title: Staurosporine, a novel protein kinase inhibitor, enhances HL-60-cell differentiation induced by various compounds.
abstract: The effect of staurosporine, a novel calcium/phospholipid-dependent protein kinase (protein kinase C) inhibitor, on differentiation of human promyelocytic leukemic HL-60 cells, was investigated. Staurosporine inhibited HL-60-cell proliferation in a concentration-dependent manner, but did not induce HL-60-cell differentiation by itself. When staurosporine was added to HL-60 cells treated with a suboptimal concentration (1 nM) of 1 alpha,25 dihydroxyvitamin D3 (1,25(OH)2D3), cell differentiation was enhanced in a concentration-dependent manner and the percentages of nitro blue tetrazolium reducing ability and nonspecific esterase activity-positive cells increased from 6% to 51% and from 8% to 54%, respectively, on day 4 at a concentration of 5 nM. Staurosporine (5 nM) achieved almost the same enhancement effect in cultures treated with suboptimal concentrations of 1 nM all-trans-beta-retinoic acid (RA), 3 ng/ml actinomycin D (Act D), 100 microM dibutyryl cyclic adenosine 3':5'-monophosphate (dbc AMP), and 50 microM prostaglandin E1 (PG E1). These results suggest that the inhibition of protein kinase C activity by staurosporine exerts an important role in HL-60-cell differentiation induced by various compounds. Moreover, staurosporine (5 nM) completely inhibited optimal concentrations (50 nM) of [12-o-tetradecanoyl phorbol-13-acetate (TPA)]-induced cell differentiation, but enhanced optimal concentrations of dbc AMP (1 mM)-induced cell differentiation. On the other hand, 1-(5-isoquinolinyl-sulfonyl)-2-methylpiperazine, which has been reported to inhibit cyclic adenosine 3':5'-monophosphate-dependent protein kinase (protein kinase A) as much as protein kinase C, completely inhibited both cell differentiations induced by optimal concentrations of TPA (50 nM) and induced by optimal concentrations of dbc AMP (1 mM), and did not significantly enhance HL-60-cell differentiation induced by suboptimal concentrations of 1,25(OH)2D3, RA, and dbc AMP. Therefore, these results suggest that the inhibition of protein kinase C, which is not accompanied by that of protein kinase A, is concerned with the induction of HL-60-cell differentiation.
authors.affiliation: Department of Internal Medicine, Faculty of Medicine, Kyoto University, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Okazaki
authors.forename: Y
authors.initials: Y
authors.lastname: Kato
authors.forename: T
authors.initials: T
authors.lastname: Mochizuki
authors.forename: M
authors.initials: M
authors.lastname: Tashima
authors.forename: H
authors.initials: H
authors.lastname: Sawada
authors.forename: H
authors.initials: H
authors.lastname: Uchino
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000470:Alkaloids / Q000494:pharmacology*; D003994:Bucladesine / Q000494:pharmacology; D002117:Calcitriol / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D019311:Staurosporine; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014212:Tretinoin / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000166:cytology*
chemical_list: D000470:Alkaloids; D007546:Isoquinolines; D010879:Piperazines; D014212:Tretinoin; D003994:Bucladesine; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D011493:Protein Kinase C; D002117:Calcitriol; D019311:Staurosporine; D013755:Tetradecanoylphorbol Acetate