Cyclosporin G inhibits proliferation of A431 cells in a dose- and time-dependent manner comparable to cyclosporin A.
Cyclosporin A (CyA), a fungal metabolite with potent immunosuppressive activity and an antiproliferative effect on epithelial cells, i.e. normal and transformed keratinocytes, is currently proposed in the treatment of psoriasis, where its use is limited mainly by possible nephrotoxicity and/or hepatotoxicity. Numerous analogs of CyA have been produced and studied. The most promising of these is the immunosuppressive analog cyclosporin G (CyG), in which norvaline is substituted for alpha-aminobutyric acid at the 2 position. This would maintain strong immunological activity, with reduced to absent nephrotoxic and hepatotoxic effects. The authors compared the antiproliferative effect of CyG and CyA on the epidermoid carcinoma cell line A431 in vitro, performing the MTT-microculture tetrazolium colorimetric assay based on the ability of viable cells to reduce the MTT compound to a blue formazan product. Subconfluent A431 cells were incubated with CyA or CyG or solvent only, for 24, 48, 72 or 96 h at concentrations of in vivo relevance (0.3, 0.6, 1.25, 2.5, 5, 7.5, 10 micrograms/ml). CyA and CyG showed similar antiproliferative effects, in low-serum-containing media in a dose- and time-dependent manner. After 24 h of incubation, the inhibition of the growth rate was irrelevant. A striking inhibition of the growth rate at the higher concentrations of the drugs (7.5 and 10 micrograms/ml) at 72 and 96 h of incubation was evident. Therefore CyG has been demonstrated to exercise an antiproliferative effect on the A431 cell line. These data suggest possible use for CyG in the treatment of immune-mediated disease, particularly in the treatment of dermatologic diseases characterized by epidermal hyperplasia and/or keratinocyte hyperproliferation.
Teofoli
P
P
Department of Immunodermatology, IDI, (IRCCS) Rome, Italy. teofoli@idi.it
De Pità
O
O
Lotti
T M
TM
D002455:Cell Division / Q000187:drug effects; D002461:Cell Line, Transformed; D003124:Colorimetry; D016572:Cyclosporine / Q000493:pharmacokinetics / Q000494:pharmacology*; D005562:Formazans; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D007700:Kinetics; D013778:Tetrazolium Salts
D005562:Formazans; D007166:Immunosuppressive Agents; D013778:Tetrazolium Salts; C079782:MTT formazan; C045571:cyclosporin G; D016572:Cyclosporine