Anti-leukemic effect of PI3K inhibition on chronic myeloid leukemia (CML) cells: shedding new light on the mitigating effect of c-Myc and autophagy on BKM120 cytotoxicity.

Abstract

The success in the identification of BCR/ABL tyrosine kinase role in the pathogenesis of chronic myeloid leukemia (CML) went as far as to find a path to cure this leukemia; however, compensatory activation of leukomogenic signals get across the message that the small molecule inhibitors of oncogenic pathways, along with tyrosine kinase inhibitors, might be a beneficial approach in CML treatment. The results of the present study showed that the abrogation of the phosphoinositide 3-kinase (PI3K) pathway using pan-PI3K inhibitor BKM120 exerted a cytotoxic effect against CML-derived K562 cells through both the induction of p21-mediated G2/M arrest and the stimulation of apoptosis. Notably, the apoptotic effect of the inhibitor was further confirmed by the molecular analysis showing that BKM120 significantly increased the expression of pro-apoptotic genes. To the best of our knowledge, the involvement of autophagy in resistance to BKM120 has not been yet described and our study suggests for the first time that the elevation of autophagy-related genes might serve as a compensatory pathway to cease the anti-leukemic effect of BKM120 in K562; since we found a reinforced anti-survival event when the cells were treated with BKM120 in combination with autophagy inhibitor. In conclusion, the results of the present study showed that the abrogation of PI3K using BKM120 might be a befitting approach in CML treatment, either as a single agent or in a combined-modal strategy; however, further evaluations including clinical trials and in vivo investigations are demanded to ascertain the safety and the efficacy of the inhibitor in treatment strategies.