title: Modulation of leukotriene signaling inhibiting cell growth in chronic myeloid leukemia.
abstract: Although tyrosine kinase inhibitors (TKIs) have dramatically improved clinical outcome in chronic myeloid leukemia (CML), cure rarely occurs. This may be due to BCR-ABL-independent, aberrant signaling pathways, one of which leads to leukotriene (LT) formation. Well-recognized as inflammatory mediators, LT can also affect oncogenic mechanisms of several tumors. We have previously discovered elevated LT-synthesis and up-regulated cysteinyl-LT-inducing enzyme in CML. Here we report on dose-dependent inhibition of CML cell growth exerted by specific blockers of LT-signaling. Thus, the cysteinyl-LT1-receptor-antagonist montelukast significantly reduced the growth of K562, KCL22, and KU812 cells, as well as primary CD34+blood cells from two CML patients. Adding montelukast to the TKI imatinib caused combined inhibition. No effect was seen on normal bone marrow cells. Similarly, growth inhibition was also observed with the 5-lipoxygenase (LO)-inhibitor BWA4C, the 5-LO-activating-protein-(FLAP)-inhibitor licofelone and the LTB4(BLT1)-receptor-antagonist LY293111. Thus, blocking of aberrant LT-signaling may provide an additional, novel therapeutic possibility in CML.
authors.affiliation: a Department of Oncology-Pathology , Karolinska Institutet , Stockholm , Sweden.
authors.forename: Elham
authors.initials: E
authors.lastname: Yektaei-Karin
authors.affiliation: a Department of Oncology-Pathology , Karolinska Institutet , Stockholm , Sweden.
authors.forename: Ana
authors.initials: A
authors.lastname: Zovko
authors.affiliation: a Department of Oncology-Pathology , Karolinska Institutet , Stockholm , Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Nilsson
authors.affiliation: a Department of Oncology-Pathology , Karolinska Institutet , Stockholm , Sweden.
authors.forename: Barbro
authors.initials: B
authors.lastname: Näsman-Glaser
authors.affiliation: a Department of Oncology-Pathology , Karolinska Institutet , Stockholm , Sweden.
authors.forename: Lena
authors.initials: L
authors.lastname: Kanter
authors.affiliation: b Department of Medical Biochemistry and Biophysics , Karolinska Institutet , Stockholm , Sweden.
authors.forename: Olof
authors.initials: O
authors.lastname: Rådmark
authors.affiliation: c Department of Public Health and Clinical Medicine , Umeå University , Umeå , Sweden.
authors.forename: Jonas
authors.initials: J
authors.lastname: Wallvik
authors.affiliation: d Department of Laboratory Medicine , Lund University, Lund, Sweden.
authors.forename: Marja
authors.initials: M
authors.lastname: Ekblom
authors.affiliation: e Department of Medicine, Center for Hematology and Regenerative Medicine , Karolinska Institutet , Stockholm , Sweden.
authors.forename: Monika
authors.initials: M
authors.lastname: Dolinska
authors.affiliation: e Department of Medicine, Center for Hematology and Regenerative Medicine , Karolinska Institutet , Stockholm , Sweden.
authors.forename: Hong
authors.initials: H
authors.lastname: Qian
authors.affiliation: a Department of Oncology-Pathology , Karolinska Institutet , Stockholm , Sweden.|f Department of Medicine, Division of Hematology , Karolinska University Hospital, Karolinska Institutet , Stockholm , Sweden.
authors.forename: Leif
authors.initials: L
authors.lastname: Stenke
mesh_terms: D053898:Biosynthetic Pathways / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000378:metabolism* / Q000473:pathology; D020024:Leukotriene Antagonists / Q000494:pharmacology; D015289:Leukotrienes / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D018077:Receptors, Leukotriene / Q000378:metabolism; D018102:Receptors, Leukotriene B4 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D020024:Leukotriene Antagonists; D015289:Leukotrienes; D047428:Protein Kinase Inhibitors; D018077:Receptors, Leukotriene; D018102:Receptors, Leukotriene B4; C083169:leukotriene D4 receptor
keywords: Chronic myeloid leukemia; leukotrienes; pharmacotherapeutics