Stem cell signaling as a target for novel drug discovery: recent progress in the WNT and Hedgehog pathways

Abstract

One of the most exciting fields in biomedical research over the past few years is stem cell biology, and therapeutic application of stem cells to replace the diseased or damaged tissues is also an active area in development. Although stem cell therapy has a number of technical challenges and regulatory hurdles to overcome, the use of stem cells as tools in drug discovery supported by mature technologies and established regulatory paths is expected to generate more immediate returns. In particular, the targeting of stem cell signaling pathways is opening up a new avenue for drug discovery. Aberrations in these pathways result in various diseases, including cancer, fibrosis and degenerative diseases. A number of drug targets in stem cell signaling pathways have been identified. Among them, WNT and Hedgehog are two most important signaling pathways, which are the focus of this review. A hedgehog pathway inhibitor, vismodegib (Erivedge), has recently been approved by the US FDA for the treatment of skin cancer, while several drug candidates for the WNT pathway are entering clinical trials. We have discovered that the stem cell signaling pathways respond to traditional Chinese medicines. Substances isolated from herbal medicine may act specifically on components of stem cell signaling pathways with high affinities. As many of these events can be explained through molecular interactions, these phenomena suggest that discovery of stem cell-targeting drugs from natural products may prove to be highly successful.

Figure 1

The discovery of the WNT genes in fly (Wingless) and mouse (int-1) models. Left: the Wingless phenotype in Drosophila; right: mouse breast tumor formation induced by MMTV insertion into the mouse int-1 locus. Wingless and int-1 are homologous to each other, and the name Wnt was coined by combining the two words, Wingless and int-1.

Figure 2

A diagram of the WNT pathway.

Figure 3

A diagram of the Hedgehog (Hh) pathway.

Figure 4

Indirubin, which can be derived from the Chinese herbal medicine Qingdai, is a potent inhibitor of GSK-3β, a key intermediate in the WNT pathway.

Figure 5

Cyclopamine, which can be derived from Chinese herbal medicine Veratrum, is a potent and specific inhibitor of SMO, a key intermediate in the Hedgehog pathway.