Coordinate involvement of cell cycle arrest and apoptosis strengthen the effect of FTY720

A novel reagent, FTY720 (2-amino-2-[2-(4-octylphenyl)ethyl]-1,3-propanediol hydrorhloride), has been shown to induce a significant decrease of lymphoc ytes and lymphoma cells and is expected to be a potent immunosuppressant an d anti-tumor drug. The decrease in lymphocytes and lymphoma cells is mainly the result of FTY720-indured apoptosis, FTY720 directly affects mitochondr ia and induces cell death. Moreover, FTY720 activates protein phosphatase I PP) 2A and affects anti-apoptotic intracellular signal transduction protein s to attenuate the anti-apoptotic effect. III this study, we examined the r elationship between FTY720-induced apoptosis and cell cycle regulation. FTY 720 induced apoptosis significantly at the G0/G1 phase and caused G0/G1 cel l cycle arrest of the human lymphoma cell lines HL-60RG and Jurkat, Simulta neously, retinoblastoma protein (pRB) was dephosphorylated, suggesting that dephosphorylation of pRB was related to FTY720-inductd G0/G1 cell cycle ar rest. Because this dephosphorylation was completely blocked by a specific P P1/2A inhibitor, okadaic acid, it appears that FTY720-artivated PP2A is ess ential for FTY720-induccd cell cycle arrest. FTY720-induced apoptosis was i nhibited by Bcl-2 overexpression in Jurkat cells, but this did not prevent FTY720-induced cell cycle arrest, suggesting that the mechanism of FTY720-i nduced cell cycle arrest is independent of the mechanism of FTY720-induced apoptosis, These two independent pathways strengthen the effect of FTY720.