accumulation of p53. Cyc202 (R-Roscovitine) is in early clinical trials in cancer patients. Given its powerful effects on zap-70-positive and -negative B-CLL cells, but not on normal lymphocytes, Roscovitine might be an attractive drug to be tested in this incurable disease.