Regulation of tumorigenic Wnt signaling by cyclooxygenase-2, 5-lipoxygenase and their pharmacological inhibitors: A basis for novel drugs targeting cancer cells?

Pharmacol Ther. 2016 Jan;157:43-64. doi: 10.1016/j.pharmthera.2015.11.001. Epub 2015 Nov 6.


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.

Keywords: Leukemic stem cells; Leukotrienes; Non-steroidal anti-inflammatory drugs; Tumor cells; Wnt inhibitor.

Publication types

  • Review

MeSH terms

  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology
  • Arachidonate 5-Lipoxygenase / metabolism*
  • Cyclooxygenase 2 / metabolism*
  • Cyclooxygenase 2 Inhibitors / pharmacology
  • Humans
  • Inflammation / metabolism
  • Lipoxygenase Inhibitors / pharmacology
  • Neoplasms / drug therapy
  • Neoplasms / metabolism*
  • Neoplastic Stem Cells / metabolism
  • Wnt Proteins / antagonists & inhibitors
  • Wnt Proteins / metabolism*
  • Wnt Signaling Pathway / drug effects


  • Anti-Inflammatory Agents, Non-Steroidal
  • Cyclooxygenase 2 Inhibitors
  • Lipoxygenase Inhibitors
  • Wnt Proteins
  • Arachidonate 5-Lipoxygenase
  • Cyclooxygenase 2