Coordinate Involvement of Cell Cycle Arrest and Apoptosis Strengthen the Effect of FTY720

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Abstract
A novel reagent, FTY720 (2‐amino‐2‐[2‐(4‐octylphenyl)ethyl]‐l,3‐propanediol hydrochloride), has been shown to induce a significant decrease of lymphocytes and lymphoma cells and is expected to be a potent immunosuppressant and anti‐tumor drug. The decrease in lymphocytes and lymphoma cells is mainly the result of FTY720‐induced apoptosis. FTY720 directly affects mitochondria and induces cell death. Moreover, FTY720 activates protein phosphatase (PP) 2A and affects anti‐apo‐ptotic intracellular signal transduction proteins to attenuate the anti‐apoptotic effect. In this study, we examined the relationship between FTY720‐induced apoptosis and cell cycle regulation. FTY720 induced apoptosis significantly at the GO/G1 phase and caused GO/G1 cell cycle arrest of the human lymphoma cell lines HL‐60RG and Jurkat. Simultaneously, retinoblastoma protein (pRB) was dephosphorylated, suggesting that dephosphorylation of pRB was related to FTY720‐induced GO/G1 cell cycle arrest. Because this dephosphorylation was completely blocked by a specific PP1/ 2A inhibitor, okadaic acid, it appears that FTY720‐activated PP2A is essential for FTY720‐induced cell cycle arrest. FTY720‐induced apoptosis was inhibited by Bcl‐2 overexpression in Jurkat cells, but this did not prevent FTY720‐induced cell cycle arrest, suggesting that the mechanism of FTY720‐induced cell cycle arrest is independent of the mechanism of FTY720‐induced apoptosis. These two independent pathways strengthen the effect of FTY720.