Potent antagonism of calmodulin activity in vitro, but lack of antiproliferative effects on keratinocytes by the novel leukotriene biosynthesis inhibitor MK-886.
MK-886, a leukotriene biosynthesis inhibitor, which prevents the translocation and activation of 5-lipoxygenase, has been proposed as an effective drug for the treatment of inflammatory disorders, including psoriasis. In the present study, we investigated the effects of MK-886 on calmodulin as a potential target protein of anti-inflammatory drug activity, and on the proliferation of cultured human keratinocytes, a calmodulin-dependent cellular response with indicative value for antipsoriatic drug activity. Despite potent calmodulin-antagonistic activity in vitro, MK-886 failed to block cell proliferation in a human keratinocyte line, whereas trifluoperazine, a well characterized calmodulin antagonist with similar effects on calmodulin activity in our in vitro assays, inhibited cell proliferation in a dose-dependent manner. Further investigations on the mechanism of action revealed that, in contrast with trifluoperazine, calmodulin antagonism by MK-886 in vitro is likely to be mediated at the level of the allosteric calmodulin-recognition site of phosphodiesterase, rather than by binding to calmodulin itself. Therefore, our data do not conflict with the proposed role of calmodulin in the regulation of cell proliferation, but demonstrate that drug-induced antagonism of calmodulin, detected by inhibition of calmodulin-dependent enzymes in vitro, is not necessarily linked to antiproliferative activity in human keratinocytes.
Hegemann
L
L
Department of Gerontopharmacology, Troponwerke GmbH & Co., KG, Cologne, Germany.
Hatzelmann
A
A
Grewig
S
S
Schmidt
B H
BH
D002147:Calmodulin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects*; D020024:Leukotriene Antagonists; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D002722:Chlorobenzenes
D002147:Calmodulin; D007211:Indoles; D020024:Leukotriene Antagonists; D010726:Phosphodiesterase Inhibitors; C060893:MK-886; D002722:Chlorobenzenes