title: Combined inhibition of integrin linked kinase and FMS-like tyrosine kinase 3 is cytotoxic to acute myeloid leukemia progenitor cells.
abstract: OBJECTIVE
  Dysregulation 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.
  
  
  METHODS
  AML 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.
  
  
  RESULTS
  In 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 >or= 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 (IC(50)=3 microM, vs 10 microM for AML-CFC and normal CFC, respectively, n=5).
  
  
  CONCLUSIONS
  Combined inhibition of ILK and FLT-3 with a small molecule kinase inhibitor can achieve selective targeting of AML rather than normal hematopoietic progenitors.
authors.affiliation: British Columbia Cancer Research Centre, Vancouver, Canada.
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Muranyi
authors.forename: Shoukat
authors.initials: S
authors.lastname: Dedhar
authors.forename: Donna E
authors.initials: DE
authors.lastname: Hogge
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use; D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000201:enzymology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007951:Leukemia, Myeloid / Q000188:drug therapy*; D007963:Leukocytes, Mononuclear / Q000201:enzymology; D008297:Male; D008875:Middle Aged; D023461:Myeloid Progenitor Cells / Q000187:drug effects*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects*; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors*; D000099200:Scaffold Protein ILK
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D017346:Protein Serine-Threonine Kinases; D051941:fms-Like Tyrosine Kinase 3; D000099200:Scaffold Protein ILK