title: Effects of tiflucarbine as a dual protein kinase C/calmodulin antagonist on proliferation of human keratinocytes and release of reactive oxygen species from human leukocytes.
abstract: Various studies have suggested that calmodulin (CaM) is involved in the pathophysiology of psoriasis. Protein kinase C (PKC) is also accepted as playing a regulatory role in cell proliferation as well as in inflammatory processes. Therefore, we investigated the effects of the known CaM antagonist tiflucarbine (BAY/TVX P 4495) on two cellular systems related to the major clinical symptoms of psoriasis: proliferation of cultured human keratinocytes (HaCa T cell line) and release of reactive oxygen species (ROS) from human polymorphonuclear leukocytes (PMNL). Tiflucarbine inhibited both cellular responses in a dose dependent manner. Furthermore, tiflucarbine directly affected PKC, and may thus be considered to be a dual PKC/CaM antagonist with putative antipsoriatic activity. The effects of tiflucarbine on the different parameters were compared with those of the structurally unrelated dual PKC/CaM inhibitor W-7 and those of the potent PKC inhibitor staurosporine. The potencies of all three compounds were found to be in the same range as their PKC-inhibiting potency. Our data indicate that PKC, rather than CaM, may play a regulatory role in the release of ROS as well as in keratinocyte proliferation. Therefore, inhibition of PKC in general might have a therapeutic benefit in psoriasis.
authors.affiliation: Department of Dermatology, University of Köln, Federal Republic of Germany.
authors.forename: L
authors.initials: L
authors.lastname: Hegemann
authors.forename: R
authors.initials: R
authors.lastname: Fruchtmann
authors.forename: B
authors.initials: B
authors.lastname: Bonnekoh
authors.forename: B H
authors.initials: BH
authors.lastname: Schmidt
authors.forename: J
authors.initials: J
authors.lastname: Traber
authors.forename: G
authors.initials: G
authors.lastname: Mahrle
authors.forename: R
authors.initials: R
authors.lastname: Müller-Peddinghaus
authors.forename: L A
authors.initials: LA
authors.lastname: van Rooijen
mesh_terms: D000470:Alkaloids / Q000494:pharmacology; D002147:Calmodulin / Q000037:antagonists & inhibitors*; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D015603:Keratinocytes / Q000166:cytology* / Q000378:metabolism*; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism*; D010100:Oxygen / Q000097:blood*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D019311:Staurosporine; D013449:Sulfonamides / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology*
chemical_list: D000470:Alkaloids; D002147:Calmodulin; D007211:Indoles; D013449:Sulfonamides; D013876:Thiophenes; C017967:W 7; D011493:Protein Kinase C; D019311:Staurosporine; C050288:tiflucarbine; D010100:Oxygen