Montelukast, a cysteinyl leukotriene receptor antagonist, inhibits the growth of chronic myeloid leukemia cells through apoptosis

Zovko,Ana; Yektaei-Karin,Elham; Salamon,Daniel; Nilsson,Anders; Wallvik,Jonas; Stenke,Leif

doi:10.3892/or.2018.6465

Montelukast, a cysteinyl leukotriene receptor antagonist, inhibits the growth of chronic myeloid leukemia cells through apoptosis

Authors:
- Ana Zovko
- Elham Yektaei-Karin
- Daniel Salamon
- Anders Nilsson
- Jonas Wallvik
- Leif Stenke
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Affiliations: Department of Oncology-Pathology, Karolinska Biomics Center, Karolinska Institute, Solna, S-171 76 Stockholm, Sweden, Department of Women's and Children's Health, Karolinska Institute, Solna, S-171 76 Stockholm, Sweden, Department of Public Health and Clinical Medicine, Umeå University, S-901 85 Umeå, Sweden
Published online on: May 25, 2018 https://doi.org/10.3892/or.2018.6465
Pages: 902-908

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Abstract

The clinical outcome for patients with chronic myeloid leukemia (CML) has improved significantly with the introduction of tyrosine kinase inhibitors (TKIs). However, their curative potential appears limited, probably as a consequence of TKI-resistant leukemic stem cells (LSCs) that persist as a result of aberrant pathways independent of the well-established oncoprotein Bcr-Abl. One such pathway involves signaling through leukotrienes (LTs), bioactive compounds that have been suggested to play a role in several other malignancies. Cysteinyl LT1 receptor (CysLT1R) has been reported to be overexpressed in a number of solid cancers, and blocking of this receptor with the antagonist montelukast (treatment approved for bronchial asthma) has resulted in the killing of cancer cells. We recently demonstrated that montelukast, alone or in combination with imatinib, can effectively reduce the growth of CML cells, while normal bone marrow cells were left unaffected. Herein, we further investigated the importance of CysLT1R for the survival of CML cells and the mechanisms by which montelukast induces cell death. Knockdown of the CysLT1R of K562 cells with siRNA reduced their growth by 25%. Montelukast had no effect on these cells, while it killed more than 50% of CysLT1R-expressing cells. Growth inhibition exerted by imatinib was unaffected by CysLT1R status. Montelukast-induced killing of K562/JURL-MK1 CML cells was paralleled by Bax overexpression, cytochrome c release, PARP-1 cleavage, and caspase-3 activation, an event further increased in a setting where montelukast was added to imatinib. Wnt/β-catenin signaling was activated by CysLT1R and we observed that montelukast could induce proteins in this pathway, a finding of relevance for LSC survival. Thus, montelukast, employed at in vivo-like concentrations, induces the killing of CML cells through apoptotic pathways and may provide an additional, novel therapeutic possibility in CML.

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