Identification and characterization of several dietary alkaloids as weak inhibitors of hedgehog signaling.
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.
Lipinski
Robert J
RJ
Molecular and Environmental Toxicology Center, University of Wisconsin-Madison, Madison, WI 53703, USA.
Dengler
Emelyne
E
Kiehn
Mark
M
Peterson
Richard E
RE
Bushman
Wade
W
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
D000470:Alkaloids; D053823:Hedgehog Proteins; D014704:Veratrum Alkaloids; D001616:beta-Galactosidase; D004144:Diosgenin; C013255:solanidine; C000541:cyclopamine