Inhibition of alpha, betaI, delta, eta, and zeta protein kinase C isoforms by xanthonolignoids.
The effect of the xanthonolignoids trans-(+/-)-kielcorin C, cis-(+/-)-kielcorin C, trans-(+/-)-kielcorin D, trans-(+/-)-isokielcorin D and trans-(+/-)-kielcorin E on isoforms alpha, betaI, delta, eta and zeta of protein kinase C (PKC) was studied using the yeast phenotypic assay. All the compounds tested revealed an effect compatible with PKC inhibition, similar to that exhibited by the well established PKC inhibitor chelerythrine, and with differences in their potency towards the distinct isoforms tested, being, in general, potent inhibitors of the atypical PKC isoform (PKC-zeta). PKC inhibition caused by these kielcorins was confirmed using an in vitro kinase assay. The present study constitutes the first attempt to unravel the molecular mechanism of kielcorins activity, and shows that xanthonolignoids are a promising group of compounds to investigate for isoform selective PKC inhibitors.
Servico de Farmacologia, CEQOFFUP, Faculdade de Farmácia, Universidade do Porto, rua Aníbal Cunha, 164, 4050-047 Porto, Portugal.
Lucília
L
Saraiva
Paula
P
Fresco
Eugénia
E
Pinto
Emília
E
Sousa
Madalena
M
Pinto
Jorge
J
Gonçalves
D000470:Alkaloids; D000818:Animals; D016718:Arachidonic Acid / Q000494:pharmacology; D053119:Benzophenanthridines; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D010617:Phenanthridines / Q000737:chemistry / 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; D051381:Rats; D044004:Xanthones / Q000737:chemistry* / Q000494:pharmacology*; D015003:Yeasts / Q000187:drug effects / Q000378:metabolism; D000099221:Protein Kinase C zeta
D000470:Alkaloids; D016718:Arachidonic Acid; D053119:Benzophenanthridines; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D010617:Phenanthridines; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D051571:Protein Kinase C-alpha; D051745:Protein Kinase C-delta; D044004:Xanthones; D000099221:Protein Kinase C zeta; C016299:chelerythrine; C497260:Prkcd protein, rat; C081975:protein kinase C eta