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 differentiation as well as inflammation in skin, processes which are abnormal in skin diseases such as psoriasis. 12-O-tetradecanoylphorbol-13-acetate (TPA) binds to and activates PKC. We investigated the effects of SCH 47112, a novel staurosporine derivative, which interacts with the catalytic domain of PKC, on TPA-induced inflammation and hyperplasia in hairless mouse skin and TPA-induced differentiation in cultured human keratinocytes. Dorsal mouse skin was treated with vehicle, TPA (2.0/ 2.5 nmol) or SCH 47112 followed by TPA. Epidermal thickness, and epidermal, upper dermal and deep dermal inflammation (assessed on an ordinal semiquantitative scale) were determined in biopsies taken 24 h and 48 h post-treatment. SCH 47112 (100 nmol) inhibited TPA-induced epidermal, upper dermal and deep dermal inflammation by 71%, 45% and 22%, respectively, at 24 h (n = 3, P < 0.05). TPA-induced epidermal hyperplasia was inhibited 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 induction 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 that PKC inhibitors may have a therapeutic role in inflammatory skin diseases.
Reynolds
N J
NJ
Department of Dermatology, University of Michigan Medical School, Ann Arbor 48109-0609, USA.
McCombie
S W
SW
Shankar
B B
BB
Bishop
W R
WR
Fisher
G J
GJ
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004817:Epidermis / Q000473:pathology; D006801:Humans; D006965:Hyperplasia; D015603:Keratinocytes / Q000187:drug effects; D008297:Male; D051379:Mice; D008812:Mice, Hairless; D015394:Molecular Structure; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D019311:Staurosporine / Q000031:analogs & derivatives* / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*
D000893:Anti-Inflammatory Agents; D004791:Enzyme Inhibitors; C109299:SCH 47112; D011493:Protein Kinase C; D019311:Staurosporine; D013755:Tetradecanoylphorbol Acetate