Isoform-selectivity of PKC inhibitors acting at the regulatory and catalytic domain of mammalian PKC-alpha, -betaI, -delta, -eta and -zeta.
The aim of the present study was to compare the potency of a series of widely used PKC inhibitors acting either at the regulatory (NPC 15437, tamoxifen and D-sphingosine) or at the catalytic domain (Ro 32-0432, chelerythrine and rottlerin) on individual mammalian PKC isoforms of the classical (alpha and betaI), novel (delta and eta) and atypical (zeta) PKC families, using the yeast phenotypic assay, in order to determine their isoform-selectivity. The PKC inhibitors studied presented differences in their ability to reduce the effect of the appropriate PKC activator (estimated as EC50 ratios) which was interpreted as an index of PKC inhibitory potency. In general, the more marked inhibition was observed on novel PKC isoforms, particularly on PKC-eta. This study indicates promising isoform-selectivity of some PKC inhibitors, namely NPC 15437 for PKC-eta or rottlerin for both novel PKC isoforms. It also suggests that the PKC domain involved in the inhibition does not seem to be relevant for the potency and isoform-selectivity of PKC inhibitors.
Serviço de Farmacologia e, CEQOFFUP, Faculdade de Farmácia, Universidade do Porto, rua Anibal Cunha, 164, 4050-047 Porto, Portugal.
Lucília
L
Saraiva
Paula
P
Fresco
Eugénia
E
Pinto
Jorge
J
Gonçalves
D000098:Acetophenones / Q000494:pharmacology; D000470:Alkaloids; D000818:Animals; D053119:Benzophenanthridines; D001578:Benzopyrans / Q000494:pharmacology; D002384:Catalysis; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004926:Escherichia coli / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D010617:Phenanthridines / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000378:metabolism; D064546:Protein Kinase C beta; D051571:Protein Kinase C-alpha; D051745:Protein Kinase C-delta; D011758:Pyrroles / Q000494:pharmacology; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D013110:Sphingosine / Q000494:pharmacology; D013629:Tamoxifen / Q000494:pharmacology; D015003:Yeasts / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D000099221:Protein Kinase C zeta
D000098:Acetophenones; D000470:Alkaloids; D053119:Benzophenanthridines; D001578:Benzopyrans; D004791:Enzyme Inhibitors; D007211:Indoles; D007527:Isoenzymes; D010617:Phenanthridines; D010880:Piperidines; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D051571:Protein Kinase C-alpha; D051745:Protein Kinase C-delta; D011758:Pyrroles; D013110:Sphingosine; D013629:Tamoxifen; D000099221:Protein Kinase C zeta; C069701:NPC 15437; C085989:Ro 32-0432; C085746:rottlerin; C016299:chelerythrine; C081975:protein kinase C eta