Inhibition of PI3K Signaling Intensified the Antileukemic Effects of Pioglitazone: New Insight into the Application of PPARγ Stimulators in Acute Lymphoblastic Leukemia.

Abstract

Over the past two decades, molecular targeted therapyhas revolutionized the landscape ofcancer treatmentdue to lower side effects as well as higher anticancer effects. Peroxisome proliferator-activated receptor gamma (PPARγ) is a member of the nuclear hormone receptor which plays a crucial role in cell proliferation and death and the efficacy of PPARγ ligands either as monotherapy or in combination with traditional chemotherapy drugs has been proved by recent studies. In this study, we aimed to investigate the effects of pioglitazone, a well-known PPARγ stimulator, in ALL-derived NALM6 cells by using trypan blue assay, MTT assay, and flow cytometry analysis. Moreover, to investigate the molecular mechanism action of pioglitazone in these cells, we assessed the possible alterations in the expression of some target genes which regulate cell proliferation, apoptosis, and autophagy system. Our result demonstrated that pioglitazone induced a remarkable antileukemic effect on NALM6 cells through a PTEN-mediated manner. Based on the fact that PI3K hyperactivation is one of the main properties of ALL cells, the effects of PI3K inhibition using CAL-101 on pioglitazone-induced cytotoxicity were evaluated by combinatorial experiments. Moreover, the result of cell cycle assay and qRT-PCR demonstrated that pioglitazone-CAL-101 induced antileukemic effect mainly through induction of p21 and p27-mediated G1 arrest. Additionally, our result showed that inhibition of proteasome and autophagy system, two main cellular processes, increased the antileukemic effects of the agents. Taken together, we suggest a novel therapeutic application for PPARγ stimulators as a single agent or in combination with PI3K inhibitors that should be clinically evaluated in ALL patients.