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.
Suzuki
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Department of Experimental Surgery and Bioengineering, National Children's Medical Research Centre, Tokyo, Japan.
Li
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Enosawa
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Shinomiya
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D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D000068876:Fingolimod Hydrochloride; D015870:Gene Expression; D019254:Genes, bcl-2; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007424:Intracellular Fluid / Q000378:metabolism; D019169:Jurkat Cells; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000502:physiology*; D011409:Propylene Glycols / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2; D013110:Sphingosine / Q000031:analogs & derivatives; D014162:Transfection; D051028:bcl-2-Associated X Protein
C494826:BAX protein, human; D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine