Rapamycin stimulates apoptosis of childhood acute lymphoblastic leukemia cells

The phosphatidyl-inositol 3 kinase (Pl3k)/Akt pathway has been implicated in childhood acute lymphoblastic leukemia (ALL). Because rapamycin suppresses the oncogenic processes sustained by PI3k/Akt, we investigated whether rapamycin affects blast survival. We found that rapamycin induces apoptosis of blasts in 56% of the bone marrow samples analyzed. Using the PI3k inhibitor wortmannin, we show that the PI3k/Akt pathway is involved in blast survival. Moreover, rapamycin increased doxorubicin-induced apoptosis even in nonresponder samples. Anthracyclines activate nuclear factor kappa B (NF-kappa B), and disruption of this signaling pathway increases the efficacy of apoptogenic stimuli. Rapamycin inhibited doxorubicin-induced NF-kappa B in ALL samples. Using a short interfering (si) RNA approach, we demonstrate that FKBP51, a large immunophilin inhibited by rapamycin, is essential for drug-induced NF-kappa B activation in human leukemia. Furthermore, rapamycin did not increase doxorubicin-induced apoptosis when NF-kappa B was overexpressed. In conclusion, rapamycin targets 2 pathways that are crucial for cell survival and chemoresistance of malignant lymphoblasts-Pl3k/Akt through the mammalian target of rapamycin and NF-kappa B through FKBP51-suggesting that the drug could be beneficial in the treatment of childhood ALL.