A new immunosuppressant, FTY720, induces bcl-2-associated apoptotic cell death in human lymphocytes. |
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| Authors: | S Suzuki X K Li S Enosawa T Shinomiya |
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| Affiliation: | Department of Experimental Surgery and Bioengineering, National Children''s Medical Research Centre, Tokyo, Japan. |
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| Abstract: | 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. |
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