Growth inhibitory effects of FK506 and cyclosporin A independent of inhibition of calcineurin.
The ability of the immunosuppressive agent FK506 to affect growth of the epidermal growth factor-receptor (EGF-R) overexpressing cell line, A431, was compared with that of the structurally unrelated immunosuppressive compound, cyclosporin A (CyA). Both were shown to inhibit growth, although neither of them caused down-regulation of the EGF-R or affected epidermal growth factor (EGF)-induced tyrosine phosphorylation of the EGF-R. Inhibition of growth was not specific to EGF-R pathways, as both FK506 and CyA also inhibited EGF- and platelet-derived growth factor (PDGF)-induced DNA synthesis in fibroblasts. In all assays FK506 was less potent than CyA even though it is 10-100 times more potent as an immunosuppressive agent. The role of calcineurin in CyA- or FK506-induced growth inhibition was investigated using the synthetic pyrethroid insecticides: cypermethrin, deltamethrin and fenvalerate, which are known calcineurin inhibitors. Failure of these agents to block cell growth or influence growth factor-induced mitogenesis indicated that the biochemical pathway(s) by which CyA or FK506 inhibited cell growth did not depend solely on inhibition of calcineurin.
Richter
A
A
CRC Medical Oncology Unit, Southampton General Hospital, U.K.
Davies
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DE
Alexander
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P
D019703:Calcineurin; D002148:Calmodulin-Binding Proteins / Q000037:antagonists & inhibitors*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology*; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000378:metabolism*; D008934:Mitogens / Q000494:pharmacology; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors*; D010766:Phosphorylation; D011722:Pyrethrins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D016559:Tacrolimus / Q000494:pharmacology*
D002148:Calmodulin-Binding Proteins; D008934:Mitogens; D011722:Pyrethrins; D004815:Epidermal Growth Factor; D016572:Cyclosporine; D066246:ErbB Receptors; D019703:Calcineurin; D010749:Phosphoprotein Phosphatases; D016559:Tacrolimus