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A new immunosuppressant, FTY720, induces bcl‐2‐associated apoptotic cell death in human lymphocytes

FTY720 is a unique immunosuppressive drug produced by modification of a metabolite from Isaria sinclairii. In vitro treatment of human mononuclear cells with FTY720 resulted in a dose‐dependent reduction of cell viability. These treated cells demonstrated characteristic DNA ladder formation on agarose gel electrophoresis. Jurkat cells transfected with human bcl‐2 gene were resistant to FTY720; their neo type was susceptible to the drug. A rapid acceleration of cell death in human mononuclear cells was seen as early as 2 hr after incubation with FTY720. The intracellular Bax protein increased remarkably 1 hr after the culture; it markedly decreased in the surviving cells at 2 and 3 hr. Coincidental to the Bax decrease, Bcl‐2 progressively decreased beginning 2 hr after the culture. Thus, the ratio of Bcl‐2 to Bax was decreased by the enhanced expression of Bax immediately after FTY720‐treatment, resulting in rapid cell death acceleration. The surviving cells (FTY720‐resistant cells) at 2 and 3 hr after culture showed a similar ratio of Bcl‐2 to Bax as was observed in the control cells. These results suggest that FTY720 displays bcl‐2‐associated apoptotic cell death in human mononuclear cells.