Cellular effects of olomoucine, an inhibitor of cyclin-dependent kinases

• Published in: Biology of the cell 1995, Vol.83 (2), p.105-120
• Main Authors: Abraham, RT, Acquarone, M, Andersen, A, Asensi, A, Bellé, R, Berger, F, Bergounioux, C, Brunn, G, Buquet-Fagot, C, Fagot, D, Glab, N, Goudeau, H, Goudeau, M, Guerrier, P, Houghton, P, Hendriks, H, Kloareg, B, Lippai, M, Marie, D, Maro, B, Meijer, L, Mester, J, Mulner-Lorillon, O, Poulet, SA, Schierenberg, E, Schutte, B, Vaulot, D, Verlhac, MH
• Format: Article
• Language: English
• Subjects: 2-(2-hydroxyethylamino)-6-benzylamino-9-methylpurine; Animals; Biological and medical sciences; cdc2; cdk1; cdk2; cell cycle; Cell Cycle - drug effects; Cell cycle, cell proliferation; Cell physiology; cyclin-dependent kinases; Cyclin-Dependent Kinases - antagonists & inhibitors; Enzyme Inhibitors - pharmacology; Fundamental and applied biological sciences. Psychology; Growth Inhibitors - pharmacology; Humans; In Vitro Techniques; Kinetin; Lymphocyte Activation - drug effects; Mitosis - drug effects; Molecular and cellular biology; olomoucine; Oocytes - drug effects; proliferation; protein kinases; purines; Purines - pharmacology; T-Lymphocytes - drug effects; Tumor Cells, Cultured - drug effects
• ISSN: 0248-4900; 1768-322X
• DOI: 10.1016/0248-4900(96)81298-6

Olomoucine (2-(2-hydroxyethylamino)-6-benzylamino-9-methylpurine) has been recently described as a competitive inhibitor (ATP-binding site) of the cell cycle regulating p34 cdc2/cyclin B, p33 cdk2/cyclin A and p33 cdk2/cyclin E kinases, the brain p33 cdk5 p35 kinase and the ERK1 AP -kinase . The unusual specificity of this compound towards cell cycle regulating enzymes suggests that it could inhibit certain steps of the cell cycle. The cellular effects of olomoucine were investigated in a large variety of plant and animal models. This compound inhibits the G1 S transition of unicellular algae (dinoflagellate and diatom). It blocks Fucus zygote cleavage and development of Laminaria gametophytes. Stimulated Petunia mesophyl protoplasts are arrested in G1 by olomoucine. By arresting cleavage it blocks the development of Calanus copepod larvae. It reversibly inhibits the early cleavages of Caenorhabditis elegans embryos and those of ascidian embryos. Olomoucine inhibits the serotonin-induced prophase/metaphase transition of clam oocytes; furthermore, it triggers the release of these oocytes from their meiotic metaphase I arrest, and induces nuclei reformation. Olomoucine slows down the prophase/metaphase transition in cleaving sea urchin embryos, but does not affect the duration of the metaphase/anaphase and anaphase/telophase transitions. It also inhibits the prophase/metaphase transition of starfish oocytes triggered by various agonists. Xenopus oocyte maturation, the in vivo and in vitro phosphorylation of elongation factor EF-1 are inhibited by olomoucine. Mouse oocyte maturation is delayed by this compound, whereas parthenogenetic release from metaphase II arrest is facilitated. Growth of a variety of human cell lines (rhabdomyosarcoma cell lines Rh1, Rh18, Rh28 and Rh30; MCF-7, KB-3-1 and their adriamycin-resistant counterparts; National Cancer Institute 60 human tumor cell lines comprising nine tumor types) is inhibited by olomoucine. Cell cycle parameter analysis of the non-small cell lung cancer cell line MR65 shows that olomoucine affects G1 and S phase transits. Olomoucine inhibits DNA synthesis in interleukin-2-stimulated T lymphocytes (CTLL-2 cells) and triggers a G1 arrest similar to interleukin-2 deprivation. Both cdc2 and cdk2 kinases (immunoprecipitated from nocodazole- and hydroxyurea-treated CTLL-2 cells, respectively) are inhibited by olomoucine. Both yeast and Drosophila embryos were insensitive to olomoucine. Taken together the results of