Natural products drug discovery has allowed the identification of many biologically
active compounds from plants, microbial species, and marine organisms. A significant
number of these compounds are currently used as drugs in therapeutic protocols, while other
naturally occurring chemical entities gave suggestions for designing nonnatural-productderived
drugs or have been modified in their structure to have semi-synthetic analogues. In
the last decade, experimental evidence that correlated the aberrant activation of the Hedgehog
(Hh) signaling pathway with many types of cancer, prompted the researchers to check natural compounds
for their ability to modulate this signaling cascade. As a result, many compounds from natural sources showed
inhibitory activity toward one or more of the Hh signaling pathway components, such as Smoothened (Smo)
and the downstream effectors Gli. On the other hand, only a few natural compounds were able to stimulate the
same pathway. This review reports a survey of the compounds extracted from natural sources (especially
plants) that showed activity in inhibiting the Hh signaling machinery by interfering with its components.
Keywords: Apoptosis, bioactivity-directed fractionation, cancer cells, cytotoxicity, Gli1-mediated transcriptional
activity, Hedgehog inhibitors, Hedgehog signaling pathway, naturally occurring compounds, small molecules, structure-
activity relationship analysis, synthesis, tetracycline-regulated Gli1 expression assay.
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