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Activity of the novel dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor NVP-BEZ235 against T-cell acute lymphoblastic leukemia.
| Content Provider | Semantic Scholar |
|---|---|
| Author | Chiarini, Francesca Grimaldi, Cecilia Ricci, Francesca Tazzari, Pier Luigi Evangelisti, Camilla Ognibene, Andrea Battistelli, Michela Falcieri, Elisabetta Melchionda, Fraia Pession, Andrea Pagliaro, Pasqualepaolo McCubrey, James A. Martelli, Alberto Maria |
| Copyright Year | 2010 |
| 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. |
| File Format | PDF HTM / HTML |
| DOI | 10.1158/0008-5472.CAN-10-1814 |
| Alternate Webpage(s) | http://cancerres.aacrjournals.org/content/canres/70/20/8097.full.pdf |
| PubMed reference number | 20876803 |
| Alternate Webpage(s) | https://doi.org/10.1158/0008-5472.CAN-10-1814 |
| Journal | Medline |
| Volume Number | 70 |
| Issue Number | 20 |
| Journal | Cancer research |
| Language | English |
| Access Restriction | Open |
| Content Type | Text |
| Resource Type | Article |
