title: Identification and characterization of several dietary alkaloids as weak inhibitors of hedgehog signaling.
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.
authors.affiliation: Molecular and Environmental Toxicology Center, University of Wisconsin-Madison, Madison, WI 53703, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Lipinski
authors.forename: Emelyne
authors.initials: E
authors.lastname: Dengler
authors.forename: Mark
authors.initials: M
authors.lastname: Kiehn
authors.forename: Richard E
authors.initials: RE
authors.lastname: Peterson
authors.forename: Wade
authors.initials: W
authors.lastname: Bushman
mesh_terms: D000014:Abnormalities, Drug-Induced; D000470:Alkaloids / Q000737:chemistry / Q000633:toxicity*; D000818:Animals; D004032:Diet; D004144:Diosgenin / Q000737:chemistry / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004625:Embryo, Nonmammalian / Q000187:drug effects / Q000196:embryology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors / Q000187:drug effects*; D051379:Mice; D015394:Molecular Structure; D041681:NIH 3T3 Cells; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic / Q000187:drug effects; D014704:Veratrum Alkaloids / Q000737:chemistry / Q000633:toxicity; D015027:Zebrafish; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: D000470:Alkaloids; D053823:Hedgehog Proteins; D014704:Veratrum Alkaloids; D001616:beta-Galactosidase; D004144:Diosgenin; C013255:solanidine; C000541:cyclopamine