دورية أكاديمية
Clinical MDR1 inhibitors enhance Smac-mimetic bioavailability to kill murine LSCs and improve survival in AML models
| العنوان: | Clinical MDR1 inhibitors enhance Smac-mimetic bioavailability to kill murine LSCs and improve survival in AML models |
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| المؤلفون: | Morrish, E, Copeland, A, Moujalled, DM, Powell, JA, Silke, N, Lin, A, Jarman, KE, Sandow, JJ, Ebert, G, Mackiewicz, L, Beach, JA, Christie, EL, Lewis, AC, Pomilio, G, Fischer, KC, MacPherson, L, Bowtell, DDL, Webb, A, Pellegrini, M, Dawson, MA, Pitson, SM, Wei, AH, Silke, J, Brumatti, G |
| بيانات النشر: | AMER SOC HEMATOLOGY |
| سنة النشر: | 2020 |
| المجموعة: | The University of Melbourne: Digital Repository |
| الوصف: | The specific targeting of inhibitor of apoptosis (IAP) proteins by Smac-mimetic (SM) drugs, such as birinapant, has been tested in clinical trials of acute myeloid leukemia (AML) and certain solid cancers. Despite their promising safety profile, SMs have had variable and limited success. Using a library of more than 5700 bioactive compounds, we screened for approaches that could sensitize AML cells to birinapant and identified multidrug resistance protein 1 inhibitors (MDR1i) as a class of clinically approved drugs that can enhance the efficacy of SM therapy. Genetic or pharmacological inhibition of MDR1 increased intracellular levels of birinapant and sensitized AML cells from leukemia murine models, human leukemia cell lines, and primary AML samples to killing by birinapant. The combination of clinical MDR1 and IAP inhibitors was well tolerated in vivo and more effective against leukemic cells, compared with normal hematopoietic progenitors. Importantly, birinapant combined with third-generation MDR1i effectively killed murine leukemic stem cells (LSCs) and prolonged survival of AML-burdened mice, suggesting a therapeutic opportunity for AML. This study identified a drug combination strategy that, by efficiently killing LSCs, may have the potential to improve outcomes in patients with AML. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| تدمد: | 2473-9529 2473-9537 |
| العلاقة: | pii: S2473-9529(20)31902-9; Morrish, E., Copeland, A., Moujalled, D. M., Powell, J. A., Silke, N., Lin, A., Jarman, K. E., Sandow, J. J., Ebert, G., Mackiewicz, L., Beach, J. A., Christie, E. L., Lewis, A. C., Pomilio, G., Fischer, K. C., MacPherson, L., Bowtell, D. D. L., Webb, A., Pellegrini, M. ,. Brumatti, G. (2020). Clinical MDR1 inhibitors enhance Smac-mimetic bioavailability to kill murine LSCs and improve survival in AML models. BLOOD ADVANCES, 4 (20), pp.5062-5077. https://doi.org/10.1182/bloodadvances.2020001576Test.; http://hdl.handle.net/11343/254274Test |
| الإتاحة: | https://doi.org/10.1182/bloodadvances.2020001576Test http://hdl.handle.net/11343/254274Test |
| رقم الانضمام: | edsbas.624A99DE |
| قاعدة البيانات: | BASE |
Full Text Finder | تدمد: | 24739529 24739537 |
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