title: Regulation of tumorigenic Wnt signaling by cyclooxygenase-2, 5-lipoxygenase and their pharmacological inhibitors: A basis for novel drugs targeting cancer cells?
abstract: Canonical Wnt signaling is a highly conserved pathway with a prominent role in embryogenic development, adult tissue homeostasis, cell polarization, stem cell biology, cell differentiation, and proliferation. Furthermore, canonical Wnt signaling is of pivotal importance in the pathogenesis of a number of cancer types and crucially affects tumor initiation, cancer cell proliferation, cancer cell apoptosis, and metastasis. Reports over the last decade have provided strong evidence for a pathophysiological role of Wnt signaling in non-malignant classical inflammatory and neurodegenerative diseases. Although, several agents suppressing the Wnt pathway at different levels have been identified, the development of clinically relevant Wnt-inhibiting agents remains challenging due to selectivity and toxicity issues. Several studies have shown that long-term administration of non-steroidal anti-inflammatory drugs protects against colon cancer and potentially other tumor types by interfering both with the COX and the Wnt pathway. Our own studies have shown that non-steroidal anti-inflammatory drugs suppress Wnt signaling by targeting the pro-inflammatory enzyme 5-lipoxygenase which is the key enzyme pathophysiologically involved in the synthesis of leukotrienes. Furthermore, we found a direct link between the 5-lipoxygenase and Wnt signaling pathways, which is essential for the maintenance of leukemic stem cells. Accordingly, genetic and pharmacological inhibition of 5-lipoxygenase led to an impairment of Wnt-dependent acute and chronic myeloid leukemic stem cells. We believe that 5-lipoxygenase inhibitors might represent a novel type of Wnt inhibitor activating a potentially naturally occurring novel mechanism of suppression of Wnt signaling that is non-toxic, at least in mice, and is potentially well tolerated in patients.
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe-University, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany. Electronic address: roos@pharmchem.uni-frankfurt.de.
authors.forename: Jessica
authors.initials: J
authors.lastname: Roos
authors.affiliation: Pharmazentrum Frankfurt/ZAFES, Institute of Clinical Pharmacology, Goethe-University, 60590, Frankfurt am Main, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Grösch
authors.affiliation: Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, University of Jena, Philosophenweg 14, 07743 Jena, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Werz
authors.affiliation: Max Planck Institute of Molecular Physiology, Otto-Hahn-Str. 11, 44227 Dortmund, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Schröder
authors.affiliation: Max Planck Institute of Molecular Physiology, Otto-Hahn-Str. 11, 44227 Dortmund, Germany.
authors.forename: Slava
authors.initials: S
authors.lastname: Ziegler
authors.affiliation: Institute for Experimental Cancer Research in Pediatrics, Goethe-University, Frankfurt, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Fulda
authors.affiliation: Department of Anesthesiology and Operative Intensive Care Medicine, Kepler University Hospital, 4021 Linz, Austria.
authors.forename: Patrick
authors.initials: P
authors.lastname: Paulus
authors.affiliation: Department of Urology and Pediatric Urology, Philipps-University Hospital, 35043 Marburg, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Urbschat
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe-University, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Kühn
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe-University, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Maucher
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe-University, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany.
authors.forename: Jasmin
authors.initials: J
authors.lastname: Fettel
authors.affiliation: Aarhus University, Department of Biomedicine & Center for Study and Prevention of Neurodegenerative Inflammation (NEURODIN), Bartholins Allé 6, 8000 Aarhus C, Denmark.
authors.forename: Thomas
authors.initials: T
authors.lastname: Vorup-Jensen
authors.affiliation: Aarhus University, Department of Biomedicine & Center for Study and Prevention of Neurodegenerative Inflammation (NEURODIN), Bartholins Allé 6, 8000 Aarhus C, Denmark.
authors.forename: Matthias
authors.initials: M
authors.lastname: Piesche
authors.affiliation: Aarhus University, Department of Biomedicine & Center for Study and Prevention of Neurodegenerative Inflammation (NEURODIN), Bartholins Allé 6, 8000 Aarhus C, Denmark.
authors.forename: Carmela
authors.initials: C
authors.lastname: Matrone
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe-University, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Steinhilber
authors.affiliation: Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Project Group for Translational Medicine and Pharmacology TMP, 60596 Frankfurt am Main, Germany.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Parnham
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe-University, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany; Aarhus University, Department of Biomedicine & Center for Study and Prevention of Neurodegenerative Inflammation (NEURODIN), Bartholins Allé 6, 8000 Aarhus C, Denmark. Electronic address: maier@biomed.au.dk.
authors.forename: Thorsten J
authors.initials: TJ
authors.lastname: Maier
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000378:metabolism; D051153:Wnt Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000187:drug effects
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D016859:Lipoxygenase Inhibitors; D051153:Wnt Proteins; D001094:Arachidonate 5-Lipoxygenase; D051546:Cyclooxygenase 2
keywords: Leukemic stem cells; Leukotrienes; Non-steroidal anti-inflammatory drugs; Tumor cells; Wnt inhibitor