PI-103 sensitizes acute myeloid leukemia stem cells to daunorubicin-induced cytotoxicity

To date, acute myeloid leukemia (AML) shows very poor outcome for conventional chemotherapy. Leukemia stem cells (LSCs) are insensitive to conventional chemotherapeutic drugs and play a central role in the pathogenesis of AML. Failure to effectively ablate these cells may lead to AML relapse following chemotherapy. Phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway is constructively activated in LSCs. This pathway can be inhibited by PI-103, a novel synthesized molecule of the pyridofuropyrimidine class, resulting in the apoptosis of LSCs. Therefore, we investigate the influences of PI-103 in combination with daunorubicin (DNR) on the LSCs. Our data indicate that PI-103 synergistically sensitizes LSCs to DNR-induced cytotoxicity. In addition, the PI-103/DNR co-treatment can induce significant apoptosis in LSCs, but sparing hematopoietic stem cells. The synergistic effect and the LSCs-specific apoptosis mechanism may be associated with the inhibition of PI3K/Akt/mTOR signaling pathway. Our results suggest that PI-103 in combination with DNR may be a potent and less toxic therapy for targeting LSCs and deserve further preclinical and clinical studies in the treatment of AML.