Activity of the Novel Dual Phosphatidylinositol 3-Kinase/Mammalian Target of Rapamycin Inhibitor NVP-BEZ235 against T-Cell Acute Lymphoblastic Leukemia

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 M.

doi:10.1158/0008-5472.can-10-1814

Cited by 154 publications

(127 citation statements)

References 49 publications

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“…The efficacy of targeting PI3K/PTEN/Akt/mTOR signaling to eliminate putative CICs in human T-ALL has been documented by two recent studies from our group, in which we used NVP-BEZ235 (a dual PI3K/mTOR inhibitor) 178 and triciribine 179 (an Akt inhibitor) for targeting the side-population of T-ALL cell lines and primary cells from T-ALL patients. The side-population, which overexpresses ABCG2 and other ABC family plasma membrane transporters like Mdr-1, is thought to be enriched in leukemic CICs.…”

Section: Mtorc1-hif Drug Resistancementioning

confidence: 99%

Targeting the translational apparatus to improve leukemia therapy: roles of the PI3K/PTEN/Akt/mTOR pathway

et al. 2011

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Section: Mtorc1-hif Drug Resistancementioning

confidence: 99%

Targeting the translational apparatus to improve leukemia therapy: roles of the PI3K/PTEN/Akt/mTOR pathway

et al. 2011

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“…The radiosensitization of GSCs was determined by performing the clonogenic assay after the treatment of cells with a combination of IR (0 Gy to 8 Gy) and NVP-BEZ235 (10 nmol/L; the concentration that produced an inhibition rate lower than 10% when given alone). The inhibition of the PI3K/mTOR signaling pathway is associated with the induction of autophagy [24][25][26] . Therefore, we used 3-MA (50 μmol/L), which blocks autophagy at an early stage [27] , before NVP-BEZ235-mediated radiosensitization increases induction of autophagy We studied the cleavage of the microtubule-associated protein LC3, a specific molecular marker of autophagosomes, to determine whether NVP-BEZ235-mediated radiosensitization would result from autophagy induction [28] .…”

Section: Nvp-bez235 Inhibits Gsc Proliferation and Enhances Radiosensmentioning

confidence: 99%

NVP-BEZ235, a novel dual PI3K/mTOR inhibitor, enhances the radiosensitivity of human glioma stem cells in vitro

et al. 2013

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Aim: NVP-BEZ235 is a novel dual PI3K/mTOR inhibitor and shows dramatic effects on gliomas. The aim of this study was to investigate the effects of NVP-BEZ235 on the radiosensitivity and autophagy of glioma stem cells (GSCs) in vitro. Methods: Human GSCs (SU-2) were tested. The cell viability and survival from ionizing radiation (IR) were evaluated using MTT and clonogenic survival assay, respectively. Immunofluorescence assays were used to identify the formation of autophagosomes. The apoptotic cells were quantified with annexin V-FITC/PI staining and flow cytometry, and observed using Hoechst 33258 staining and fluorescence microscope. Western blot analysis was used to analyze the expression levels of proteins. Cell cycle status was determined by measuring DNA content after staining with PI. DNA repair in the cells was assessed using a comet assay. Results: Treatment of SU-2 cells with NVP-BEZ235 (10-320 nmol/L) alone suppressed the cell growth in a concentration-dependent manner. A low concentration of NVP-BEZ235 (10 nmol/L) significantly increased the radiation sensitivity of SU-2 cells, which could be blocked by co-treatment with 3-MA (50 µmol/L). In NVP-BEZ235-treated SU-2 cells, more punctate patterns of microtubule-associated protein LC3 immunoreactivity was observed, and the level of membrane-bound LC3-II was significantly increased. A combination of IR with NVP-BEZ235 significantly increased the apoptosis of SU-2 cells, as shown in the increased levels of BID, Bax, and active caspase-3, and decreased level of Bcl-2. Furthermore, the combination of IR with NVP-BEZ235 led to G 1 cell cycle arrest. Moreover, NVP-BEZ235 significantly attenuated the repair of IR-induced DNA damage as reflected by the tail length of the comet. Conclusion: NVP-BEZ235 increases the radiosensitivity of GSCs in vitro by activating autophagy that is associated with synergistic increase of apoptosis and cell-cycle arrest and decrease of DNA repair capacity.

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“…[64] One agent that warrants special mention is BEZ235 as it is being investigated extensively in preclinical models of pediatric leukemias. [95][96][97] It is currently in early-phase trials in adults with solid tumors. BEZ235 inhibits PI3K, mTORC1, and mTORC2.…”

Section: Pi3k Inhibitorsmentioning

confidence: 99%

Targeting the PI3K/AKT/mTOR Signaling Axis in Children with Hematologic Malignancies

et al. 2012

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The phosphatidylinositiol 3-kinase (PI3K), AKT, mammalian target of rapamycin (mTOR) signaling pathway (PI3K/AKT/mTOR) is frequently dysregulated in disorders of cell growth and survival, including a number of pediatric hematologic malignancies. The pathway can be abnormally activated in childhood acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), and chronic myelogenous leukemia (CML), as well as in some pediatric lymphomas and lymphoproliferative disorders. Most commonly, this abnormal activation occurs as a consequence of constitutive activation of AKT, providing a compelling rationale to target this pathway in many of these conditions. A variety of agents, beginning with the rapamycin analogue (rapalog) sirolimus, have been used successfully to target this pathway in a number of pediatric hematologic malignancies. Rapalogs demonstrate significant preclinical activity against ALL, which has led to a number of clinical trials. Moreover, rapalogs can synergize with a number of conventional cytotoxic agents and overcome pathways of chemotherapeutic resistance for drugs commonly used in ALL treatment, including methotrexate and corticosteroids. Based on preclinical data, rapalogs are also being studied in AML, CML, and non-Hodgkin's lymphoma. Recently, significant progress has been made using rapalogs to treat pre-malignant lymphoproliferative disorders, including the autoimmune lymphoproliferative syndrome (ALPS); complete remissions in children with otherwise therapy-resistant disease have been seen.Rapalogs only block one component of the pathway (mTORC1), and newer agents are under preclinical and clinical development that can target different and often multiple protein kinases in the PI3K/AKT/mTOR pathway. Most of these agents have been tolerated in early-phase clinical trials. A number of PI3K inhibitors are under investigation. Of note, most of these also target other protein kinases. Newer agents are under development that target both mTORC1 and mTORC2, mTORC1 and PI3K, and the triad of PI3K, mTORC1, and mTORC2. Preclinical data suggest these dual-and multi-kinase inhibitors are more potent than rapalogs against many of the aforementioned hematologic malignancies. Two classes of AKT inhibitors are under development, the alkyl-lysophospholipids (APLs) and small molecule AKT inhibitors. Both classes have agents currently in clinical trials. A number of drugs are in development that target other components of the pathway, including eukaryotic translation initiation factor (eIF) 4E (eIF4E) and phosphoinositide-dependent protein kinase 1 (PDK1). Finally, a number of other key signaling pathways interact with PI3K/AKT/mTOR, including Notch, MNK, Syk, MAPK, and aurora kinase. These alternative pathways are being targeted alone and in combination with PI3K/AKT/mTOR inhibitors with promising preclinical results in pediatric hematologic malignancies. This review provides a comprehensive overview of the abnormalities in the PI3K/AKT/mTOR signaling pathway in pediatric hematologic malignanc...

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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

Cited by 154 publications

References 49 publications

Targeting the translational apparatus to improve leukemia therapy: roles of the PI3K/PTEN/Akt/mTOR pathway

Targeting the translational apparatus to improve leukemia therapy: roles of the PI3K/PTEN/Akt/mTOR pathway

NVP-BEZ235, a novel dual PI3K/mTOR inhibitor, enhances the radiosensitivity of human glioma stem cells in vitro

Targeting the PI3K/AKT/mTOR Signaling Axis in Children with Hematologic Malignancies

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