Differential inhibition by staurosporine, a potent protein kinase C inhibitor, of 12-O-tetradecanoylphorbol-13-acetate-caused skin tumor promotion, epidermal ornithine decarboxylase induction, hyperplasia and inflammation.
The effect of staurosporine on 7,12-dimethylbenz[a]anthracene (DMBA)-initiated and 12-O-tetradecanoylphorbol-13-acetate (TPA)-promoted skin papilloma formation was examined in CD-1 mice. A topical application of staurosporine 15 min prior to each TPA treatment resulted in a dose-related inhibition of tumor formation. Staurosporine by itself had no tumor producing activity in DMBA-initiated mice. Staurosporine failed to prevent TPA-induced edema formation, whereas quercetin markedly suppressed it. Staurosporine by itself did not induce a significant edema. Histological studies revealed that staurosporine failed to inhibit TPA-induced inflammation but rather augmented TPA-induced polymorphonuclear leukocyte (PMN) infiltration. Staurosporine by itself induced a slight PMN infiltration 1 h after the drug application, but the effect was only transient. Although staurosporine failed to inhibit the TPA-induced epidermal hyperplasia and DNA synthesis significantly, nuclear atypism of the superficial layer of the epidermis appeared to be less remarkable in staurosporine-pretreated mice. TPA-caused epidermal ornithine decarboxylase (ODC) induction was not inhibited by staurosporine but rather augmented by this agent. TPA enhanced the phosphorylation of 34 kd protein in intact epidermal cells in a concentration-dependent manner. Staurosporine and 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H-7) suppressed the TPA-stimulated phosphorylation of 34 kd protein, but palmitoylcarnitine failed to suppress it. In addition, TPA-stimulated superoxide generation of rabbit peritoneal PMN was potently inhibited by staurosporine. It is possible that TPA induces inflammation, ODC activity, epidermal hyperplasia and tumor promotion through the activation of different type(s) of protein kinase C and staurosporine inhibits only certain type(s) of protein kinase C. Another possible explanation is that the protein kinase C inhibition by staurosporine depends on the nature of the substrate proteins or the intracellular localization of the enzyme.
Yamamoto
S
S
Department of Pharmacology, School of Medicine, Keio University, Tokyo, Japan.
Kiyoto
I
I
Aizu
E
E
Nakadate
T
T
Hosoda
Y
Y
Kato
R
R
D015127:9,10-Dimethyl-1,2-benzanthracene; D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D004487:Edema; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D006965:Hyperplasia; D007249:Inflammation; D007700:Kinetics; D051379:Mice; D008815:Mice, Inbred Strains; D009955:Ornithine Decarboxylase / Q000096:biosynthesis*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D012016:Reference Values; D012867:Skin / Q000187:drug effects / Q000473:pathology*; D012878:Skin Neoplasms / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D019311:Staurosporine; D013481:Superoxides / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity*
D000470:Alkaloids; D013481:Superoxides; D015127:9,10-Dimethyl-1,2-benzanthracene; D011493:Protein Kinase C; D009955:Ornithine Decarboxylase; D019311:Staurosporine; D013755:Tetradecanoylphorbol Acetate