The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Laura Zambonin - One of the best experts on this subject based on the ideXlab platform.
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Improving Nelarabine efficacy in T cell acute lymphoblastic leukemia by targeting aberrant PI3K/AKT/mTOR signaling pathway
Journal of Hematology & Oncology, 2016Co-Authors: Annalisa Lonetti, Alessandra Cappellini, Alice Bertaina, Franco Locatelli, Andrea Pession, Francesca Buontempo, Camilla Evangelisti, Ester Orsini, Laura ZamboninAbstract:Background Although in recent years, the introduction of novel chemotherapy protocols has improved the outcome of T cell acute lymphoblastic leukemia (T-ALL) patients, refractory and/or relapsing disease remains a foremost concern. In this context, a major contribution was provided by the introduction of the nucleoside analog Nelarabine, approved for salvage treatment of T-ALL patients with refractory/relapsed disease. However, Nelarabine could induce a life-threatening, dose-dependent neurotoxicity. To improve Nelarabine efficacy, we have analyzed its molecular targets, testing selective inhibitors of such targets in combination with Nelarabine. Methods The effectiveness of Nelarabine as single agent or in combination with PI3K, Bcl2, and MEK inhibitors was evaluated on human T-ALL cell lines and primary T-ALL refractory/relapsed lymphoblasts. The efficacy of signal modulators in terms of cytotoxicity, induction of apoptosis, and changes in gene and protein expression was assessed by flow cytometry, western blotting, and quantitative real-time PCR in T-ALL settings. Results Treatment with Nelarabine as a single agent identified two groups of T-ALL cell lines, one sensitive and one resistant to the drug. Whereas sensitive T-ALL cells showed a significant increase of apoptosis and a strong down-modulation of PI3K signaling, resistant T-ALL cells showed a hyperactivation of AKT and MEK/ERK1/2 signaling pathways, not caused by differences in the expression of Nelarabine transporters or metabolic activators. We then studied the combination of Nelarabine with the PI3K inhibitors (both pan and dual γ/δ inhibitors), with the Bcl2 specific inhibitor ABT199, and with the MEK inhibitor trametinib on both T-ALL cell lines and patient samples at relapse, which displayed constitutive activation of PI3K signaling and resistance to Nelarabine alone. The combination with the pan PI3K inhibitor ZSTK-474 was the most effective in inhibiting the growth of T-ALL cells and was synergistic in decreasing cell survival and inducing apoptosis in Nelarabine-resistant T-ALL cells. The drug combination caused AKT dephosphorylation and a downregulation of Bcl2, while Nelarabine alone induced an increase in p-AKT and Bcl2 signaling in the resistant T-ALL cells and relapsed patient samples. Conclusions These findings indicate that Nelarabine in combination with PI3K inhibitors may be a promising therapeutic strategy for the treatment of T-ALL relapsed patients.
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improving Nelarabine efficacy in t cell acute lymphoblastic leukemia by targeting aberrant pi3k akt mtor signaling pathway
Journal of Hematology & Oncology, 2016Co-Authors: Annalisa Lonetti, Alessandra Cappellini, Alice Bertaina, Franco Locatelli, Andrea Pession, Francesca Buontempo, Camilla Evangelisti, Ester Orsini, Laura ZamboninAbstract:Although in recent years, the introduction of novel chemotherapy protocols has improved the outcome of T cell acute lymphoblastic leukemia (T-ALL) patients, refractory and/or relapsing disease remains a foremost concern. In this context, a major contribution was provided by the introduction of the nucleoside analog Nelarabine, approved for salvage treatment of T-ALL patients with refractory/relapsed disease. However, Nelarabine could induce a life-threatening, dose-dependent neurotoxicity. To improve Nelarabine efficacy, we have analyzed its molecular targets, testing selective inhibitors of such targets in combination with Nelarabine. The effectiveness of Nelarabine as single agent or in combination with PI3K, Bcl2, and MEK inhibitors was evaluated on human T-ALL cell lines and primary T-ALL refractory/relapsed lymphoblasts. The efficacy of signal modulators in terms of cytotoxicity, induction of apoptosis, and changes in gene and protein expression was assessed by flow cytometry, western blotting, and quantitative real-time PCR in T-ALL settings. Treatment with Nelarabine as a single agent identified two groups of T-ALL cell lines, one sensitive and one resistant to the drug. Whereas sensitive T-ALL cells showed a significant increase of apoptosis and a strong down-modulation of PI3K signaling, resistant T-ALL cells showed a hyperactivation of AKT and MEK/ERK1/2 signaling pathways, not caused by differences in the expression of Nelarabine transporters or metabolic activators. We then studied the combination of Nelarabine with the PI3K inhibitors (both pan and dual γ/δ inhibitors), with the Bcl2 specific inhibitor ABT199, and with the MEK inhibitor trametinib on both T-ALL cell lines and patient samples at relapse, which displayed constitutive activation of PI3K signaling and resistance to Nelarabine alone. The combination with the pan PI3K inhibitor ZSTK-474 was the most effective in inhibiting the growth of T-ALL cells and was synergistic in decreasing cell survival and inducing apoptosis in Nelarabine-resistant T-ALL cells. The drug combination caused AKT dephosphorylation and a downregulation of Bcl2, while Nelarabine alone induced an increase in p-AKT and Bcl2 signaling in the resistant T-ALL cells and relapsed patient samples. These findings indicate that Nelarabine in combination with PI3K inhibitors may be a promising therapeutic strategy for the treatment of T-ALL relapsed patients.
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Additional file 4: Figure S4. of Improving Nelarabine efficacy in T cell acute lymphoblastic leukemia by targeting aberrant PI3K/AKT/mTOR signaling pathway
2016Co-Authors: Annalisa Lonetti, Alessandra Cappellini, Alice Bertaina, Franco Locatelli, Andrea Pession, Francesca Buontempo, Camilla Evangelisti, Ester Orsini, Laura ZamboninAbstract:The combination of Nelarabine and ZSTK-474 is synergistic in CEM-R cells, which overexpress P-gp. Cell viability assay of CEM-R cell line treated for 48Â h with increasing concentrations of Nelarabine alone or combined with the pan PI3K p110 inhibitor ZSTK-474. One representative of two different experiments is shown.
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Additional file 5: Figure S5. of Improving Nelarabine efficacy in T cell acute lymphoblastic leukemia by targeting aberrant PI3K/AKT/mTOR signaling pathway
2016Co-Authors: Annalisa Lonetti, Alessandra Cappellini, Alice Bertaina, Franco Locatelli, Andrea Pession, Francesca Buontempo, Camilla Evangelisti, Ester Orsini, Laura ZamboninAbstract:Specific effects of Nelarabine on PI3K/AKT and MEK/ERK1/2 pathways. Western blotting analyses for the expression of p-AKT and p-ERK in resistant T-ALL cell lines treated with the specific inhibitors LY294002 (PI3K inhibitor), CCI-779 (mTOR allosteric inhibitor) or trametinib (MEK1/2 inhibitor) alone or in combination with Nelarabine. Thirty micrograms of protein was blotted to each lane. Antibody to β-actin served as a loading control. Molecular weights are indicated on the right. CTRL: untreated cells; Nela and N: Nelarabine at 10 μM; LY: LY294002 at 10 μM; CCI: CCI-779 at 100 nM; Tram: trametinib at 1 μM. Cells were treated for 48 h
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additional file 4 figure s4 of improving Nelarabine efficacy in t cell acute lymphoblastic leukemia by targeting aberrant pi3k akt mtor signaling pathway
2016Co-Authors: Annalisa Lonetti, Alessandra Cappellini, Alice Bertaina, Franco Locatelli, Andrea Pession, Francesca Buontempo, Camilla Evangelisti, Ester Orsini, Laura ZamboninAbstract:The combination of Nelarabine and ZSTK-474 is synergistic in CEM-R cells, which overexpress P-gp. Cell viability assay of CEM-R cell line treated for 48Â h with increasing concentrations of Nelarabine alone or combined with the pan PI3K p110 inhibitor ZSTK-474. One representative of two different experiments is shown.
Annalisa Lonetti - One of the best experts on this subject based on the ideXlab platform.
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improving Nelarabine efficacy in t cell acute lymphoblastic leukemia by targeting aberrant pi3k akt mtor signaling pathway
Journal of Hematology & Oncology, 2016Co-Authors: Annalisa Lonetti, Alessandra Cappellini, Alice Bertaina, Franco Locatelli, Andrea Pession, Francesca Buontempo, Camilla Evangelisti, Ester Orsini, Laura ZamboninAbstract:Although in recent years, the introduction of novel chemotherapy protocols has improved the outcome of T cell acute lymphoblastic leukemia (T-ALL) patients, refractory and/or relapsing disease remains a foremost concern. In this context, a major contribution was provided by the introduction of the nucleoside analog Nelarabine, approved for salvage treatment of T-ALL patients with refractory/relapsed disease. However, Nelarabine could induce a life-threatening, dose-dependent neurotoxicity. To improve Nelarabine efficacy, we have analyzed its molecular targets, testing selective inhibitors of such targets in combination with Nelarabine. The effectiveness of Nelarabine as single agent or in combination with PI3K, Bcl2, and MEK inhibitors was evaluated on human T-ALL cell lines and primary T-ALL refractory/relapsed lymphoblasts. The efficacy of signal modulators in terms of cytotoxicity, induction of apoptosis, and changes in gene and protein expression was assessed by flow cytometry, western blotting, and quantitative real-time PCR in T-ALL settings. Treatment with Nelarabine as a single agent identified two groups of T-ALL cell lines, one sensitive and one resistant to the drug. Whereas sensitive T-ALL cells showed a significant increase of apoptosis and a strong down-modulation of PI3K signaling, resistant T-ALL cells showed a hyperactivation of AKT and MEK/ERK1/2 signaling pathways, not caused by differences in the expression of Nelarabine transporters or metabolic activators. We then studied the combination of Nelarabine with the PI3K inhibitors (both pan and dual γ/δ inhibitors), with the Bcl2 specific inhibitor ABT199, and with the MEK inhibitor trametinib on both T-ALL cell lines and patient samples at relapse, which displayed constitutive activation of PI3K signaling and resistance to Nelarabine alone. The combination with the pan PI3K inhibitor ZSTK-474 was the most effective in inhibiting the growth of T-ALL cells and was synergistic in decreasing cell survival and inducing apoptosis in Nelarabine-resistant T-ALL cells. The drug combination caused AKT dephosphorylation and a downregulation of Bcl2, while Nelarabine alone induced an increase in p-AKT and Bcl2 signaling in the resistant T-ALL cells and relapsed patient samples. These findings indicate that Nelarabine in combination with PI3K inhibitors may be a promising therapeutic strategy for the treatment of T-ALL relapsed patients.
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Improving Nelarabine efficacy in T cell acute lymphoblastic leukemia by targeting aberrant PI3K/AKT/mTOR signaling pathway
Journal of Hematology & Oncology, 2016Co-Authors: Annalisa Lonetti, Alessandra Cappellini, Alice Bertaina, Franco Locatelli, Andrea Pession, Francesca Buontempo, Camilla Evangelisti, Ester Orsini, Laura ZamboninAbstract:Background Although in recent years, the introduction of novel chemotherapy protocols has improved the outcome of T cell acute lymphoblastic leukemia (T-ALL) patients, refractory and/or relapsing disease remains a foremost concern. In this context, a major contribution was provided by the introduction of the nucleoside analog Nelarabine, approved for salvage treatment of T-ALL patients with refractory/relapsed disease. However, Nelarabine could induce a life-threatening, dose-dependent neurotoxicity. To improve Nelarabine efficacy, we have analyzed its molecular targets, testing selective inhibitors of such targets in combination with Nelarabine. Methods The effectiveness of Nelarabine as single agent or in combination with PI3K, Bcl2, and MEK inhibitors was evaluated on human T-ALL cell lines and primary T-ALL refractory/relapsed lymphoblasts. The efficacy of signal modulators in terms of cytotoxicity, induction of apoptosis, and changes in gene and protein expression was assessed by flow cytometry, western blotting, and quantitative real-time PCR in T-ALL settings. Results Treatment with Nelarabine as a single agent identified two groups of T-ALL cell lines, one sensitive and one resistant to the drug. Whereas sensitive T-ALL cells showed a significant increase of apoptosis and a strong down-modulation of PI3K signaling, resistant T-ALL cells showed a hyperactivation of AKT and MEK/ERK1/2 signaling pathways, not caused by differences in the expression of Nelarabine transporters or metabolic activators. We then studied the combination of Nelarabine with the PI3K inhibitors (both pan and dual γ/δ inhibitors), with the Bcl2 specific inhibitor ABT199, and with the MEK inhibitor trametinib on both T-ALL cell lines and patient samples at relapse, which displayed constitutive activation of PI3K signaling and resistance to Nelarabine alone. The combination with the pan PI3K inhibitor ZSTK-474 was the most effective in inhibiting the growth of T-ALL cells and was synergistic in decreasing cell survival and inducing apoptosis in Nelarabine-resistant T-ALL cells. The drug combination caused AKT dephosphorylation and a downregulation of Bcl2, while Nelarabine alone induced an increase in p-AKT and Bcl2 signaling in the resistant T-ALL cells and relapsed patient samples. Conclusions These findings indicate that Nelarabine in combination with PI3K inhibitors may be a promising therapeutic strategy for the treatment of T-ALL relapsed patients.
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Additional file 4: Figure S4. of Improving Nelarabine efficacy in T cell acute lymphoblastic leukemia by targeting aberrant PI3K/AKT/mTOR signaling pathway
2016Co-Authors: Annalisa Lonetti, Alessandra Cappellini, Alice Bertaina, Franco Locatelli, Andrea Pession, Francesca Buontempo, Camilla Evangelisti, Ester Orsini, Laura ZamboninAbstract:The combination of Nelarabine and ZSTK-474 is synergistic in CEM-R cells, which overexpress P-gp. Cell viability assay of CEM-R cell line treated for 48Â h with increasing concentrations of Nelarabine alone or combined with the pan PI3K p110 inhibitor ZSTK-474. One representative of two different experiments is shown.
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Additional file 5: Figure S5. of Improving Nelarabine efficacy in T cell acute lymphoblastic leukemia by targeting aberrant PI3K/AKT/mTOR signaling pathway
2016Co-Authors: Annalisa Lonetti, Alessandra Cappellini, Alice Bertaina, Franco Locatelli, Andrea Pession, Francesca Buontempo, Camilla Evangelisti, Ester Orsini, Laura ZamboninAbstract:Specific effects of Nelarabine on PI3K/AKT and MEK/ERK1/2 pathways. Western blotting analyses for the expression of p-AKT and p-ERK in resistant T-ALL cell lines treated with the specific inhibitors LY294002 (PI3K inhibitor), CCI-779 (mTOR allosteric inhibitor) or trametinib (MEK1/2 inhibitor) alone or in combination with Nelarabine. Thirty micrograms of protein was blotted to each lane. Antibody to β-actin served as a loading control. Molecular weights are indicated on the right. CTRL: untreated cells; Nela and N: Nelarabine at 10 μM; LY: LY294002 at 10 μM; CCI: CCI-779 at 100 nM; Tram: trametinib at 1 μM. Cells were treated for 48 h
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additional file 4 figure s4 of improving Nelarabine efficacy in t cell acute lymphoblastic leukemia by targeting aberrant pi3k akt mtor signaling pathway
2016Co-Authors: Annalisa Lonetti, Alessandra Cappellini, Alice Bertaina, Franco Locatelli, Andrea Pession, Francesca Buontempo, Camilla Evangelisti, Ester Orsini, Laura ZamboninAbstract:The combination of Nelarabine and ZSTK-474 is synergistic in CEM-R cells, which overexpress P-gp. Cell viability assay of CEM-R cell line treated for 48Â h with increasing concentrations of Nelarabine alone or combined with the pan PI3K p110 inhibitor ZSTK-474. One representative of two different experiments is shown.
Camilla Evangelisti - One of the best experts on this subject based on the ideXlab platform.
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Improving Nelarabine efficacy in T cell acute lymphoblastic leukemia by targeting aberrant PI3K/AKT/mTOR signaling pathway
Journal of Hematology & Oncology, 2016Co-Authors: Annalisa Lonetti, Alessandra Cappellini, Alice Bertaina, Franco Locatelli, Andrea Pession, Francesca Buontempo, Camilla Evangelisti, Ester Orsini, Laura ZamboninAbstract:Background Although in recent years, the introduction of novel chemotherapy protocols has improved the outcome of T cell acute lymphoblastic leukemia (T-ALL) patients, refractory and/or relapsing disease remains a foremost concern. In this context, a major contribution was provided by the introduction of the nucleoside analog Nelarabine, approved for salvage treatment of T-ALL patients with refractory/relapsed disease. However, Nelarabine could induce a life-threatening, dose-dependent neurotoxicity. To improve Nelarabine efficacy, we have analyzed its molecular targets, testing selective inhibitors of such targets in combination with Nelarabine. Methods The effectiveness of Nelarabine as single agent or in combination with PI3K, Bcl2, and MEK inhibitors was evaluated on human T-ALL cell lines and primary T-ALL refractory/relapsed lymphoblasts. The efficacy of signal modulators in terms of cytotoxicity, induction of apoptosis, and changes in gene and protein expression was assessed by flow cytometry, western blotting, and quantitative real-time PCR in T-ALL settings. Results Treatment with Nelarabine as a single agent identified two groups of T-ALL cell lines, one sensitive and one resistant to the drug. Whereas sensitive T-ALL cells showed a significant increase of apoptosis and a strong down-modulation of PI3K signaling, resistant T-ALL cells showed a hyperactivation of AKT and MEK/ERK1/2 signaling pathways, not caused by differences in the expression of Nelarabine transporters or metabolic activators. We then studied the combination of Nelarabine with the PI3K inhibitors (both pan and dual γ/δ inhibitors), with the Bcl2 specific inhibitor ABT199, and with the MEK inhibitor trametinib on both T-ALL cell lines and patient samples at relapse, which displayed constitutive activation of PI3K signaling and resistance to Nelarabine alone. The combination with the pan PI3K inhibitor ZSTK-474 was the most effective in inhibiting the growth of T-ALL cells and was synergistic in decreasing cell survival and inducing apoptosis in Nelarabine-resistant T-ALL cells. The drug combination caused AKT dephosphorylation and a downregulation of Bcl2, while Nelarabine alone induced an increase in p-AKT and Bcl2 signaling in the resistant T-ALL cells and relapsed patient samples. Conclusions These findings indicate that Nelarabine in combination with PI3K inhibitors may be a promising therapeutic strategy for the treatment of T-ALL relapsed patients.
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improving Nelarabine efficacy in t cell acute lymphoblastic leukemia by targeting aberrant pi3k akt mtor signaling pathway
Journal of Hematology & Oncology, 2016Co-Authors: Annalisa Lonetti, Alessandra Cappellini, Alice Bertaina, Franco Locatelli, Andrea Pession, Francesca Buontempo, Camilla Evangelisti, Ester Orsini, Laura ZamboninAbstract:Although in recent years, the introduction of novel chemotherapy protocols has improved the outcome of T cell acute lymphoblastic leukemia (T-ALL) patients, refractory and/or relapsing disease remains a foremost concern. In this context, a major contribution was provided by the introduction of the nucleoside analog Nelarabine, approved for salvage treatment of T-ALL patients with refractory/relapsed disease. However, Nelarabine could induce a life-threatening, dose-dependent neurotoxicity. To improve Nelarabine efficacy, we have analyzed its molecular targets, testing selective inhibitors of such targets in combination with Nelarabine. The effectiveness of Nelarabine as single agent or in combination with PI3K, Bcl2, and MEK inhibitors was evaluated on human T-ALL cell lines and primary T-ALL refractory/relapsed lymphoblasts. The efficacy of signal modulators in terms of cytotoxicity, induction of apoptosis, and changes in gene and protein expression was assessed by flow cytometry, western blotting, and quantitative real-time PCR in T-ALL settings. Treatment with Nelarabine as a single agent identified two groups of T-ALL cell lines, one sensitive and one resistant to the drug. Whereas sensitive T-ALL cells showed a significant increase of apoptosis and a strong down-modulation of PI3K signaling, resistant T-ALL cells showed a hyperactivation of AKT and MEK/ERK1/2 signaling pathways, not caused by differences in the expression of Nelarabine transporters or metabolic activators. We then studied the combination of Nelarabine with the PI3K inhibitors (both pan and dual γ/δ inhibitors), with the Bcl2 specific inhibitor ABT199, and with the MEK inhibitor trametinib on both T-ALL cell lines and patient samples at relapse, which displayed constitutive activation of PI3K signaling and resistance to Nelarabine alone. The combination with the pan PI3K inhibitor ZSTK-474 was the most effective in inhibiting the growth of T-ALL cells and was synergistic in decreasing cell survival and inducing apoptosis in Nelarabine-resistant T-ALL cells. The drug combination caused AKT dephosphorylation and a downregulation of Bcl2, while Nelarabine alone induced an increase in p-AKT and Bcl2 signaling in the resistant T-ALL cells and relapsed patient samples. These findings indicate that Nelarabine in combination with PI3K inhibitors may be a promising therapeutic strategy for the treatment of T-ALL relapsed patients.
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Additional file 4: Figure S4. of Improving Nelarabine efficacy in T cell acute lymphoblastic leukemia by targeting aberrant PI3K/AKT/mTOR signaling pathway
2016Co-Authors: Annalisa Lonetti, Alessandra Cappellini, Alice Bertaina, Franco Locatelli, Andrea Pession, Francesca Buontempo, Camilla Evangelisti, Ester Orsini, Laura ZamboninAbstract:The combination of Nelarabine and ZSTK-474 is synergistic in CEM-R cells, which overexpress P-gp. Cell viability assay of CEM-R cell line treated for 48Â h with increasing concentrations of Nelarabine alone or combined with the pan PI3K p110 inhibitor ZSTK-474. One representative of two different experiments is shown.
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Additional file 5: Figure S5. of Improving Nelarabine efficacy in T cell acute lymphoblastic leukemia by targeting aberrant PI3K/AKT/mTOR signaling pathway
2016Co-Authors: Annalisa Lonetti, Alessandra Cappellini, Alice Bertaina, Franco Locatelli, Andrea Pession, Francesca Buontempo, Camilla Evangelisti, Ester Orsini, Laura ZamboninAbstract:Specific effects of Nelarabine on PI3K/AKT and MEK/ERK1/2 pathways. Western blotting analyses for the expression of p-AKT and p-ERK in resistant T-ALL cell lines treated with the specific inhibitors LY294002 (PI3K inhibitor), CCI-779 (mTOR allosteric inhibitor) or trametinib (MEK1/2 inhibitor) alone or in combination with Nelarabine. Thirty micrograms of protein was blotted to each lane. Antibody to β-actin served as a loading control. Molecular weights are indicated on the right. CTRL: untreated cells; Nela and N: Nelarabine at 10 μM; LY: LY294002 at 10 μM; CCI: CCI-779 at 100 nM; Tram: trametinib at 1 μM. Cells were treated for 48 h
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additional file 4 figure s4 of improving Nelarabine efficacy in t cell acute lymphoblastic leukemia by targeting aberrant pi3k akt mtor signaling pathway
2016Co-Authors: Annalisa Lonetti, Alessandra Cappellini, Alice Bertaina, Franco Locatelli, Andrea Pession, Francesca Buontempo, Camilla Evangelisti, Ester Orsini, Laura ZamboninAbstract:The combination of Nelarabine and ZSTK-474 is synergistic in CEM-R cells, which overexpress P-gp. Cell viability assay of CEM-R cell line treated for 48Â h with increasing concentrations of Nelarabine alone or combined with the pan PI3K p110 inhibitor ZSTK-474. One representative of two different experiments is shown.
Tapan M Kadia - One of the best experts on this subject based on the ideXlab platform.
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Nelarabine related rhabdomyolysis in a patient with t cell acute lymphoblastic leukemia
Leukemia & Lymphoma, 2020Co-Authors: Ramesh Pandey, Farhad Ravandi, Tapan M Kadia, E Jabbour, Adam J Dipippo, Naveen Pemmaraju, Biruh Workeneh, Nitin JainAbstract:Nelarabine is a purine analog antimetabolite approved for relapsed and refractory T cell acute lymphoblastic leukemia (T-ALL) and T cell lymphoblastic lymphoma (T-LBL), after at least 2 prior chemo...
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cxcr4 inhibition with bl 8040 in combination with Nelarabine in patients with relapsed or refractory t cell acute lymphoblastic leukemia lymphoblastic lymphoma
Blood, 2019Co-Authors: Tapan M Kadia, Wendy Stock, Jonathan E Brammer, Osnat Bohanakashtan, Abi Vainstein, Ella Sorani, Hemda Chen, John F Dipersio, Daniel C LinkAbstract:Background: The chemokine receptor, CXCR4, mediates the trafficking and retention of hematopoietic stem cells to the marrow through its interaction with the chemokine, CXCL12. CXCR4 is the most highly expressed chemokine receptor on T-ALL cells, and preclinical data demonstrate that CXCR4 is critical for the growth and survival of T-cell acute lymphoblastic lymphoma (T-ALL). Genetic loss or pharmacologic blockade of CXCR4 signaling suppresses T-ALL cell growth and leukemia initiating activity in murine models. BL-8040 is a novel synthetic peptide antagonist of the chemokine receptor, CXCR4. Compared to other CXCR4 inhibitors, BL-8040 is a more potent mobilizer of normal HSCs with sustained occupancy and inhibition of CXCR4. We previously reported that BL-8040 potently suppresses T-ALL cell growth in xenotransplantation models of T-ALL. To test the efficacy of BL-8040 in T-ALL by conducting a multicenter, open label pilot study of BL-8040 in combination with Nelarabine in patients with relapsed or refractory disease (ClinicalTrials.gov: NCT0276338). Methods: Adults with relapsed or refractory T-ALL/LBL, age ≥18 years and ECOG PS ≤2, were eligible for the study. A peripheral blood lymphoblast count ≤50,000/mm3 was required prior to starting treatment. During cycle 1, subjects received daily subcutaneous administration of BL-8040 1.5 mg/kg from Day 1 to Day 6 with Nelarabine 1,500 mg/m2 intravenously over 2 hours on Days 2, 4 and 6. In subsequent 21-day cycles, BL-8040 1.5 mg/kg was administered daily on days 1-5 with Nelarabine 1,500 mg/m2 given on days 1, 3 and 5. Up to 4 cycles of treatment was allowed. Results: Nine patients with median age of 29 years (range 20-75) have been enrolled in the study out of which including fout patients were in untreated 1st relapse, one in 2nd relapse, two with relapsed and refractory disease, and two primary refractory patient. Two patients had failed prior allogeneic hematopoietic cell transplant. The rate of complete remission is 56% (5/9) with all responses occurring after 1 cycle of treatment. Adverse events occurred in 2 subjects requiring dose modification. Consistent with the known mechanism of BL-8040, one subject developed G3 leukocytosis after BL-8040 administration with the peripheral WBC increasing from 5.3 to 273 h/mm3 with evidence of spontaneous tumor lysis requiring interruption of BL-8040 and leukapheresis. A second patient developed injection site pain requiring omission of the final dose of BL-8040. Peripheral blood analyzed at baseline and 24 hours after the first dose of BL-8040 (prior to Nelarabine) showed the following: 1) sustained blockade of CXCR4 on leukemic blasts; 2) mobilization of leukemic blasts into the blood; and 3) no induction of leukemia blast apoptosis as measured by activated caspase 3 expression. Conclusions: BL-8040 can be combined with Nelarabine in subjects with relapsed or refractory T-ALL with encouraging CR rates. Evidence of on target effects on CXCR4 has been observed in this study with sustained CXCR4 receptor occupancy at 24 hours after administration along with tumor mobilization of ALL blasts into the peripheral circulation. Disclosures Uy: Astellas: Consultancy; Pfizer: Consultancy; Curis: Consultancy; GlycoMimetics: Consultancy. Kadia: Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Bioline RX: Research Funding; BMS: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Research Funding. Stock: Astellas: Membership on an entity's Board of Directors or advisory committees; Daiichi: Membership on an entity's Board of Directors or advisory committees; Research to Practice: Honoraria; UpToDate: Honoraria; Agios: Membership on an entity's Board of Directors or advisory committees; Kite, a Gilead Company: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees. Brammer: Verastem, Inc: Research Funding; Viracta Therapeutics, Inc.: Research Funding; Bioniz Therapeutics, Inc.: Research Funding. Bohana-Kashtan: BiolineRx: Employment, Equity Ownership. Vainstein: BiolineRx: Employment, Equity Ownership. Sorani: BiolineRx: Employment, Equity Ownership. Chen: BiolineRx: Employment. DiPersio: Bioline Rx: Research Funding, Speakers Bureau; Macrogenics: Research Funding, Speakers Bureau; Celgene: Consultancy; Amphivena Therapeutics: Consultancy, Research Funding; Magenta Therapeutics: Equity Ownership; NeoImmune Tech: Research Funding; RiverVest Venture Partners Arch Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cellworks Group, Inc.: Membership on an entity's Board of Directors or advisory committees; WUGEN: Equity Ownership, Patents & Royalties, Research Funding; Incyte: Consultancy, Research Funding; Karyopharm Therapeutics: Consultancy. OffLabel Disclosure: BL-8040 for ALL
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hyper cvad plus Nelarabine in newly diagnosed adult t cell acute lymphoblastic leukemia and t lymphoblastic lymphoma
American Journal of Hematology, 2018Co-Authors: Yasmin Abaza, Tapan M Kadia, G Borthakur, E Jabbour, Deborah A Thomas, Stefan Faderl, Nitin Jain, Hagop M Kantarjian, Joseph D Khoury, Jan A BurgerAbstract:Nelarabine, a water soluble prodrug of 9-β-D-arabinofuranosylguanine (ara-G), is a T-cell specific purine nucleoside analogue. Given its activity in relapsed and refractory T acute lymphoblastic leukemia (T-ALL) and T lymphoblastic lymphoma (T-LBL), we sought to define its role in the frontline treatment of adult patients. Therefore, we conducted a single arm phase 2 study to determine the safety and efficacy of Nelarabine in combination with hyper-CVAD in newly diagnosed patients. For induction/consolidation, patients received eight cycles of hyper-CVAD alternating with high-dose methotrexate and cytarabine plus two cycles of Nelarabine given at a dose of 650 mg/m2 intravenously daily for 5 days. This was followed by thirty months of POMP maintenance chemotherapy with two additional cycles of Nelarabine given instead of cycles 6 and 7 of POMP maintenance. Sixty-seven patients, including 40 with T-ALL and 26 with T-LBL, were enrolled. Complete response rates in both T-ALL and T-LBL were 87% and 100% respectively. Grade 3 to 4 neurotoxic adverse events were reported in 5 patients. There were 21 relapses (31%) including 2 after allogeneic stem cell transplantation. Median duration of follow-up was 42.5 months. The 3-year complete remission duration (CRD) and overall survival (OS) rates were 66% and 65%, respectively. Compared to our historic hyper-CVAD data, there was no survival benefit with the addition of Nelarabine. In conclusion, hyper-CVAD plus Nelarabine was well tolerated and active in the frontline treatment of adult T-ALL/LBL patients.
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Nelarabine in the treatment of pediatric and adult patients with t cell acute lymphoblastic leukemia and lymphoma
Expert Review of Hematology, 2017Co-Authors: Tapan M Kadia, Varsha GandhiAbstract:ABSTRACTIntroduction: T-cell acute lymphoblastic leukemia (ALL) and lymphoma (LBL) are aggressive hematologic neoplasms that are treated with combination chemotherapy in the frontline, but have limited options in the relapsed or refractory setting. Based on observations in patients with purine nucleoside phosphorylase (PNP) deficiency, a guanosine nucleoside analogue, arabinosylguanine (ara-G) was developed that provided T-cell specificity. Nelarabine was developed as the water-soluble, clinically useful-prodrug of ara-G and based on its activity was approved for the treatment of relapsed or refractory T-ALL/LBL.Areas covered: In this narrative review, we will summarize the preclinical studies, early dose-finding studies, and efficacy studies that led to approval of Nelarabine. The review will succinctly cover response rates and safety signals reported during clinical development. We will also cover more recent work with Nelarabine, including combination studies, modified dosing schedules, and frontline t...
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phase ii study of hyper cvad plus Nelarabine in previously untreated adult t cell acute lymphoblastic leukemia and t lymphoblastic lymphoma
Blood, 2016Co-Authors: Yasmin Abaza, Tapan M Kadia, Jan A Burger, G Borthakur, E Jabbour, Deborah A Thomas, Nitin Jain, Hagop M Kantarjian, William G Wierda, Stefan FaderlAbstract:Background: Despite the high complete remission (CR) rates, a significant proportion of adult patients (pts) with T-cell acute lymphoblastic leukemia (T-ALL) and T-lymphoblastic lymphoma (T-LL) treated with standard combination cytotoxic regimens will relapse underscoring the need for better therapeutic strategies. Nelarabine combined with intensive chemotherapy has been shown to be safe and effective in the frontline treatment of pediatric T-ALL. There is limited data on the use of Nelarabine in the frontline setting in adult T-ALL and T-LL. Methods: This single-arm phase 2 study was designed to determine the CR rate, overall survival (OS), and safety of adding Nelarabine cycles to the standard hyper-CVAD regimen in previously untreated or minimally pretreated (failure to 1 induction course or CR after ≤ 2 cycles) pts with T-ALL and T-LL. Treatment consisted of 8 induction/consolidation cycles of hyper-CVAD (odd courses 1, 3, 5, 7) alternating with high-dose methotrexate (MTX) and cytarabine (Ara-C; even courses 2, 4, 6, 8) followed by 30 months of POMP (monthly vincristine, prednisone, 6-mercaptopurine, and MTX) maintenance therapy. Pts received Nelarabine at a dose of 650 mg/m2 IV daily over 2 hrs for 5 days after the 8 cycles of induction/consolidation (Regimen 1). After 30 pts, the protocol was amended to deliver Nelarabine after cycles 4 and 5 of induction/consolidation (Regimen 2). All patients also receive Nelarabine instead of cycles 6 and 7 of POMP maintenance as early intensification. Late intensification consisted of MTX (100 mg/m2 IV on day 1) plus PEG-asparaginase (2000 IU/m2 IV on day 2) and hyper-CVAD given instead of cycles 18 and 19 of POMP maintenance. CNS prophylaxis consisted of 8 intrathecal treatments of MTX alternating with Ara-C. Pts with initial bulky mediastinal disease or with residual disease after induction were considered for local radiation therapy prior to the start of POMP maintenance. Results: To date, sixty-seven pts have been enrolled; 40 pts (60%) had T-ALL, 26 pts (39%) had T-LL, and 1 pt (1%) had biphenotypic disease. Median age was 37 years (range, 18-78) with 76% (N=51) of the pts males. Performance status was 2 in 9 pts (13%). Four pts (6%) had CNS involvement and 31 pts (46%) had mediastinal disease at diagnosis. Median WBC count at presentation was 8.1 x109/L (range, 0.8-309.2) and 11 pts (16%) had a WBC count > 100 x109/L. Based on immunophenotype, pts were categorized as thymic (N=24), mature (N=8), early T-cell precursor ALL (ETP; N=24), early non-ETP (N=2), and not otherwise specified (N=9). At diagnosis, 41 pts (61%) had diploid cytogenetics, 19 pts (28%) had miscellaneous karyotypic abnormalities, and 7 pts (10%) had indeterminate karyotype due to lack of testing and insufficient metaphases. Eleven pts were in CR at the time of initial presentation after having received 1-2 prior courses of therapy. Overall response rate was 96% (54/56 pts); with 52 pts (93%) achieving CR, 2 pts (4%) PR, and 2 pts (4%) no response. CR rates were similar for T-ALL and T-LL, 87% and 100%, respectively. There were no early deaths within the first month of treatment. With a median follow-up of 35 months (range, 2-98), 44 pts (66%) remain alive of which 41 pts (93%) are in remission. Ten pts (15%) received SCT after achieving CR and remain alive post-SCT; 8 remained in CR and 2 relapsed post-SCT. Nineteen pts relapsed with a median time to relapse of 6.5 months (range, 1.4-62). The site of relapses were: 10 hematologic (BM + blood), 5 extramedullary (EM), 3 BM + EM, and 1 BM + CNS. Twenty-three pts (34%) died including 17 pts with CR dying after relapse. Probability of CR duration at 3 years was 68% (95% CI 54-79 %). The 3-year probability of OS was 65% (95% CI 50-76 %) with a median OS of 82 months. There was no statistically significant difference in OS among the two different Nelarabine regimens (Figure 1; p-value=0.93). Grade 3-4 nonhematological toxicity was reported in 60 (90%) pts, most frequent toxicities being infection (82%), elevated alanine aminotransferase (ALT) (16%), and thrombotic events (12%). Conclusion: Hyper-CVAD plus Nelarabine is safe and effective in the frontline treatmentof adult T-ALL/T-LL and induces durable remissions. Administration of Nelarabine earlier during the course of therapy does not appear to influence the outcome. Disclosures Jabbour:ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. Burger:Janssen: Consultancy, Other: Travel, Accommodations, Expenses; Roche: Other: Travel, Accommodations, Expenses; Portola: Consultancy; Pharmacyclics, LLC, an AbbVie Company: Research Funding; Gilead: Research Funding. Wierda:Gilead: Research Funding; Genentech: Research Funding; Abbvie: Research Funding; Novartis: Research Funding; Acerta: Research Funding. Jain:Servier: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Celgene: Research Funding; Novimmune: Consultancy, Honoraria; Infinity: Research Funding; BMS: Research Funding; Seattle Genetics: Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Consultancy, Honoraria, Research Funding; Abbvie: Research Funding; Genentech: Research Funding; Novartis: Consultancy, Honoraria; Incyte: Research Funding. O9Brien:Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria. Konopleva:Cellectis: Research Funding; Calithera: Research Funding. Daver:Pfizer: Consultancy, Research Funding; Otsuka: Consultancy, Honoraria; Ariad: Research Funding; Karyopharm: Honoraria, Research Funding; Kiromic: Research Funding; BMS: Research Funding; Sunesis: Consultancy, Research Funding. Thompson:Pharmacyclics: Consultancy, Honoraria. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding.
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Improving Nelarabine efficacy in T cell acute lymphoblastic leukemia by targeting aberrant PI3K/AKT/mTOR signaling pathway
Journal of Hematology & Oncology, 2016Co-Authors: Annalisa Lonetti, Alessandra Cappellini, Alice Bertaina, Franco Locatelli, Andrea Pession, Francesca Buontempo, Camilla Evangelisti, Ester Orsini, Laura ZamboninAbstract:Background Although in recent years, the introduction of novel chemotherapy protocols has improved the outcome of T cell acute lymphoblastic leukemia (T-ALL) patients, refractory and/or relapsing disease remains a foremost concern. In this context, a major contribution was provided by the introduction of the nucleoside analog Nelarabine, approved for salvage treatment of T-ALL patients with refractory/relapsed disease. However, Nelarabine could induce a life-threatening, dose-dependent neurotoxicity. To improve Nelarabine efficacy, we have analyzed its molecular targets, testing selective inhibitors of such targets in combination with Nelarabine. Methods The effectiveness of Nelarabine as single agent or in combination with PI3K, Bcl2, and MEK inhibitors was evaluated on human T-ALL cell lines and primary T-ALL refractory/relapsed lymphoblasts. The efficacy of signal modulators in terms of cytotoxicity, induction of apoptosis, and changes in gene and protein expression was assessed by flow cytometry, western blotting, and quantitative real-time PCR in T-ALL settings. Results Treatment with Nelarabine as a single agent identified two groups of T-ALL cell lines, one sensitive and one resistant to the drug. Whereas sensitive T-ALL cells showed a significant increase of apoptosis and a strong down-modulation of PI3K signaling, resistant T-ALL cells showed a hyperactivation of AKT and MEK/ERK1/2 signaling pathways, not caused by differences in the expression of Nelarabine transporters or metabolic activators. We then studied the combination of Nelarabine with the PI3K inhibitors (both pan and dual γ/δ inhibitors), with the Bcl2 specific inhibitor ABT199, and with the MEK inhibitor trametinib on both T-ALL cell lines and patient samples at relapse, which displayed constitutive activation of PI3K signaling and resistance to Nelarabine alone. The combination with the pan PI3K inhibitor ZSTK-474 was the most effective in inhibiting the growth of T-ALL cells and was synergistic in decreasing cell survival and inducing apoptosis in Nelarabine-resistant T-ALL cells. The drug combination caused AKT dephosphorylation and a downregulation of Bcl2, while Nelarabine alone induced an increase in p-AKT and Bcl2 signaling in the resistant T-ALL cells and relapsed patient samples. Conclusions These findings indicate that Nelarabine in combination with PI3K inhibitors may be a promising therapeutic strategy for the treatment of T-ALL relapsed patients.
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improving Nelarabine efficacy in t cell acute lymphoblastic leukemia by targeting aberrant pi3k akt mtor signaling pathway
Journal of Hematology & Oncology, 2016Co-Authors: Annalisa Lonetti, Alessandra Cappellini, Alice Bertaina, Franco Locatelli, Andrea Pession, Francesca Buontempo, Camilla Evangelisti, Ester Orsini, Laura ZamboninAbstract:Although in recent years, the introduction of novel chemotherapy protocols has improved the outcome of T cell acute lymphoblastic leukemia (T-ALL) patients, refractory and/or relapsing disease remains a foremost concern. In this context, a major contribution was provided by the introduction of the nucleoside analog Nelarabine, approved for salvage treatment of T-ALL patients with refractory/relapsed disease. However, Nelarabine could induce a life-threatening, dose-dependent neurotoxicity. To improve Nelarabine efficacy, we have analyzed its molecular targets, testing selective inhibitors of such targets in combination with Nelarabine. The effectiveness of Nelarabine as single agent or in combination with PI3K, Bcl2, and MEK inhibitors was evaluated on human T-ALL cell lines and primary T-ALL refractory/relapsed lymphoblasts. The efficacy of signal modulators in terms of cytotoxicity, induction of apoptosis, and changes in gene and protein expression was assessed by flow cytometry, western blotting, and quantitative real-time PCR in T-ALL settings. Treatment with Nelarabine as a single agent identified two groups of T-ALL cell lines, one sensitive and one resistant to the drug. Whereas sensitive T-ALL cells showed a significant increase of apoptosis and a strong down-modulation of PI3K signaling, resistant T-ALL cells showed a hyperactivation of AKT and MEK/ERK1/2 signaling pathways, not caused by differences in the expression of Nelarabine transporters or metabolic activators. We then studied the combination of Nelarabine with the PI3K inhibitors (both pan and dual γ/δ inhibitors), with the Bcl2 specific inhibitor ABT199, and with the MEK inhibitor trametinib on both T-ALL cell lines and patient samples at relapse, which displayed constitutive activation of PI3K signaling and resistance to Nelarabine alone. The combination with the pan PI3K inhibitor ZSTK-474 was the most effective in inhibiting the growth of T-ALL cells and was synergistic in decreasing cell survival and inducing apoptosis in Nelarabine-resistant T-ALL cells. The drug combination caused AKT dephosphorylation and a downregulation of Bcl2, while Nelarabine alone induced an increase in p-AKT and Bcl2 signaling in the resistant T-ALL cells and relapsed patient samples. These findings indicate that Nelarabine in combination with PI3K inhibitors may be a promising therapeutic strategy for the treatment of T-ALL relapsed patients.
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Additional file 4: Figure S4. of Improving Nelarabine efficacy in T cell acute lymphoblastic leukemia by targeting aberrant PI3K/AKT/mTOR signaling pathway
2016Co-Authors: Annalisa Lonetti, Alessandra Cappellini, Alice Bertaina, Franco Locatelli, Andrea Pession, Francesca Buontempo, Camilla Evangelisti, Ester Orsini, Laura ZamboninAbstract:The combination of Nelarabine and ZSTK-474 is synergistic in CEM-R cells, which overexpress P-gp. Cell viability assay of CEM-R cell line treated for 48Â h with increasing concentrations of Nelarabine alone or combined with the pan PI3K p110 inhibitor ZSTK-474. One representative of two different experiments is shown.
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Additional file 5: Figure S5. of Improving Nelarabine efficacy in T cell acute lymphoblastic leukemia by targeting aberrant PI3K/AKT/mTOR signaling pathway
2016Co-Authors: Annalisa Lonetti, Alessandra Cappellini, Alice Bertaina, Franco Locatelli, Andrea Pession, Francesca Buontempo, Camilla Evangelisti, Ester Orsini, Laura ZamboninAbstract:Specific effects of Nelarabine on PI3K/AKT and MEK/ERK1/2 pathways. Western blotting analyses for the expression of p-AKT and p-ERK in resistant T-ALL cell lines treated with the specific inhibitors LY294002 (PI3K inhibitor), CCI-779 (mTOR allosteric inhibitor) or trametinib (MEK1/2 inhibitor) alone or in combination with Nelarabine. Thirty micrograms of protein was blotted to each lane. Antibody to β-actin served as a loading control. Molecular weights are indicated on the right. CTRL: untreated cells; Nela and N: Nelarabine at 10 μM; LY: LY294002 at 10 μM; CCI: CCI-779 at 100 nM; Tram: trametinib at 1 μM. Cells were treated for 48 h
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additional file 4 figure s4 of improving Nelarabine efficacy in t cell acute lymphoblastic leukemia by targeting aberrant pi3k akt mtor signaling pathway
2016Co-Authors: Annalisa Lonetti, Alessandra Cappellini, Alice Bertaina, Franco Locatelli, Andrea Pession, Francesca Buontempo, Camilla Evangelisti, Ester Orsini, Laura ZamboninAbstract:The combination of Nelarabine and ZSTK-474 is synergistic in CEM-R cells, which overexpress P-gp. Cell viability assay of CEM-R cell line treated for 48Â h with increasing concentrations of Nelarabine alone or combined with the pan PI3K p110 inhibitor ZSTK-474. One representative of two different experiments is shown.
