کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
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2134297 | 1087461 | 2009 | 11 صفحه PDF | دانلود رایگان |
ObjectiveDysregulation of signaling pathways leading to enhanced cell proliferation and resistance to apoptosis is frequent in acute myeloid leukemia (AML). The effectiveness of inhibiting two such pathways, the phosphatidylinosityl-3-kinase pathway via the intermediate integrin-linked kinase (ILK), and FMS-like tyrosine kinase–3 (FLT-3) signaling pathway in killing AML cells was studied.Materials and MethodsAML colony-forming cell (CFC) assays were used to determine the effects of a small molecule inhibitor of both ILK and FLT-3 (QLT0267) on poor prognosis primary AML sample viability. Kinase assays and Western blots were used to analyze effects of the compound on target molecules.ResultsIn 31/36 AML blast samples p-Akt was detected indicating phosphatidylinosityl-3-kinase activation. ILK was ubiquitously and FLT-3 abundantly expressed. Downregulation of ILK in the AML cell line TF-1 using small interfering RNA caused ≥50% CFC death, suggesting ILK inhibition might also be toxic to primary AML cells. In vitro kinase assays on three AML samples showed inhibition of both ILK and FLT-3 by QLT0267. Treatment of AML patient blast cells (n = 27) with QLT0267, caused a dose- and time-dependent downregulation of p-Akt and kill of AML-CFC with AML samples containing FLT-3 mutations being more sensitive to QLT0267 than those without. AML samples were more sensitive to QLT0267 killing than normal bone marrow (IC50 = 3 μM, vs 10 μM for AML-CFC and normal CFC, respectively, n = 5).ConclusionCombined inhibition of ILK and FLT-3 with a small molecule kinase inhibitor can achieve selective targeting of AML rather than normal hematopoietic progenitors.
Journal: - Volume 37, Issue 4, April 2009, Pages 450–460