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

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• 作者：Jessica Roos^a ; ¹ ; ^{roos@pharmchem.uni-frankfurt.de" class="auth_mail" title="E-mail the corresponding author} ; Sabine Grö ; sch^b ; ¹ ; Oliver Werz^c ; ¹ ; Peter Schrö ; der^d ; ¹ ; Slava Ziegler^d ; Simone Fulda^e ; Patrick Paulus^f ; Anja Urbschat^g ; Benjamin Kü ; hn^a ; Isabelle Maucher^a ; Jasmin Fettel^a ; Thomas Vorup-Jensen^h ; Matthias Piesche^h ; Carmela Matrone^h ; Dieter Steinhilber^a ; Michael J. Parnhamⁱ ; ¹ ; Thorsten J. Maier^a ; ^h ; ¹ ; ^{maier@biomed.au.dk" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Wnt inhibitor ; Tumor cells ; Leukemic stem cells ; Leukotrienes ; Non-steroidal anti-inflammatory drugs
• 刊名：Pharmacology and Therapeutics
• 出版年：2016
• 出版时间：January 2016
• 年：2016
• 卷：157
• 期：Complete
• 页码：43-64
• 全文大小：2380 K

文摘

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.