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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

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Summary

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 (HaCaT 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.

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Abbreviations

CaM:

calmodulin

CL:

chemiluminescence

DMSO:

dimethyl sulfoxide

EDTA:

ethylene diamine tetraacetic acid

EGTA:

ethylene glycol-bis (Β-aminoethylether) tetraacetic acid

PBS:

Dulbecco's buffered phosphate saline

PKC:

protein kinase C

PMA:

phorbol-12-myristate-13-acetate

PMNL:

polymorphonuclear leukocytes

PS:

phosphatidylserine

ROS:

reactive oxygen species

W-7:

N-(6-aminohexyl)-5-chloro-1-naphthalene sulfonamide

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Author notes

  1. L. A. A. van Rooijen

    Present address: Pharma Research Center, Bayer AG, W-5600, Wuppertal, Germany

Authors and Affiliations

  1. Department of Dermatology, University of Köln, Köln, Germany

    L. Hegemann, B. Bonnekoh & G. Mahrle

  2. Institute for Neurobiology, Troponwerke GmbH & Co. KG, Köln, Germany

    L. Hegemann, B. H. Schmidt, J. Traber & L. A. A. van Rooijen

  3. Department of Inflammation Research, Troponwerke GmbH & Co. KG, Köln, Germany

    R. Fruchtmann & R. Müller-Peddinghaus

Authors
  1. L. Hegemann
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  2. R. Fruchtmann
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  4. B. H. Schmidt
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  5. J. Traber
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  6. G. Mahrle
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  7. R. Müller-Peddinghaus
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  8. L. A. A. van Rooijen
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Hegemann, L., Fruchtmann, R., Bonnekoh, B. et al. 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. Arch Dermatol Res 283, 456–460 (1991). https://doi.org/10.1007/BF00371782

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  • DOI: https://doi.org/10.1007/BF00371782

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