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ToxSci Advance Access originally published online on August 28, 2007
Toxicological Sciences 2007 100(2):456-463; doi:10.1093/toxsci/kfm222
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© The Author 2007. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Identification and Characterization of Several Dietary Alkaloids as Weak Inhibitors of Hedgehog Signaling

Robert J. Lipinski*,{dagger}, Emelyne Dengler*, Mark Kiehn{dagger}, Richard E. Peterson* and Wade Bushman*,{dagger},1

* Molecular and Environmental Toxicology Center, University of Wisconsin-Madison, Madison, Wisconsin 53703 {dagger} Department of Surgery, 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. Fax: (608) 265-8133. E-mail: bushman{at}surgery.wisc.edu.

Received July 6, 2007; accepted August 22, 2007


  Abstract

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 zebra fish. 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 zebra fish developmental assay, we found that while cyclopamine exposure caused HPE-like defects, exposure to one of these dietary compounds, solanidine, did not.


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R. J. Lipinski, P. R. Hutson, P. W. Hannam, R. J. Nydza, I. M. Washington, R. W. Moore, G. G. Girdaukas, R. E. Peterson, and W. Bushman
Dose- and Route-Dependent Teratogenicity, Toxicity, and Pharmacokinetic Profiles of the Hedgehog Signaling Antagonist Cyclopamine in the Mouse
Toxicol. Sci., July 1, 2008; 104(1): 189 - 197.
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