title: Small molecule inhibitors of WNT signaling effectively induce apoptosis in acute myeloid leukemia cells.
abstract: In a significant proportion of acute myeloid leukemia (AML) cases the canonical WNT pathway is upregulated and targeting the WNT/LEF1 signaling cascade in AML may be a promising approach to develop new treatments for this entity. Recently two compounds (CGP049090 and PFK115-584) have been identified, which specifically inhibit complexation of beta-catenin (CTNNB1) and lymphoid enhancer-binding factor 1 (LEF1) leading to transcriptional inactivation of LEF1 in colon carcinoma cell lines. To evaluate the effect of WNT inhibition utilizing theses compounds with regard to their effectivity in AML we treated the AML cell lines Kasumi-1 and HL-60, primary AML blasts and healthy peripheral blood mononuclear cells (PBMCs) with varying concentrations of both substances. Treatment with both compounds for 24 h resulted in a significant killing of AML cell lines and primary AML blasts with 50% effective concentration doses (EC(50)) within the submicromolar range. PBMCs were not significantly affected as indicated by EC(50)-values 100-fold higher than for AML cells. Cell kill was mediated by apoptosis as indicated by induction of caspases 3 and 7 and cleavage of poly(ADP-ribose) polymerase (PARP) upon treatment. Furthermore, we could show that both compounds substantially decrease expression of CTNNB1/LEF1 target genes c-myc, cyclin D1 and survivin, proofing the specificity of the substances. This was shown in both, AML cell lines and most of the tested primary samples. Our data demonstrate that targeting this pathway seems to be an innovative approach in the treatment of AML.
authors.affiliation: Department I of Internal Medicine, University at Cologne, Cologne, Germany.
authors.forename: Katharina Salome
authors.initials: KS
authors.lastname: Minke
authors.forename: Peter
authors.initials: P
authors.lastname: Staib
authors.forename: Adriane
authors.initials: A
authors.lastname: Puetter
authors.forename: Iris
authors.initials: I
authors.lastname: Gehrke
authors.forename: Rajesh Kumar
authors.initials: RK
authors.lastname: Gandhirajan
authors.forename: Axel
authors.initials: A
authors.lastname: Schlösser
authors.forename: Esther Katharina
authors.initials: EK
authors.lastname: Schmitt
authors.forename: Michael
authors.initials: M
authors.lastname: Hallek
authors.forename: Karl-Anton
authors.initials: KA
authors.lastname: Kreuzer
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000187:drug effects*; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism* / Q000473:pathology*; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D015394:Molecular Structure; D010569:Perylene / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D014407:Tumor Cells, Cultured; D051153:Wnt Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
chemical_list: C538948:CGP049090; C495270:CTNNB1 protein, human; D051821:Lymphoid Enhancer-Binding Factor 1; C538949:PKF115-584; D051153:Wnt Proteins; D051176:beta Catenin; D010569:Perylene; D000255:Adenosine Triphosphate