Inhibition of cyclin-dependent kinase 1 (CDK1) by indirubin derivatives in human tumour cells.

Content Provider	Europe PMC
Author	Marko, D Schätzle, S Friedel, A Genzlinger, A Zankl, H Meijer, L Eisenbrand, G
Copyright Year	2001
Abstract	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
ISSN	00070920
Journal	British Journal of Cancer
Volume Number	84
PubMed Central reference number	PMC2363695
Issue Number	2
PubMed reference number	11161389
e-ISSN	15321827
DOI	10.1054/bjoc.2000.1546
Language	English
Publisher	Nature Publishing Group
Publisher Date	2001-01-01
Access Restriction	Open
Rights License	This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material.If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit https://creativecommons.org/licenses/by/4.0/. Copyright © 2001 Cancer Research Campaign
Subject Keyword	CDK1 cyclin B indirubin indirubin-3′-monoxime cyclin-dependent kinase
Content Type	Text
Resource Type	Article
Subject	Cancer Research Oncology