Inhibition of Hedgehog/Gli Signaling by Botanicals: A Review of Compounds with Potential Hedgehog Pathway Inhibitory Activities
Sara K. Drenkhahn,
Glenn A. Jackson,
Nicholas J.E. Starkey,
Dennis B. Lubahn.
The hedgehog (Hh) signaling pathway is an important therapeutic target in cancer; involvement of the Hh
pathway has been shown in a variety of cancers including basal cell carcinoma, medulloblastoma, leukemia, and
gastrointestinal, breast, prostate, lung, and pancreatic cancers [1-10]. Currently, several Hh pathway inhibitory drugs are
in clinical development, and the FDA recently approved Erivedge (vismodegib) from Curis/Genentech [11-15]. These
new drugs are effective in many, but not all patients . In fact there are documented reports of tumors developing
mutations that confer resistance to the drugs [14, 17-19]. This highlights the importance of finding second generation
drugs that can be used on cancers that develop resistance to the first generation Hh inhibitors. Botanicals may serve as the
backbone for such research. The gold-standard pathway inhibitor, cyclopamine, is itself a naturally occurring alkaloid
found in Veratrum californicum . In this review we will summarize the available literature on botanical compounds in
Hh-related studies. In particular we will look at curcumin, genistein, EGCG, resveratrol, quercetin, baicalen, and apigenin
along with novel compounds isolated from Southeast Asian plants, such as the potent sub-micromolar gitoxigenin
derivatives. Due to the nature of the pathway, most of the research published has focused on functional Gli-transcriptional
assays, which we will describe and summarize.
Keywords: Botanicals, cancer, dietary chemoprevention, gli, hedgehog signaling, nutraceuticals.
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