BCL-2 ANTAGONIZES APOPTOTIC CELL-DEATH INDUCED BY 2 NEW CERAMIDE ANALOGS

Ceramides which arise in part from the breakdown of sphingomyelin comp rise a class of antiproliferative lipids and have been implicated in t he regulation of programmed cell death better known as apoptosis, In t he present study, two new synthetic ceramide analogues, N-thioacetylsp hingosine and FS-5, mere used in Molt 4 cells to induce cell death, Be sides their cytotoxic effects at concentrations greater than or equal to 14 mu M the data obtained clearly show that both analogues induced apoptosis at concentrations below this critical concentration as asses sed by trypan blue exclusion and cleavage of the death substrate poly- (ADP-ribose) polymerase (PARP), Additional experiments in bcl-2-transf ected Molt 4 cells revealed that the apoptotic but not the lytic effec ts of the analogues mere antagonized by the apoptosis inhibitor Bcl-2, Furthermore, neither N-thio-acetylsphingosine nor FS-5 induced PARP c leavage in bcl-2-transfected Molt 4 cells indicating that the inductio n of apoptotic cell death by cell permeable ceramides is not due to un specific disturbance of the cell membrane. (C) 1997 Federation of Euro pean Biochemical Societies.