The weak immunosuppressant cyclosporine D as well as the immunologically inactive cyclosporine H are potent inhibitors in vivo of phorbol ester TPA-induced biological effects in mouse skin and of Ca2+/calmodulin dependent EF-2 phosphorylation in vitro.
Various biological effects induced by the tumor promoting phorbol ester TPA in mouse skin are comparably suppressed by the immunologically inactive cyclosporine H (CsH) and by the strongly immunosuppressive cyclosporine A (CsA). These effects inhibited include the development of edema, stimulation of alkaline phosphatase activity, DNA and protein synthesis, as well as tumor promotion. Furthermore, CsH, like CsA, inhibits the Ca2+/calmodulin-dependent phosphorylation of the elongation factor 2 (EF-2) in vitro and the TPA-induced increases in the amount of EF-2 in vivo. Similar observations were made using the weak immunosuppressant CsD. We conclude from these results that the ability of cyclosporines to act as immunosuppressants and their ability to inhibit TPA-effects are based on two different mechanisms of action. Inhibition of TPA-effects may involve suppression of calmodulin-dependent processes, such as augmentation and phosphorylation of EF-2.
Gschwendt
M
M
German Cancer Research Center, Institute of Biochemistry, Heidelberg, F.R.G.
Kittstein
W
W
Marks
F
F
D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D016572:Cyclosporine; D003524:Cyclosporins / Q000494:pharmacology*; D003600:Cytosol / Q000378:metabolism; D004261:DNA Replication / Q000187:drug effects; D051379:Mice; D020652:Peptide Elongation Factor 2; D010445:Peptide Elongation Factors / Q000378:metabolism*; D010766:Phosphorylation; D014176:Protein Biosynthesis; D011494:Protein Kinases / Q000378:metabolism*; D012867:Skin / Q000187:drug effects / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*
D003524:Cyclosporins; D020652:Peptide Elongation Factor 2; D010445:Peptide Elongation Factors; D016572:Cyclosporine; C050026:cyclosporin D; D011494:Protein Kinases; D000469:Alkaline Phosphatase; C050025:cyclosporin H; D013755:Tetradecanoylphorbol Acetate