ZFIN ID: ZDB-PUB-070907-17
Identification and Characterization of Several Dietary Alkaloids as Weak Inhibitors of Hedgehog Signaling
Lipinski, R.J., Dengler, E., Kiehn, M., Peterson, R.E., and Bushman, W.
Date: 2007
Source: Toxicological sciences : an official journal of the Society of Toxicology   100(2): 456-463 (Journal)
Registered Authors: Peterson, Richard E.
Keywords: none
MeSH Terms:
  • Abnormalities, Drug-Induced
  • Alkaloids/chemistry
  • Alkaloids/toxicity*
  • Animals
  • Diet*
  • Diosgenin/chemistry
  • Diosgenin/toxicity
  • Dose-Response Relationship, Drug
  • Embryo, Nonmammalian/drug effects
  • Embryo, Nonmammalian/embryology
  • Fibroblasts/drug effects
  • Fibroblasts/metabolism
  • Hedgehog Proteins/antagonists & inhibitors
  • Hedgehog Proteins/drug effects*
  • Mice
  • Molecular Structure
  • NIH 3T3 Cells
  • Structure-Activity Relationship
  • Transcription, Genetic/drug effects
  • Veratrum Alkaloids/chemistry
  • Veratrum Alkaloids/toxicity
  • Zebrafish
  • beta-Galactosidase/metabolism
PubMed: 17728282 Full text @ Toxicol. Sci.
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.