Different effects of staurosporine, an inhibitor of protein kinases, on the cell cycle and chromatin structure of normal and leukemic lymphocytes.
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.
Bruno
S
S
Cancer Research Institute, New York Medical College, Valhalla 10595.
Ardelt
B
B
Skierski
J S
JS
Traganos
F
F
Darzynkiewicz
Z
Z
D000470:Alkaloids / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects*; D002843:Chromatin / Q000187:drug effects* / Q000648:ultrastructure; D004305:Dose-Response Relationship, Drug; D006801:Humans; D066298:In Vitro Techniques; D007938:Leukemia / Q000201:enzymology / Q000473:pathology*; D008213:Lymphocyte Activation / Q000187:drug effects; D008214:Lymphocytes / Q000187:drug effects* / Q000201:enzymology; D010835:Phytohemagglutinins; D047428:Protein Kinase Inhibitors; D019311:Staurosporine; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000470:Alkaloids; D002843:Chromatin; D010835:Phytohemagglutinins; D047428:Protein Kinase Inhibitors; D019311:Staurosporine