Abstract
Recent findings have highlighted that constitutively active phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling is a common feature of T-cell acute lymphoblastic leukemia (T-ALL), where it upregulates cell proliferation, survival, and drug resistance. These observations lend compelling weight to the application of PI3K/Akt/mTOR inhibitors in the therapy of T-ALL. Here, we have analyzed the therapeutic potential of the novel dual PI3K/mTOR inhibitor NVP-BEZ235, an orally bioavailable imidazoquinoline derivative, which has entered clinical trials for solid tumors, on both T-ALL cell lines and patient samples. NVP-BEZ235 was cytotoxic to a panel of T-ALL cell lines as determined by MTT assays. NVP-BEZ235 treatment resulted in cell cycle arrest and apoptosis. Western blots showed a dose- and time-dependent dephosphorylation of Akt and mTORC1 downstream targets in response to NVP-BEZ235. Remarkably, NVP-BEZ235 targeted the side population of both T-ALL cell lines and patient lymphoblasts, which might correspond to leukemia-initiating cells, and synergized with chemotherapeutic agents (cyclophosphamide, cytarabine, dexamethasone) currently used for treating T-ALL patients. NVP-BEZ235 reduced chemoresistance to vincristine induced in Jurkat cells by coculturing with MS-5 stromal cells, which mimic the bone marrow microenvironment. NVP-BEZ235 was cytotoxic to T-ALL patient lymphoblasts displaying pathway activation, where the drug dephosphorylated eukaryotic initiation factor 4E-binding protein 1, at variance with rapamycin. Taken together, our findings indicate that longitudinal inhibition at two nodes of the PI3K/Akt/mTOR network with NVP-BEZ235, either alone or in combination with chemotherapeutic drugs, may be an efficient treatment of those T-ALLs that have aberrant upregulation of this signaling pathway for their proliferation and survival.
Highlights
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive disorder of precursor cells committed to the T-cell lineage [1]
Pathway upregulation in T-ALL is due to several reasons, which include Notch1 activation leading to HES1-mediated transcriptional suppression of the PTEN gene [6, 7], PTEN phosphorylation or oxidation [8], interleukin (IL)-4 secreted by bone marrow stromal cells [9], or mutations affecting phosphatidylinositol 3-kinase (PI3K), PTEN, or Akt [10]
When used at equimolar concentrations, PI-103 was less effective than NVP-BEZ235 in affecting T-ALL cell line growth (Fig. 1B) at all the concentrations tested
Summary
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive disorder of precursor cells committed to the T-cell lineage [1]. Over the past 20 years, survival rates of T-ALL patients have improved, mainly because of advances in chemotherapy protocols. Adolescents with T-ALL are 70% to 75%, whereas for adults, the rates are 35% to 40% [2] In spite of these improvements, novel and less toxic treatment strategies for T-ALL are needed [3]. About 85% of T-ALL patients display increased PI3K/ Akt/mTOR activation at diagnosis [8, 11]. Allosteric mTOR inhibitors, which include rapamycin and its analogues (rapalogues), mainly target mTORC1. These inhibitors display promising effects in preclinical models of T-ALL [13, 14]
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