ToxSci Advance Access published online on August 28, 2007
Toxicological Sciences, doi:10.1093/toxsci/kfm222
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Identification and Characterization of Several Dietary Alkaloids as Weak Inhibitors of Hedgehog Signaling
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* Molecular and Environmental Toxicology Center, University of Wisconsin-Madison, Madison, Wisconsin, 53703
Department of Surgery, The University of Wisconsin-Madison, Madison, Wisconsin, 53703
1 To whom correspondence should be addressed at Department of Surgery, University of Wisconsin Medical School, K6/562 Clinical Science Center, 600 Highland Avenue, Madison, WI 53792. Tel. 608-265-8705; Fax. 608-265-8133; E-mail: bushman{at}surgery.wisc.edu
Received July 6, 2007; revision received August 21, 2007; accepted August 22, 2007
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Abstract |
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The Hedgehog (Hh) signaling pathway plays an integral role in the patterning and development of diverse structures in the vertebrate embryo. Aberrations in Hh signaling are associated with a range of developmental defects including failure of interhemispheric division of the embryonic forebrain as well as midline facial dysmorphia including cleft lip/palate and cyclopia, collectively termed holoprosencephaly (HPE). Postnatally, Hh signaling has been postulated to play a pivotal role in healing and repair processes and inappropriate Hh pathway activation has been implicated in several types of cancers. The Veratrum alkaloid cyclopamine is a potent inhibitor of Hh signaling and causes HPE-like defects in diverse species including sheep, hamster, mouse, and zebrafish. Using murine cell-based assays we have determined that a number of dietary alkaloids similar in structure to cyclopamine also inhibit Hh signaling, but with significantly lower potency. We found that these dietary compounds act additively through a mechanism similar to cyclopamine, downstream of Ptc1 and upstream of Gli1. Using an embryonic zebrafish developmental assay, we found that while cyclopamine exposure caused HPE-like defects, exposure to one of these dietary compounds, solanidine, did not.
RL – Madison, WI 53792 lipinski{at}surgery.wisc.edu, ED – Madison, WI 53792 dengler{at}wisc.edu, MK – Madison, WI 53792 kiehn{at}surgery.wisc.edu, DP – Madison, WI 53792 repeterson{at}pharmacy.wisc.edu, WB – Madison, WI 53792 bushman{at}surgery.wisc.edu
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