Differential inhibition of cytosolic and membrane-derived protein kinase C activity by staurosporine and other kinase inhibitors.
The hypothesis was tested that 9 kinase inhibitors with diverse specificities for protein kinase C (PKC), including staurosporine and four of its analogues, interfere differently with PKC derived from either the cytosolic or particulate fractions of MCF-7 breast carcinoma cells. GF 109203X inhibited the enzyme identically in either preparation. CGP 41251 and calphostin C inhibited cytosolic PKC more effectively than membrane-derived PKC with ratios of IC50 (cytosolic PKC) over IC50 (membrane-derived PKC) of 0.07 and 0.04, respectively. The other six agents inhibited membrane-derived PKC more potently than cytosolic enzyme. Staurosporine and RO 31 8220 exhibited IC50 ratios of 12.3 and 21.6, respectively. The results suggest that there are dramatic differences between kinase inhibitors in their divergent effects on cytosolic and membrane-derived PKC which should be borne in mind in the interpretation of their pharmacological properties.
Budworth
J
J
Medical Research Council Toxicology Unit, University of Leicester, UK.
Gescher
A
A
D000470:Alkaloids / Q000494:pharmacology*; D001943:Breast Neoplasms; D002462:Cell Membrane / Q000201:enzymology*; D003600:Cytosol / Q000201:enzymology*; D006801:Humans; D015151:Immunoblotting; D007211:Indoles / Q000494:pharmacology; D009281:Naphthalenes; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D011083:Polycyclic Compounds / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019311:Staurosporine / Q000031:analogs & derivatives; D014407:Tumor Cells, Cultured
D000470:Alkaloids; D007211:Indoles; D009281:Naphthalenes; D011083:Polycyclic Compounds; D015240:Phorbol 12,13-Dibutyrate; D011493:Protein Kinase C; D019311:Staurosporine; C058819:calphostin C; C059539:midostaurin; C064758:Ro 31-8220