Development of the new treatment strategy of ATRA-resistant APL using PP2A-FOXO3A activation pathway

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Acute promyelotic leukemia (APL) patients usually respond to all-trans retinoic acid (ATRA) treatment, however, some patients are refractory and resistant to ATRA. Therefore, an alternative strategy to treat APL patients is demanded. Here, we showed that FTY720, an immunosuppressive drug, is capable of inducing apoptosis in both ATRA-sensitive and & -resistant APL cells in vitro and regresses tumor mass generated from ATRA-resistant APL cells in vivo. This demonstrates its capability as a potential therapeutic compound in APL treatment. In addition, we have shown that N-acetylcysteine (NAC) rescues FTY720-dependent apoptosis induction in NB4 cells, implying that FTY720 cytotoxic effect to NB4 cells are due at least partly if not all, to a generation of reactive oxygen species (ROS). These observations demonstrate a potential of FTY720 as a therapeutic compound against APL irrespective of whether it is resistant to ATRA.