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

Abstract

A novel reagent, FTY720 (2-amino-2-[2-(4-octylphenyl)ethyl]-1,3-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-apoptotic 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 G0/G1 phase and caused G0/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 G0/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.

FTY720 produces caspase-independent cell death of acute lymphoblastic leukemia cells

“…This explains why a very small amount of PARP cleavage is present in Figure 2C. While this caspase-independent mechanism contrasts with a number of reports, [15][16][17]19,20 caspase-independent cell death has also been reported in chronic lymphocytic leukemia and mantle cell lymphoma. 21,22 FTY720 has been shown to mediate its antimalignant effect through mechanisms other than the binding of its phosphorylated form to the S1P 1 receptor.…”

Pharmacokinetics and Cell Trafficking Dynamics of 2-Amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol Hydrochloride (FTY720) in Cynomolgus Monkeys after Single Oral and Intravenous Doses

“…Diverse pharmacological mechanisms of action were found for FTY720: it can produce cell cycle arrest of lymphocytes (Nagahara et al, 2001), and it can alter production (Yagi et al, 2000), trafficking (Chiba et al, 1998;Brinkmann et al, 2000Brinkmann et al, , 2001Pinschewer et al, 2000), infiltration (Yanagawa et al, 2000), and apoptosis (Enosawa et al, 1996;Bohler at al., 2000;Nagahara et al, 2000) of lymphocytes. Perplexities about FTY720 regarding preclinical and clinical data include that the maximum effects of FTY720 on cell trafficking were achieved at doses smaller than those producing protection This research was supported by Novartis Pharma AG, Basel, Switzerland, and by Grant GM24211 from the National Institute of General Medical Sciences, National Institutes of Health.…”

FTY720 demonstrates promising preclinical activity for chronic lymphocytic leukemia and lymphoblastic leukemia/lymphoma

“…Previous studies have also suggested that FTY720 might also promote activation of the serine/threonine phosphatase PP2a. 20,21 Based upon the potential of FTY720 to activate PP2a and recent studies demonstrating FTY720 induced apoptosis in T lymphocytes 20,22,23 and multiple myeloma cell lines, 24 we sought to investigate the in vitro and in vivo activity of this agent in ALL and CLL. Herein, we report that FTY720 has potent in vitro and in vivo activity in a variety of B-cell malignancies and mediates apoptosis in a Bcl-2-and caspaseindependent manner through activation of the serine/threonine phosphatase PP2a.…”