Effect of cyclosporins A, G, and H on normal and ichthyotic keratinocyte growth in culture

Abstract

Cyclosporin A (CsA) was first used in organ transplantation and for the treatment of autoimmune disorders because of its strong immunosuppressant properties. Several laboratory studies have demonstrated that CsA exerts an inhibitory action on the growth of various cell types in culture, including human skin cells. Such an influence on epidermal keratinocytes, if not associated with the serious adverse effects of CsA medication, would be of interest for the treatment of hyperproliferative genodermatoses such as non-bullous congenital ichthyotic erythroderma (NBCIE). In our study, we used cyclosporin G (CsG) and H (CsH), analogues CsA, to examine the impact of these three cyclosporins on normal and ichthyotic keratinocyte growth in vitro. Epidermal cells were grown in a low-calcium, serum-free medium in the presence or absence of cyclosporins A, G or H (1-10 micrograms/ml). The effects of a 72-h exposure to the drugs were evaluated by cell counting, 3H-thymidine incorporation and cytofluorimetric analysis of the BrdU-labelled cell suspensions. Our findings indicate a dose-dependent keratinocyte growth inhibition by the three cyclosporins. The data obtained with the three quantitation methods were in agreement and the cyclosporin-mediated effects were observed in both normal and ichthyotic keratinocyte cultures. CsG and CsH proved less effective than CsA, which induced a highly significant reduction even at 1 microgram/ml. Our results suggest, however, that ichthyotic keratinocytes are more sensitive to CsG and H when compared with normal cells (50% inhibition of 3H-thymidine uptake at significantly lower doses). A possible therapeutic action of non-toxic doses of CsG and CsH on NBCIE and other hyperproliferative epidermal diseases needs to be confirmed clinically.