SCH-47112, A NOVEL STAUROSPORINE DERIVATIVE, INHIBITS 12-O-TETRADECANOYLPHORBOL-13-ACETATE-INDUCED INFLAMMATION AND EPIDERMAL HYPERPLASIA IN HAIRLESS MOUSE SKIN

Protein kinase C (PKC) regulates keratinocyte growth and differentiati on as well as inflammation in skin, processes which are abnormal in sk in diseases such as psoriasis, 12-O-tetradecanoylphorbol-13-acetate (T PA) binds to and activates PKC, We investigated the effects of SCH 471 12, a novel staurosporine derivative, which interacts with the catalyt ic domain of PKC, on TPA-induced inflammation and hyperplasia in hairl ess mouse skin and TPA-induced differentiation in cultured human kerat inocytes, Dorsal mouse skin was treated with vehicle, TPA (2.0/2.5 nmo l) or SCH 47112 followed by TPA, Epidermal thickness, and epidermal, u pper dermal and deep dermal inflammation (assessed on an ordinal semiq uantitative scale) were determined in biopsies taken 24 h and 48 h pos t-treatment, SCH 47112 (100 nmol) inhibited TPA-induced epidermal, upp er dermal and deep dermal inflammation by 71%, 45% and 22%, respective ly, at 24 h (n = 3, P < 0.05), TPA-induced epidermal hyperplasia was i nhibited by SCH 47112 (400 nmol) by 38% at 48 h (n = 3, P < 0.05), In addition, in cultured human keratinocytes, SCH 47112 inhibited TPA ind uction of transglutaminase I protein, which catalyzes the formation of crosslinked envelopes, These results indicate that SCH 47112 exhibits biological activity, inhibiting TPA-induced changes in hairless mouse skin in vivo and cultured human keratinocytes in vitro, and suggest t hat PKC inhibitors may have a therapeutic role in inflammatory skin di seases.