Activation of PPARγ intensified the effects of arsenic trioxide in acute promyelocytic leukemia through the suppression of PI3K/Akt pathway: Proposing a novel anticancer effect for pioglitazone.

The indulgent success of arsenic trioxide (ATO) in the induction of complete remission in acute promyelocytic leukemia (APL) patients has accommodated this agent into the therapeutic protocols. However, the intrusion of unfavorable side effects had put an unanswered question on the way of the application of this agent; whether the benefits of ATO may outweigh its drawbacks. In this study, we found that when ATO is accompanied by an activator of peroxisome proliferator-activated receptors gamma (PPARγ), even the lower concentrations could induce significant inhibitory effects on the survival of NB4 through diminishing the ability of the cells to replicate DNA in the S phase of cell cycle. We also found that through suppression of the PI3K pathway, the combination of pioglitazone and ATO provided a signal through which the induction of apoptotic cell death was enhanced probably via the elevation of reactive oxygen species (ROS). With respect to the tight connection between PI3K pathway and autophagy system and given to the inhibitory effect of pioglitazone-plus-ATO on PI3K, we found that the combination of these agents not only suppressed the expression of autophagy-related genes, but also their efficacy was augmented when autophagy was inhibited in NB4; clarifying the encouraging role of autophagy in the survival maintenance of APL cells. In conclusion, given the significant efficacy as well as the safety profile of pioglitazone in potentiating the anticancer effects of chemotherapeutic drugs, the present study suggests it as a promising agent to be used in adjuvant strategy for the treatment of APL.