Article

Rapamycin stimulates apoptosis of childhood acute lymphoblastic leukemia cells

Universita' degli Studi "Magna Græcia" di Catanzaro, Catanzaro, Calabria, Italy
Blood (Impact Factor: 10.43). 09/2005; 106(4):1400-6. DOI: 10.1182/blood-2005-03-0929
Source: PubMed

ABSTRACT 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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    • "A recent ongoing phase I/II study from Amadori et al. performed in acute myeloid leukemia (AML) by combining the RAD001 with clofarabine, has been preliminary reported with encouraging results in a poor prognosis patient population overexpressing the drug-target (Amadori et al., 2010). It has been reported that inhibition of mTOR by rapamicin leads to apoptosis of blasts from ALL patients of both B-cell and T-cell origin (Avellino et al., 2005). The efficacy of CCI-779 (temsirolimus) in primary human ALL was also evaluated by Teachey et al. (2006), who demonstrated its activity using both NOD/SCID xenograft models and bone marrow-derived stromal cell co-culture systems. "
    Novel Aspects in Acute Lymphoblastic Leukemia, 11/2011; , ISBN: 978-953-307-753-6
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    • "Most prior studies have focused on signaling via IL-7 (Dibirdik et al., 1991; Barata et al., 2004a,b,c, 2005; González- Garcia et al., 2009; Shochat et al., 2011; Silva et al., 2011) or mutational activation of intermediates in the PI3K–Akt pathway (Palomero et al., 2007; Gutierrez et al., 2009). The importance of PI3K–Akt activation in T-ALL is underscored by multiple studies showing that PI3K–Akt/mTOR inhibitors block growth/survival of T-ALL cells (Avellino et al., 2005; Wei et al., 2006; Palomero et al., 2007; Chiarini et al., 2009; Cullion et al., 2009). Notably, our observation that complete JEM Vol. "
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    ABSTRACT: T cell acute lymphoblastic leukemia (T-ALL) is an aggressive cancer of immature T cells that often shows aberrant activation of Notch1 and PI3K-Akt pathways. Although mutations that activate PI3K-Akt signaling have previously been identified, the relative contribution of growth factor-dependent activation is unclear. We show here that pharmacologic inhibition or genetic deletion of insulin-like growth factor 1 receptor (IGF1R) blocks the growth and viability of T-ALL cells, whereas moderate diminution of IGF1R signaling compromises leukemia-initiating cell (LIC) activity as defined by transplantability in syngeneic/congenic secondary recipients. Furthermore, IGF1R is a Notch1 target, and Notch1 signaling is required to maintain IGF1R expression at high levels in T-ALL cells. These findings suggest effects of Notch on LIC activity may be mediated in part by enhancing the responsiveness of T-ALL cells to ambient growth factors, and provide strong rationale for use of IGF1R inhibitors to improve initial response to therapy and to achieve long-term cure of patients with T-ALL.
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    • "Anthracycline compounds activate NF-B, and disruption of this signaling pathway increases the efficacy of apoptogenic stimuli. Avellino et al. [274] showed that rapamycin inhibited doxorubicin-induced NF-B and stimulated apoptosis of childhood ALL cells. Using siRNA approach, they demonstrated that the inhibition of immunophilin FKBP51 by rapamycin is essential for suppression of NF-B activity [274]. "
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