Inhibition of α, βI, δ, η and ζ 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.