Blood 2005,
PMID: 15878982
Avellino, Raffaella; Romano, Simona; Parasole, Rosanna; Bisogni, Rita; Lamberti, Annalisa; Poggi, Vincenzo; Venuta, Salvatore; Romano, Maria Fiammetta
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.
Diseases/Pathways annotated by Medline MESH: Blast Crisis, Precursor Cell Lymphoblastic Leukemia-Lymphoma
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Text Mining Data
NF-kappaB → FKBP51: "
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
"
Manually curated Databases
No curated data.