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.