Small Molecule Wnt Pathway Modulators from Natural Sources: History, State of the Art and Perspectives

Abstract

The Wnt signaling is one of the major pathways known to regulate embryonic development, tissue renewal and regeneration in multicellular organisms. Dysregulations of the pathway are a common cause of several types of cancer and other diseases, such as osteoporosis and rheumatoid arthritis. This makes Wnt signaling an important therapeutic target. Small molecule activators and inhibitors of signaling pathways are important biomedical tools which allow one to harness signaling processes in the organism for therapeutic purposes in affordable and specific ways. Natural products are a well known source of biologically active small molecules with therapeutic potential. In this article, we provide an up-to-date overview of existing small molecule modulators of the Wnt pathway derived from natural products. In the first part of the review, we focus on Wnt pathway activators, which can be used for regenerative therapy in various tissues such as skin, bone, cartilage and the nervous system. The second part describes inhibitors of the pathway, which are desired agents for targeted therapies against different cancers. In each part, we pay specific attention to the mechanisms of action of the natural products, to the models on which they were investigated, and to the potential of different taxa to yield bioactive molecules capable of regulating the Wnt signaling.

Hexane Extract of Chloranthus japonicus Increases Adipocyte Differentiation by Acting on Wnt/β-Catenin Signaling Pathway

“…Natural products are well-acknowledged sources of small molecules biologically active in various signaling pathways and these are often used for drug development [ 31 , 32 ]. Similarly, various plant extracts exert biological activities by acting on the Wnt signaling pathway [ 33 , 34 ].…”

Wnt signaling activation: targets and therapeutic opportunities for stem cell therapy and regenerative medicine

“…Extensive screenings of the natural product library also identified many plant extracts that can activate Wnt/β-catenin. 12 However, again, the underlying mechanisms of action remain largely unknown. Among them, Sanguisorba officinalis L. and flavonoids are potential drug therapeutic agents against non-alcoholic fatty liver disease, 151 obesity, 152 and osteoporosis.…”

“…Reciprocally, when overactivated, it triggers various types of cancers, such as colon, stomach, liver, breast, and ovarian 10 . Thus, the search of Wnt signaling modulators, both inhibitors and activators, as potential drug therapies, has become an ongoing topic of interest for cancer, regenerative medicine, stem cell therapy, bone growth, and wound healing 11,12 . Theoretically, by activating Wnt, one could promote SC proliferation to restore tissue or organ impaired functions, the ultimate goal of SC therapy and regenerative medicine.…”

Evaluation of β-Catenin Inhibition of Axitinib and Nitazoxanide in Human Monocyte-Derived Dendritic Cells

“…It is conceivable that β-catenin inhibition could have both anti-oncogenic and immunotherapeutic effects that could provide synergetic cancer therapy. While many compounds have been found to inhibit various steps of Wnt/β-catenin signaling, several of which are in clinical trials, none of these compounds have been approved for clinical standard of care yet [9,13,14]. New, small molecular β-catenin inhibitors are thus in great demand.…”