Lack of an effect of novel inhibitors with high specificity for protein kinase C on the action of the phorbol ester 12-O-tetradecanoylphorbol-13-acetate on mouse skin in vivo

Abstract

The inhibitory effects of three novel staurosporine-derived compounds were tested with five different types of protein kinases, including protein kinase C (PKC). IC₅₀ values of two of these compounds were found to be 300 to ≻5000 times lower for PKCαβγ (a mixture of the PKC isoeiviymes α, β and γ) than for any of the other protein kinases. The inhibitory action of the most selective inhibitor was tested also with the Ca²⁺-unresponsive PKC isoenzyme δ and was found to suppress PKCαβγ and PKC differentially. The highly specific PKC inhibitors are active both in cell culture and in vivo. They inhibit the PKC-catalyzed phosphoryla tion of the specific PKC substrate MARCKS in Swiss-3T3 fibroblasts and the okadaic acid-induced edema of the mouse ear. However, the more complex biological processes triggered by the phorbol ester 12-O-tetradecanoylphorbol-13-acetate in mouse skin, such as Inflammation, stimulation of cellular hyperproliferation and tumor promotion, remain largely unaffected upon topical application of these com pounds.