New Hedgehog/GLI signaling inhibitors from Excoecaria agallocha

Bioorg Med Chem Lett. 2011 Jan 15;21(2):718-22. doi: 10.1016/j.bmcl.2010.11.126. Epub 2010 Dec 5.

Abstract

The inhibition of the Hedgehog (Hh) signaling pathway has emerged as an anti-cancer strategy. Three flavonoid glycosides including 2 new compounds (1-2) were isolated from Excoecaria agallocha as Hedgehog/GLI1-mediated transcriptional inhibitors and exhibited cytotoxicity against human pancreatic (PANC1) and prostate (DU145) cancer cells. Our data revealed that compound 1 clearly inhibited the expression of GLI-related proteins (PTCH and BCL-2) and blocked the translocation of GLI1 transcription factors into the nucleus in PANC1. Deleting the Smoothened (Smo) function in PANC1 treated with 1 led to downregulation of the mRNA expression of Ptch. This study describes the first Hh signaling inhibitor which blocks GLI1 movement into the nucleus without interfering with Smo.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents, Phytogenic / chemistry
  • Antineoplastic Agents, Phytogenic / isolation & purification
  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Euphorbiaceae / chemistry*
  • Flavonoids / chemistry
  • Flavonoids / isolation & purification
  • Flavonoids / pharmacology*
  • Gene Expression Regulation, Neoplastic / drug effects
  • Glycosides / chemistry
  • Glycosides / isolation & purification
  • Glycosides / pharmacology
  • Hedgehog Proteins / genetics
  • Hedgehog Proteins / metabolism*
  • Humans
  • Male
  • Neoplasms / drug therapy*
  • Neoplasms / genetics
  • Neoplasms / metabolism
  • Pancreatic Neoplasms / drug therapy
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / metabolism
  • Patched Receptors
  • Patched-1 Receptor
  • Prostatic Neoplasms / drug therapy
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / metabolism
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / metabolism
  • Signal Transduction / drug effects
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transcriptional Activation / drug effects
  • Zinc Finger Protein GLI1

Substances

  • Antineoplastic Agents, Phytogenic
  • Flavonoids
  • GLI1 protein, human
  • Glycosides
  • Hedgehog Proteins
  • PTCH1 protein, human
  • Patched Receptors
  • Patched-1 Receptor
  • Receptors, Cell Surface
  • Transcription Factors
  • Zinc Finger Protein GLI1