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Different Effects of Staurosporine, an Inhibitor of Protein Kinases, on the Cell Cycle and Chromatin Structure of Normal and Leukemic Lymphocytes¹

The Cancer Research Institute, New York Medical College Valhalla, New York 10595

Staurosporine, a microbial alkaloid, is a strong inhibitor of protein kinases. The effects of staurosporine on the cell cycle progression and nuclear morphology of normal human lymphocytes stimulated to proliferate by phytohemagglutinin were studied and compared with the effects of this drug on human lymphocytic leukemic MOLT-4 cells. Exposure of normal lymphocytes to either 5–10 or 50–100 ng/ml of staurosporine resulted in the preferential accumulation of cells in G₁ or G₁ and G₂ phases of the cell cycle, respectively. In contrast, regardless of the concentration (5–100 ng/ml), staurosporine arrested MOLT-4 cells initially in G₂; these cells then initiated additional rounds of DNA replication, without division. Staurosporine (5–100 ng/ml) induced severe changes in the nuclear morphology of MOLT-4 cells, manifested as nuclear elongation, deep invaginations of the nuclear membrane, extensive fragmentation, and micronucleation. At concentrations of 5–10 ng/ml, staurosporine had no apparent effect on the nuclear morphology of normal lymphocytes and at 50–100 ng/ml it produced minor changes in the nuclear shapes of these cells. The data indicate that the kinase(s) involved in the regulation of cell exit from G₁ and G₂, respectively, in normal and leukemic lymphocytes may have different sensitivities to staurosporine, which suggests that the mechanisms controlling exit from G₁ in these cells may be different. In MOLT-4 cells the staurosporine-sensitive kinase(s) appear to also be involved in phosphorylation of nuclear constituents essential for organization of gross chromatin structure. The different response of normal versus leukemic lymphocytes to staurosporine, if confirmed on clinical material, opens new strategies of tumor treatment.

¹ Supported by National Cancer Institute Grants R37 CA23296 and RO1 CA28704 and by the Carl Inserra Foundation. S. B., on leave from Istituto Nazionale per la Ricerca sul Cancro, Genova (Italy), was supported by a fellowship from Associazione Italiana per la Ricerca sul Cancro.

² To whom requests for reprints should be addressed, at the Cancer Research Institute, New York Medical College, Valhalla, NY 10595.

Received 3/20/91. Accepted 11/27/91.

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