Synergistic Effects of PI3K Inhibition on Arsenic Trioxide Cytotoxicity in Acute Promyelocytic Leukemia Cells: A New Portrait of Idelalisib as an Adjuvant Therapy.

Abstract

The advent of small-molecule inhibitors targeting the components of oncogenic signaling pathways has revolutionized cancer treatment, where the pharmacological approaches have gone from an era of non-specific chemotherapeutic drugs to the golden age of targeted therapies. In the present study, we evaluated the therapeutic value of an isoform-specific inhibitor of PI3K (Idelalisib) in potentiating the anti-leukemic effects of arsenic trioxide (ATO), an eminent drug used in the treatment of acute promyelocytic leukemia (APL). We found that the abrogation of the PI3K axis profoundly reinforced the anti-leukemic effects of the lower concentrations of ATO, as revealed by the superior reduction in the viability, cell number, and metabolic activity of APL-derived NB4 cells as compared to either agent alone. The cytotoxic effect of Idelalisib in combination with ATO was probably mediated through suppression of c-Myc that was coupled with the elevation in the intracellular level of reactive oxygen species and induction of caspase-3-dependent apoptosis. Notably, our results showed that the suppression of autophagy reinforced the ability of the drugs in eradicating the leukemic cells, suggesting that the compensatory activation of this system may probably overshadow the success of Idelalisib-plus-ATO in APL cells. All in all and given the significant efficacy of Idelalisib against NB4 cells, we proposed the application of this PI3K inhibitor as a foreseeable approach with a safe profile in the treatment of APL.