Differential inhibition of the epidermal growth factor-, platelet-derived growth factor-, and protein kinase C-mediated signal transduction pathways by the staurosporine derivative CGP 41251.
The microbial alkaloid staurosporine is a potent but nonselective inhibitor of protein kinases. The derivative CGP 41251 has been shown to exert a high degree of selectivity for inhibition of protein kinase C activity. Both compounds are powerful inhibitors of proliferation of both normal and transformed cells in vitro and exert antitumor efficacy in vivo. In this work we have studied the mode of action of these compounds by analyzing their effects on early events in the induction of proliferation by different growth stimuli. Both drugs blocked the phorbol ester-induced expression of the c-fos proto-oncogene. The effect of CGP 41251 was reversible, since its removal led to a normal expression of c-fos mRNA in response to phorbol 12-myristate 13-acetate. Submicromolar concentrations of CGP 41251 and staurosporine directly inhibited both the platelet-derived growth factor (PDGF) receptor autophosphorylation and the c-fos mRNA expression induced by PDGF stimulation of intact BALB/c 3T3 cells. In contrast, ligand-induced epidermal growth factor receptor autokinase activity in A431 carcinoma cells and epidermal growth factor-dependent c-fos mRNA expression were relatively insensitive to inhibition by CGP 41251. Staurosporine suppressed signal generation by the epidermal growth factor receptor by reducing overall levels of the receptor. We conclude that CGP 41251 is a potent reversible inhibitor of protein kinase C and PDGF-mediated signal transduction. It inhibits the kinase activity of both protein kinase C and the PDGF receptor tyrosine kinase and the subsequent signaling cascade. The broad inhibition of kinases by staurosporine is also reflected at the cellular level and might contribute to the high toxicity of this compound, in comparison to CGP 41251.
Andrejauskas-Buchdunger
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Oncology and Virology Research Department, Ciba-Geigy Ltd., Basel, Switzerland.
Regenass
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D016475:3T3 Cells; D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D004815:Epidermal Growth Factor / Q000037:antagonists & inhibitors* / Q000494:pharmacology / Q000502:physiology; D015870:Gene Expression / Q000187:drug effects; D016762:Genes, fos / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors* / Q000494:pharmacology / Q000502:physiology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000494:pharmacology / Q000502:physiology; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics; D017479:Receptors, Platelet-Derived Growth Factor / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D019311:Staurosporine / Q000031:analogs & derivatives; D013268:Stimulation, Chemical; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D000470:Alkaloids; D000970:Antineoplastic Agents; D010982:Platelet-Derived Growth Factor; D012333:RNA, Messenger; D004815:Epidermal Growth Factor; D017479:Receptors, Platelet-Derived Growth Factor; D011493:Protein Kinase C; D019311:Staurosporine; C059539:midostaurin; D013755:Tetradecanoylphorbol Acetate