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.
    Journal of Experimental Medicine 08/2011; 208(9):1809-22. DOI:10.1084/jem.20110121 · 13.91 Impact Factor
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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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    ABSTRACT: Nuclear factor-kappaB (NF-κB) upregulates the transcription of proteins that promote cell survival, stimulate growth, induce angiogenesis and reduce susceptibility to apoptosis. NF-κB signaling pathway is constitutively activated in myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), lymphomas and in multiple myeloma (MM). Inactive NF-κB is bound in the cytoplasm to its inhibitor IκB, which masks its nuclear localisation signal. Two protein kinases with a high degree of sequence similarity, IKKα and IKKβ, mediate phosphorylation of IκB proteins and represent a convergence point for most signal transduction pathways leading to NF-κB activation. The overexpression of NF-κB and its anti-apoptotic cytoprotective effect suggest that it might be a useful therapeutic target for the treatment of hematologic malignancies. Several drugs effective for the treatment of MM, including proteasome inhibitors, thalidomide, lenalidomide and arsenic trioxide, block NF-κB activation. New agents with NF-κB inhibitory activity enhance the anti-MM effects of conventional chemotherapeutic agents and reduce different side-effects. Triptolide (diterpenoid triepoxyde), a purified component of a traditional Chinese medicine, extracted from a shrub-like vine named Trypterygium wilfordii Hook F (TWHF) inhibits transcriptional activation of NF-κB and downregulates the expression of various NF-κB-regulated genes. Triptolide (10-80 ng/ml) induces apoptosis of MM cells and effectively inhibits cell growth of MM cells. NF-κB activation can be also inhibited by IKKβ-selective inhibitors, PS-1145dihydrochloride, MLN120B (both Millennium Pharmaceuticals, Cambridge, MA) and BMS-345541 (Bristol-Myers Squibb, Princeton, NJ). LC-1, the dimethylamino-parthenolide (DMAPT) derivative demonstrated significant cytotoxicity to AML blasts targeting NF-κB.
    Current Molecular Pharmacology 11/2010; 3(3):98-122. DOI:10.2174/1874210205941874672
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