Inhibition of cyclin-dependent kinase 1 (CDK1) by indirubin derivatives in human tumour cells.
Inhibition of cyclin-dependent kinase 1 (CDK1) by indirubin derivatives in human tumour cells.
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DOI：
10.1054/bjoc.2000.1546
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发表时间：
2001-01
影响因子：
8.8
通讯作者：
Eisenbrand G
中科院分区：
文献类型：
--
作者：
Marko D;Schätzle S;Friedel A;Genzlinger A;Zankl H;Meijer L;Eisenbrand G
早在30多年前，双吲哚吲哚红就被描述为在治疗人类慢性髓细胞性白血病方面具有临床活性。然而，其潜在的作用机制仍不清楚。我们以前报道过靛玉红及其类似物是细胞周期蛋白依赖性激酶（CDK）的有效和选择性抑制剂。在这项研究中，我们研究了靛玉红及其衍生物对人肿瘤细胞中CDK1/cyclin B激酶的影响，其浓度已知可诱导生长抑制。在2 μM靛玉红-3′-单肟存在下，经血清剥夺同步的乳腺癌细胞系MCF-7细胞在血清充盈后停留在细胞周期的G1/G0期。在较高的药物浓度（≥5 μM）下，G2/M期细胞数量增加。诺可达唑在G2/M期同步的细胞释放后，在靛红素-3′-单肟（≥5 μM）存在下仍停留在G2/M期。10 μM靛玉红-3′-单肟处理24 h后出现亚g2峰，提示凋亡细胞开始死亡。用生长抑制浓度的靛红素-3 ' -单肟处理MCF-7细胞可诱导细胞内CDK1活性的剂量依赖性抑制。处理24小时后，观察到CDK1蛋白水平明显下降，与CDK1复合物的细胞周期蛋白B减少。综上所述，本研究的结果强烈表明，抑制人类肿瘤细胞中的CDK活性是靛玉红衍生物发挥其强大抗肿瘤功效的主要机制。©2001癌症研究运动http://www.bjcancer.com
The bisindole indirubin has been described, more than 30 years ago, as being clinically active in the treatment of human chronic myelocytic leukaemia. However, the underlying mechanism of action has remained unclear. We have reported previously that indirubin and its analogues are potent and selective inhibitors of cyclin-dependent kinases (CDK). In this study, we investigated the influence of indirubin and derivatives on CDK1/cyclin B kinase in human tumour cells at concentrations known to induce growth inhibition. Cells of the mammary carcinoma cell line MCF-7, synchronized by serum deprivation, after serum repletion stay arrested in the G1/G0 phase of the cell cycle in the presence of 2 μM indirubin-3′-monoxime. At higher drug concentrations (≥ 5 μM) an increase of the cell population in the G2/M phase is additionally observed. Cells synchronized in G2/M phase by nocodazole remain arrested in the G2/M phase after release, in the presence of indirubin-3′-monoxime (≥5 μM). After 24 h treatment with 10 μM indirubin-3′-monoxime a sub-G2 peak appears, indicative for the onset of apoptotic cell death. Treatment of MCF-7 cells with growth inhibitory concentrations of indirubin-3′-monoxime induces dose-dependent inhibition of the CDK1 activity in the cell. After 24 h treatment, a strong decrease of the CDK1 protein level along with a reduction of cyclin B in complex with CDK1 is observed. Taken together, the results of this study strongly suggest that inhibition of CDK activity in human tumour cells is a major mechanism by which indirubin derivatives exert their potent antitumour efficacy. © 2001 Cancer Research Campaign http://www.bjcancer.com
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影响因子：
21.3
作者：
Hoessel, R;Leclerc, S;Meijer, L
通讯作者：
Meijer, L
影响因子：
2.7
作者：
ABRAHAM, RT;ACQUARONE, M;VERLHAC, MH
通讯作者：
VERLHAC, MH
DOI：
10.1073/pnas.96.14.7938
发表时间：
1999-07-06
影响因子：
11.1
作者：
Takizawa, CG;Weis, K;Morgan, DO
通讯作者：
Morgan, DO
影响因子：
10.3
作者：
SKEHAN, P;STORENG, R;BOYD, MR
通讯作者：
BOYD, MR
影响因子：
2.6
作者：
Marko, Doris;Romanakis, Konstantinos;Eisenbrand, Gerhard
通讯作者：
Eisenbrand, Gerhard