Differential effects of UCN-01, staurosporine and CGP 41 251 on cell cycle progression and CDC2/cyclin B1 regulation in A431 cells synchronized at M phase by nocodazole.
UCN-01 (7-hydroxystaurosporine) and CGP 41 251 (4'-N-benzoyl staurosporine), both of which were discovered as protein kinase C selective inhibitors, have entered in phase 1 clinical trials as anti-cancer drugs. In this study, we have directly compared the effects of these drugs as well as staurosporine (STP) on cell cycle progression of A431 human epidermoid carcinoma cells synchronized at M phase by treatment with nocodazole. The nocodazole-synchronized cells progressed from M to G1 phase in the absence of the drug, which was accompanied by a decrease of cyclin B1 protein expression, disappearance of the complex formation of CDC2 with cyclin B1 and reduction of the kinase activity. Treatments of the M phase cells with UCN-01, STP and CGP 41 251 at 80% growth-inhibitory concentrations (IC80S) resulted in specific G1 block, G2M block and polyploidy, respectively. Decreases of cyclin B1 protein expression was partially prevented by treatments with STP and CGP 41 251 but not with UCN-01 at IC80S. Reductions of active complex and kinase activity of CDC2/cyclin B1 were also observed in the presence of the three drugs. In addition, augmentation of CDC2 protein tyrosine phosphorylation was induced only when the cells were treated with STP. These observations demonstrated that higher concentrations of UCN-01, STP and CGP 41 251 showed different effects on cell cycle progression as well as CDC2/cyclin B1 regulation in A431 cells synchronized at M phase. The data suggest that UCN-01 and CGP 41 251 may act at quite different points on the cell cycle.
Akiyama
T
T
Pharmaceutical Research Institute, Kyowa Hakko Kogyo Co, Ltd, Shizuoka-ken, Japan.
Shimizu
M
M
Okabe
M
M
Tamaoki
T
T
Akinaga
S
S
D000470:Alkaloids / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D016203:CDC2 Protein Kinase / Q000187:drug effects / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects*; D018797:Cell Cycle Proteins / Q000187:drug effects / Q000378:metabolism; D002474:Cell-Free System; D019926:Cyclin B / Q000187:drug effects / Q000378:metabolism*; D056744:Cyclin B1; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008938:Mitosis / Q000187:drug effects; D015739:Nocodazole / Q000494:pharmacology; D010749:Phosphoprotein Phosphatases / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation; D011506:Proteins / Q000187:drug effects / Q000378:metabolism; D012878:Skin Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D019311:Staurosporine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D014443:Tyrosine / Q000378:metabolism; D020687:cdc25 Phosphatases
D000470:Alkaloids; D000970:Antineoplastic Agents; C534699:CCNB1 protein, human; D018797:Cell Cycle Proteins; D019926:Cyclin B; D056744:Cyclin B1; D004791:Enzyme Inhibitors; D011506:Proteins; D014443:Tyrosine; C054852:7-hydroxystaurosporine; D016203:CDC2 Protein Kinase; D010749:Phosphoprotein Phosphatases; D020687:cdc25 Phosphatases; D019311:Staurosporine; C059539:midostaurin; D015739:Nocodazole