SCH 47112, a novel staurosporine derivative, inhibits 12-O-tetradecanoylphorbol-13-acetate-induced inflammation and epidermal hyperplasia in hairless mouse skin.

Abstract

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.

• Authors: N J Reynolds, S W McCombie, B B Shankar, W R Bishop, G J Fisher
• Journal: Archives of dermatological research (Arch Dermatol Res) Vol. 289 Issue 9 Pg. 540-6 (Aug 1997) ISSN: 0340-3696 [Print] Germany
• PMID: 9341975 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Anti-Inflammatory Agents
• Enzyme Inhibitors
• SCH 47112
• Protein Kinase C
• Staurosporine
• Tetradecanoylphorbol Acetate

Topics

• Animals
• Anti-Inflammatory Agents (pharmacology)
• Cells, Cultured
• Enzyme Inhibitors (pharmacology)
• Epidermis (pathology)
• Humans
• Hyperplasia
• Keratinocytes (drug effects)
• Male
• Mice
• Mice, Hairless
• Molecular Structure
• Protein Kinase C (antagonists & inhibitors)
• Staurosporine (analogs & derivatives, pharmacology)
• Tetradecanoylphorbol Acetate (pharmacology)