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by Gli2 as well, albeit through a different mechanism. Table 3: Hh related natural products
HPI-4 appears to act by perturbing ciliogenesis. [73] Natural compounds Target
Another synthetic molecule, named Robotnikinin, Cyclopamine Smo
specifically binds to extracellular Shh and blocks Shh- Genistein Gli1
signaling in cell lines, human primary keratinocytes Curcumin (diferuloylmethane) Shh, Gli1
Epigallocatechin‑3‑gallate
Ihh, Gli1
and a synthetic model of human skin, [74] which may Resveratrol Gli1
represent an alternative treatment for tumors resistant Hh: Hedgehog; Ihh: indian Hedgehog; Shh: sonic Hedgehog; Smo: smoothened
to Smo inhibitors.
defects of combined therapy should be evaluated in
In addition to synthetic drugs, several natural molecules clinical trials [Table 3 and Figure 2].
have been found to target the Hh pathway. Genistein
is an isoflavone found in soybeans and most soy- CONCLUSION
protein products. Both in vitro and vivo studies have
demonstrated that genistein may inhibit Gli1 mRNA the Hh signaling pathway plays a pivotal role in the
expression and down-regulate Gli reporter activity, process of embryonic development. Aberrant activation
leading to significant inhibition of prostate cancer of Hh signaling contributes to cancer development,
cell proliferation. [75] Cyclopamine, derived from progression, and the processes of cancer invasion
Veratrum californicum, has been showed directly to and metastasis, leading to the formation of gliomas.
bind to Smo, blocking the Hh pathway and preventing GSCs are at the core of glioma biology and play an
transcription. [76] In addition, cyclopamine reduces important role in cancer invasion, metastasis, drug
neurosphere formation in glioblastoma cell lines. [77] resistance and tumor recurrence. Thus, strategies
Epigallocatechin-3-gallate (EGCG) is one of the most specifically targeting Hh signaling in GSCs could lead
potent anticarcinogenic compounds known as catechins to promising therapies that inhibit tumor initiation
found in green tea. Studies indicate that EGCG could and progression. A variety of synthetic molecules and
decrease the expression of Gli1 mRNA and inhibit natural products are currently under investigation
Gli reporter activity. [75] Another study found that in both fundamental research studies and clinical
EGCG down-regulates Ihh, Gli1, and Bcl-2 expression, trials. Although some benefits have been observed,
which may inhibit cell proliferation and induce there are still problems that remain to be solved. In
apoptosis. Another natural inhibitor of the Hh pathway particular, further studies are needed to (1) identify
[78]
is resveratrol, a stilbenoid found in the skin of red grapes more effective methods of differentiating GSCs
and peanuts. Experimental studies have shown that from NSCs; (2) evaluate the benefits of combination
resveratrol suppresses cancer cell proliferation and therapy with HPIs and conventional chemotherapeutic
induces apoptosis partially through the down-regulation agents; and (3) determine the mechanisms behind
of Gli1 mRNA expression and the inhibition of Gli nutraceuticals that inhibit the Hh pathway for the
reporter activity. [75] Curcumin (diferuloylmethane), prevention of human malignancies in vitro, in vivo,
derived from Curcuma longa, inhibits the nuclear and in clinical trials.
factor-κB, PI3K/Akt, and activator protein-1 signaling
pathways, resulting in antiinflammatory, antioxidant and ACKNOWLEDGMENTS
anticancer effects. Curcumin also regulates Hh signaling
by down-regulating Shh and Gli1. [79] In addition, This project was supported by the National High Technology
curcumin reduces the protein levels of β-catenin and Research and Development Program 863 (2012AA02A508),
its downstream targets, c-Myc and cyclin D1, suggesting national 11th 5 years supporting project (2007BA105B08)
that curcumin could interrupt the cross-talk between and Heilongjiang Natural Science key projects (C03030307).
Hh and Wnt signaling. [79] In an advanced model of
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56 Neuroimmunol Neuroinflammation | Volume 1 | Issue 2 | September 2014