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Antiproliferative effect of plant cytokinin analogues with an inhibitory activity on cyclin-dependent kinases

Leukemia volume 16, pages 299–305 (2002)Cite this article

Abstract

In this study, analogues of olomoucine, a previously described plant cytokinin analogue with cyclin-dependent kinase (CDK) inhibitory activity, were investigated for effect on CDK1 and CDK2 and for effect on cell proliferation. Eight new compounds exhibit stronger inhibitory activity on CDK1 and CDK2 and on cell proliferation than olomoucine. Some active compounds showed low inhibition of proliferation of normal myeloid growth. Improvement of inhibitory activity of known compounds with a C6-benzylamino group was brought about by substitution with one hydroxyl. Also, new C2 substituents associated with inhibitory activity on CDK and on cell proliferation are described. There was a significant correlation between effect on CDK and antiproliferative effect on the KG1 and Molt3 cell lines and on primary human lymphocytes, strongly suggesting that at least part of the antiproliferative effect of cytokinin analogues was due to inhibition of CDK activity. Cytokinin analogues induced apoptosis in a time- and concentration-dependent manner and changes in cell cycle distribution. The antiproliferative and pro-apoptotic effects of plant cytokinin analogues suggest that they are a new class of cytostatic agents and that they may find an application in the chemotherapy of cancer.

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Acknowledgements

This work was supported by the Concerted Research Action (GOA No. 21/1996) of the University of Antwerp and by the Czech Government Research Agency grants (1301/02/0475 and MSM153100008 to MS). We thank Prof David Lane (Department of Biochemistry, University of Dundee, UK) for the gift of the baculoviruses. We thank Prof W Stevens, Dr P Vermeulen and R Salgado for help with the statistical analysis of the data.

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Authors and Affiliations

  1. Laboratory of Experimental Hematology, University of Antwerp, Antwerp University Hospital, Edegem, Belgium

    K Vermeulen, A Van der Aa, M Lenjou, G Nijs, DR Van Bockstaele & ZN Berneman

  2. Laboratory of Growth Regulators, Institute of Experimental Botany, ASCR and Palacký University, Olomouc, Czech Republic

    M Strnad, V Kryštof & L Havlícěk

  3. Department of Biology, University of Antwerp, Antwerp, Belgium

    H van Onckelen

  4. Department of Cardiac Surgery, Antwerp University Hospital, Edegem, Belgium

    I Rodrigus & B Stockman

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  1. K Vermeulen
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Vermeulen, K., Strnad, M., Kryštof, V. et al. Antiproliferative effect of plant cytokinin analogues with an inhibitory activity on cyclin-dependent kinases. Leukemia 16, 299–305 (2002). https://doi.org/10.1038/sj.leu.2402378

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