کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
10899510 | 1084383 | 2015 | 26 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Identification of a novel synergistic induction of cell death by Smac mimetic and HDAC inhibitors in acute myeloid leukemia cells
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کلمات کلیدی
PBLXIAPRIP1NSAnecrostatin-1IAPFSC/SSCFLT3FCSTNFR1SMACMLKLHDACTNFAMLGAPDHHEPESzVAD.fmknecrosulfonamideFACSNF-κBN-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid - 4- (2-hydroxyethyl) -1-piperazineethanesulfonic acidcIAP - ciapHDACis - HDACNec-1 - NEC-1Ring - حلقهApoptosis - خزان یاختهایfetal calf serum - سرم گوساله جنینcombination index - شاخص ترکیبیtumor necrosis factor - فاکتور نکروز تومورnuclear factor kappaB - فاکتور هسته ای kappaBTRAIL - قطارperipheral blood lymphocyte - لنفوسیت خون محیطیleukemia - لوسمیacute myeloid leukemia - لوسمی حاد میلوئیدی یا به اختصار AMLTNF-related apoptosis-inducing ligand - لیگاند ناشی از آپوپتوز مرتبط با TNFHDAC inhibitors - مانع از HDACFMS-like tyrosine kinase 3 - مانند تریروزین کیناز 3 FMS مانندinhibitor of apoptosis protein - مهار کننده پروتئین آپوپتوزیسX-linked inhibitor of apoptosis - مهارکننده آپوپتوز X مرتبط با آنcellular inhibitor of apoptosis protein - مهارکننده سلولی پروتئین آپوپتوزNecroptosis - نئروپتوزیسhistone deacetylase - هیستون داستیلازreceptor-interacting protein 1 - پروتئین تعامل گیرنده 1mixed lineage kinase domain-like protein - پروتئین مشابه پروتئین کیناز لینوکسی مخلوطPropidium iodide - پروتئین یدیدreally interesting new gene - ژن جدید واقعا جالبglyceraldehyde 3-phosphate dehydrogenase - گلیسرولیدید 3-فسفات دهیدروژنازtumor necrosis factor receptor 1 - گیرنده فاکتور نکروز تومور 1
موضوعات مرتبط
علوم زیستی و بیوفناوری
بیوشیمی، ژنتیک و زیست شناسی مولکولی
تحقیقات سرطان
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
Inhibitor of Apoptosis (IAP) proteins are expressed at high levels in acute myeloid leukemia (AML) and contribute to resistance to programmed cell death. Here, we report that inhibition of IAP proteins by the small-molecule Smac mimetic BV6 acts together with histone deacetylase (HDAC) inhibitors (HDACIs) such as MS275 or SAHA to trigger cell death in AML cell lines in a synergistic manner, as underscored by calculation of combination index (CI). Also, BV6 and HDACIs cooperate to trigger DNA fragmentation, a marker of apoptotic cell death, and to suppress long-term clonogenic survival of AML cells. In contrast, equimolar concentrations of BV6 and MS275 or SAHA do not synergize to elicit cell death in normal peripheral blood lymphocytes (PBLs), emphasizing some tumor cell selectivity of this combination treatment. Addition of the tumor necrosis factor (TNF)α-blocking antibody Enbrel significantly reduces BV6/MS275-induced cell death in the majority of AML cell lines, indicating that autocrine/paracrine TNFα signaling contributes to cell death. Remarkably, the broad-range caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (zVAD.fmk) fails to rescue MV4-11, Molm13 and OCI-AML3 cells and even enhances BV6/MS275-mediated cell death, whereas zVAD.fmk reduces BV6/MS275-induced cell death in NB4 cells. Annexin-V/propidium iodide (PI) double staining reveals that BV6/MS275 cotreatment predominately increases the percentage of double-positive cells. Of note, the Receptor-Interacting Protein (RIP)1 inhibitor necrostatin-1 (Nec-1) or the Mixed Lineage Kinase Domain-Like protein (MLKL) inhibitor necrosulfonamide (NSA) significantly reduce BV6/MS275-induced cell death in the presence of zVAD.fmk, suggesting that BV6/MS275 cotreatment triggers necroptosis when caspases are inhibited. Thus, BV6 acts in concert with HDACIs to induce cell death in AML cells and can bypass apoptosis resistance, at least in several AML cell lines, by engaging necroptosis as an alternative route of regulated cell death. The identification of a novel synergism of BV6 and HDACIs has important implications for the development of new treatment strategies for AML.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Cancer Letters - Volume 366, Issue 1, 28 September 2015, Pages 32-43
Journal: Cancer Letters - Volume 366, Issue 1, 28 September 2015, Pages 32-43
نویسندگان
Sofie Steinwascher, Anne-Lucie Nugues, Hannah Schoeneberger, Simone Fulda,