Avellino R, Romano S, Parasole R, Bisogni R, Lamberti A, Poggi V et al.. Rapamycin stimulates apoptosis of childhood acute lymphoblastic leukemia cells. Blood 106: 1400-1406

Universita' degli Studi "Magna Græcia" di Catanzaro, Catanzaro, Calabria, Italy
Blood (Impact Factor: 10.45). 09/2005; 106(4):1400-6. DOI: 10.1182/blood-2005-03-0929
Source: PubMed


The phosphatidyl-inositol 3 kinase (PI3k)/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 kappaB (NF-kappaB), and disruption of this signaling pathway increases the efficacy of apoptogenic stimuli. Rapamycin inhibited doxorubicin-induced NF-kappaB 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-kappaB activation in human leukemia. Furthermore, rapamycin did not increase doxorubicin-induced apoptosis when NF-kappaB was overexpressed. In conclusion, rapamycin targets 2 pathways that are crucial for cell survival and chemoresistance of malignant lymphoblasts--PI3k/Akt through the mammalian target of rapamycin and NF-kappaB through FKBP51--suggesting that the drug could be beneficial in the treatment of childhood ALL.

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    • "The decrease in the MMP in the cell is considered as one of the principal features to demonstrate the induction of the basic apoptotic pathway. So, to know the effect of Dt–Dd–PLGA–MNPs on the cells that confer the apoptotic pathway, a mitochondrial membrane depolarization study was done in both MCF7 and G1 cell lines by using cationic JC-1.56 The study of the loss of MMP by Dt–Dd–PLGA– MNPs in MCF7 and G1 cells was analyzed by confocal imaging (Figure 10). "
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    • "The third therapeutic approach is the inhibition of oncogenic PI3K/AKT/mTOR pathway. The PI3K/AKT pathway was found high-frequency abnormalities in T-ALL (59), and mTOR inhibitor rapamycin showed promising effects in preclinical models and Jurkat cell line (68,69). "
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