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

急性早幼粒细胞白血病(APL)患者通常对全反式维甲酸(ATRA)治疗有效，然而，一些患者对ATRA具有顽固性和耐药性。因此，需要一种替代策略来治疗APL患者。在这里，我们发现FTY720，一种免疫抑制药物，能够在体外诱导ATRA敏感和耐药的APL细胞凋亡，并在体内减少ATRA耐药的APL细胞产生的肿瘤体积。这证明了它在APL治疗中作为潜在的治疗化合物的能力。此外，我们还发现N-乙酰半胱氨酸(NAC)挽救了依赖FTY720的NB4细胞的凋亡诱导，这意味着FTY720对NB4细胞的细胞毒作用至少部分地(如果不是全部的话)是由于一种活性氧物种(ROS)的产生。这些观察结果表明，FTY720作为治疗APL的化合物具有潜力，无论它是否对ATRA具有耐药性。

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.