Improving nelarabine efficacy in T cell acute lymphoblastic leukemia by targeting aberrant PI3K/AKT/mTOR signaling pathway
| Autor: | Francesca Buontempo, Camilla Evangelisti, Andrea Pession, Luca M. Neri, Francesca Chiarini, Annalisa Lonetti, Alessandra Cappellini, Laura Zambonin, Alice Bertaina, Alberto M. Martelli, Cecilia Evangelisti, Ester Orsini, Franco Locatelli |
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| Přispěvatelé: | Lonetti, A., Cappellini, A., Bertaina, A., Locatelli, F., Pession, A., Buontempo, F., Evangelisti, C., Orsini, E., Zambonin, L., Neri, L.M., Martelli, A.M., Chiarini, F. |
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Cancer Research medicine.medical_treatment Apoptosis Pharmacology Precursor T-Cell Lymphoblastic Leukemia-Lymphoma 0302 clinical medicine Antineoplastic Combined Chemotherapy Protocols Tumor Cells Cultured PI3K signaling Phosphoinositide-3 Kinase Inhibitors Trametinib Sulfonamides Triazines Keywords: PI3K signaling Apoptosis Drug resistance Combination therapy TOR Serine-Threonine Kinases MEK inhibitor Drug Synergism Hematology lcsh:Diseases of the blood and blood-forming organs lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens 3. Good health medicine.anatomical_structure Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA Oncology 030220 oncology & carcinogenesis apoptosis combination therapy drug resistance Signal Transduction medicine.drug Combination therapy Cell Survival Pyridones T cell Pyrimidinones Drug resistance lcsh:RC254-282 NO 03 medical and health sciences medicine Humans Protein kinase B Molecular Biology PI3K/AKT/mTOR pathway Chemotherapy business.industry lcsh:RC633-647.5 Research Keywords: PI3K signaling Apoptosi Bridged Bicyclo Compounds Heterocyclic 030104 developmental biology Nelarabine Arabinonucleosides business Proto-Oncogene Proteins c-akt |
| Zdroj: | Journal of Hematology & Oncology, Vol 9, Iss 1, Pp 1-16 (2016) Journal of Hematology & Oncology Europe PubMed Central |
| ISSN: | 1756-8722 |
| DOI: | 10.1186/s13045-016-0344-4 |
| Popis: | 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. Electronic supplementary material The online version of this article (doi:10.1186/s13045-016-0344-4) contains supplementary material, which is available to authorized users. |
| Databáze: | OpenAIRE |
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