کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
10801767 | 1055635 | 2016 | 10 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Combination of galectin inhibitor GCS-100 and BH3 mimetics eliminates both p53 wild type and p53 null AML cells
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کلمات کلیدی
LGALS3AMLFANCD2TET1p53Mcl-1ERKqRT-PCRGCN2GSK3NPM1Bcl2Bcl-xLReal-time PCR - PCR به موقعAkt - آکتB cell lymphoma 2 - لنفوم سلول B 2leukemia - لوسمیacute myeloid leukemia - لوسمی حاد میلوئیدی یا به اختصار AMLMyeloid cell leukemia 1 - لوسمی سلول میلوئید 1Acute lymphoblastic leukemia - لوسمی لنفوبلاستیک حادNucleophosmin 1 - نوکلئوفسمی 1Signal transduction - هدایت سیگنالprotein kinase B - پروتئین کیناز Bgeneral control nonderepressible 2 - کنترل کلی غیر قابل تعویض 2extracellular receptor kinase - کیناز گیرنده خارج سلولیgalectin - گالکتینgalectin 1 - گالکتین 1galectin 3 - گالکتین 3glycogen synthase kinase 3 - گلیکوزین سنتاز کیناز 3
موضوعات مرتبط
علوم زیستی و بیوفناوری
بیوشیمی، ژنتیک و زیست شناسی مولکولی
زیست شیمی
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
Galectin 3 (LGALS3) expression is prognostic for poor survival in acute myeloid leukemia (AML) patients. GCS-100 is a novel galectin inhibitor that may prove useful for AML therapy. In this study, we found that GCS-100 induced apoptosis in AML cells. The agent reduced MCL-1 expression suggesting that GCS-100 could be more effective when combined with a BH3 mimetic. Indeed, potent synergistic cytotoxicity was achieved when GCS-100 was combined with ABT-737 or ABT-199. Furthermore, the GCS-100/ABT-199 combination was effective against primary AML blast cells from patients with FLT3 ITD mutations, which is another prognostic factor for poor outcome in AML. This activity may involve wild-type p53 as shRNA knockdown of LGALS3 or galectin 1 (LGALS1) sensitized wild-type p53 OCI-AML3 cells to GCS-100/ABT-737-induced apoptosis to a much greater extent than p53 null THP-1 cells. Suppression of LGALS3 by shRNA inhibited MCL-1 expression in OCI-AML3 cells, but not THP-1 cells, suggesting the induced sensitivity to ABT-737 may involve a MCL-1 mediated mechanism. OCI-AML3 cells with LGALS1 shRNA were also sensitized to ABT-737. However, these cells exhibited increased MCL-1 expression, so MCL-1 reduction is apparently not required in this process. A role for p53 appears important as GCS-100 induces p53 expression and shRNA knockdown of p53 protected OCI-AML3 cells from the cytotoxic effects of the GCS-100/ABT-737 treatment combination. Our results suggest that galectins regulate a survival axis in AML cells, which may be targeted via combined inhibition with drugs such as GCS-100 and ABT-199.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Biochimica et Biophysica Acta (BBA) - Molecular Cell Research - Volume 1863, Issue 4, April 2016, Pages 562-571
Journal: Biochimica et Biophysica Acta (BBA) - Molecular Cell Research - Volume 1863, Issue 4, April 2016, Pages 562-571
نویسندگان
Peter P. Ruvolo, Vivian R. Ruvolo, Christopher B. Benton, Ahmed AlRawi, Jared K. Burks, Wendy Schober, James Rolke, George Tidmarsh, Numsen Jr, R. Eric Davis, Michael Andreeff,