THE ANTIPROLIFERATIVE EFFECT OF CYCLOSPORINE ON HEMATOPOIETIC AND LYMPHOBLASTOID CELL LINES‐COMMON MECHANISTIC ELEMENTS WITH INTERFERON‐ALPHA

Cyclosporine, but not its nonimmunosuppressive analog cyclosporine H (CsH), caused in a variety of hematopoietic cell types a growth arrest in the G0/G1 phase of the cell cycle. This arrest was associated with a significant reduction in the c-myc mRNA levels, which could be observed already 1 hr following CsA treatment. Similarity between the antiproliferative effects of CsA and IFN-α was observed. Thus, the IFN-α sensitive human B-lymphoblastoid cell line Daudi was also sensitive to CsA while an IFN-α resistant variant of Daudi cells was found to be resistant to CsA as well. Inhibition of protein synthesis with cycloheximide during IFN-α or CsA treatment blocked their ability to reduce the expression of c-myc. Depletion of protein kinase C (PKC) activity from cells by pretreatment of Daudi cells with phorbol-12-myristate 13-acetate (PMA) abolished the G0/G1 arrest induced by both CsA and IFN-α. Combinations of low concentrations of CsA and IFN-α had synergistic effects on cell-cycle distribution and on c-myc mRNA level, suggesting that CsA and IFN-α differ in some features of their antiproliferative action. This conclusion was supported by the observation that a CsA-resistant variant of Daudi cells was found to retain its sensitivity to IFN-α. In addition, reduction of ornithine decarboxylase mRNA expression was obtained with IFN-α but not with CsA. Taken together, our results suggest that CsA and IFN-α share some common element(s) in the pathways of their antiproliferative activity. The possible mechanisms of their antigrowth effects and the clinical significance of our findings are discussed.