title: 5-Lipoxygenase is a candidate target for therapeutic management of stem cell-like cells in acute myeloid leukemia.
abstract: Nonsteroidal anti-inflammatory drugs such as sulindac inhibit Wnt signaling, which is critical to maintain cancer stem cell-like cells (CSC), but they also suppress the activity of 5-lipoxygenase (5-LO) at clinically feasible concentrations. Recently, 5-LO was shown to be critical to maintain CSC in a model of chronic myeloid leukemia. For these reasons, we hypothesized that 5-LO may offer a therapeutic target to improve the management of acute myeloid leukemia (AML), an aggressive disease driven by CSCs. Pharmacologic and genetic approaches were used to evaluate the effects of 5-LO blockade in a PML/RARα-positive model of AML. As CSC models, we used Sca-1(+)/lin(-) murine hematopoietic stem and progenitor cells (HSPC), which were retrovirally transduced with PML/RARα. We found that pharmacologic inhibition of 5-LO interfered strongly with the aberrant stem cell capacity of PML/RARα-expressing HSPCs. Through small-molecule inhibitor studies and genetic disruption of 5-LO, we also found that Wnt and CSC inhibition is mediated by the enzymatically inactive form of 5-LO, which hinders nuclear translocation of β-catenin. Overall, our findings revealed that 5-LO inhibitors also inhibit Wnt signaling, not due to the interruption of 5-LO-mediated lipid signaling but rather due to the generation of a catalytically inactive form of 5-LO, which assumes a new function. Given the evidence that CSCs mediate AML relapse after remission, eradication of CSCs in this setting by 5-LO inhibition may offer a new clinical approach for immediate evaluation in patients with AML. Cancer Res; 74(18); 5244-55. ©2014 AACR.
authors.affiliation: Department of Hematology, Goethe University, Frankfurt, Germany.
authors.forename: Jessica
authors.initials: J
authors.lastname: Roos
authors.affiliation: Department of Hematology, Goethe University, Frankfurt, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Oancea
authors.affiliation: Department of Hematology, Goethe University, Frankfurt, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Heinssmann
authors.affiliation: Department of Hematology, Goethe University, Frankfurt, Germany.
authors.forename: Dilawar
authors.initials: D
authors.lastname: Khan
authors.affiliation: Department of Hematology, Goethe University, Frankfurt, Germany.
authors.forename: Hannelore
authors.initials: H
authors.lastname: Held
authors.affiliation: Department of Pharmaceutical Chemistry, Goethe University, Frankfurt, Germany.
authors.forename: Astrid S
authors.initials: AS
authors.lastname: Kahnt
authors.affiliation: Department of Pharmaceutical Chemistry, Goethe University, Frankfurt, Germany.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Capelo
authors.affiliation: Department of Pharmaceutical Chemistry, Goethe University, Frankfurt, Germany.
authors.forename: Estel
authors.initials: E
authors.lastname: la Buscató
authors.affiliation: Department of Pharmaceutical Chemistry, Goethe University, Frankfurt, Germany.
authors.forename: Ewgenij
authors.initials: E
authors.lastname: Proschak
authors.affiliation: Institute for Molecular Biology and Tumor Research, Philipps University, Marburg, Germany.
authors.forename: Elena
authors.initials: E
authors.lastname: Puccetti
authors.affiliation: Department of Pharmaceutical Chemistry, Goethe University, Frankfurt, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Steinhilber
authors.affiliation: Centre of Molecular Medicine, Goethe University, Frankfurt, Germany.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Fleming
authors.affiliation: Department of Pharmaceutical Chemistry, Goethe University, Frankfurt, Germany. Institute of Biomedicine, Pharmacology, Aarhus University, Aarhus C, Denmark.
authors.forename: Thorsten J
authors.initials: TJ
authors.lastname: Maier
authors.affiliation: Department of Hematology, Goethe University, Frankfurt, Germany. ruthardt@em.uni-frankfurt.de.
authors.forename: Martin
authors.initials: M
authors.lastname: Ruthardt
mesh_terms: D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism*; D045744:Cell Line, Tumor; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology*; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D010957:Plasmids; D015398:Signal Transduction; D014162:Transfection
chemical_list: D016859:Lipoxygenase Inhibitors; D001094:Arachidonate 5-Lipoxygenase