Abstract

The reputation of conventional treatment in acute lymphoblastic leukemia (ALL) has recently been questioned due to the considerable increment in the number of relapsed patients. The remarkable role of histone deacetylase (HDAC) enzymes in induction of chemo-resistance has provided an opportunity for HDAC inhibitors to be used as a treatment strategy in ALL; however, the compensatory activation of oncogenic pathways may negatively affect their promising effects. In the present study, we found an attenuating effect for PI3K axis on the anti-leukemic effects of panobinostat in pre-B ALL-derived Nalm-6 cells, as the harnessing of this pathway using BKM120 or CAL-101 resulted in a significant reduction in the number of viable cells as well as the metabolic activity. Moreover, we found the altered expression of p21, p27, c-Myc, and CDK4 upon co-treatment of the cells with panobinostat and BKM120, which was associated with a substantial blockage of cell cycle progression at G2/M phase. The companionship of the PI3K inhibitor with HDAC inhibitor also potentiated panobinostat-induced apoptotic cell death and enhanced the mRNA of Foxo3a and Foxo4. Conclusively, this study sheds light on the adjuvantive effects of BKM120 on panobinostat efficacy and outlined that the simultaneous inhibition of PI3K and HDACs may be a promising therapeutic approach to improve the cure rates of ALL.

摘要

由于复发患者数量的显着增加，急性淋巴细胞白血病 (ALL) 常规治疗的声誉最近受到质疑。组蛋白去乙酰化酶 (HDAC) 在诱导化疗耐药中的显着作用为 HDAC 抑制剂用作 ALL 的治疗策略提供了机会。然而，致癌途径的补偿性激活可能对其有希望的效果产生负面影响。在本研究中，我们发现 PI3K 轴对 pre-B ALL 衍生的 Nalm-6 细胞中帕比司他的抗白血病作用有减弱作用，因为使用 BKM120 或 CAL-101 利用该途径导致显着降低在活细胞的数量以及代谢活动方面。此外，我们发现 p21、p27、c-Myc、和 CDK4 与 panobinostat 和 BKM120 共同处理细胞后，这与 G2/M 期细胞周期进程的显着阻断有关。PI3K 抑制剂与 HDAC 抑制剂的协同作用也增强了 panobinostat 诱导的细胞凋亡并增强 Foxo3a 和 Foxo4 的 mRNA。总之，这项研究阐明了 BKM120 对帕比司他疗效的辅助作用，并概述了同时抑制 PI3K 和 HDAC 可能是提高 ALL 治愈率的有希望的治疗方法。