Guggulsterone sensitizes glioblastoma cells to Sonic hedgehog inhibitor SANT-1 induced apoptosis in a Ras/NFκB dependent manner

Cancer Lett. 2013 Aug 19;336(2):347-58. doi: 10.1016/j.canlet.2013.03.025. Epub 2013 Mar 31.


Since Shh pathway effector, Gli1, is overexpressed in gliomas, we investigated the effect of novel Shh inhibitor SANT-1 on glioma cell viability. Though SANT-1 failed to induce apoptosis, it reduced proliferation of glioma stem-like cells. Apart from canonical Shh cascade, Gli1 is also induced by non-canonical pathways including NFκB. Therefore, a combinatorial strategy with Ras/NFκB inhibitor, Guggulsterone, was employed to enhance effectiveness of SANT-1. Guggulsterone inhibited Ras and NFκB activity and sensitized cells to SANT-1 induced apoptosis via intrinsic apoptotic mechanism. Inhibition of either Ras or NFκB activity was sufficient to sensitize cells to SANT-1. Guggulsterone induced ERK activation also contributed to Caspase-9 activation. Since SANT-1 and Guggulsterone differentially target stem-like and non-stem glioma cells respectively, this combination warrants investigation as an effective anti-glioma therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects
  • Caspases / metabolism
  • Cell Line, Tumor
  • Drug Synergism
  • Gene Expression Regulation, Neoplastic
  • Glioblastoma / drug therapy*
  • Glioblastoma / metabolism
  • Glioblastoma / pathology
  • Hedgehog Proteins / antagonists & inhibitors*
  • Hedgehog Proteins / genetics
  • Hedgehog Proteins / metabolism
  • Humans
  • NF-kappa B / genetics
  • NF-kappa B / metabolism*
  • Piperazines / pharmacology*
  • Pregnenediones / pharmacology*
  • Pyrazoles / pharmacology*
  • Signal Transduction
  • Transcription Factors / metabolism
  • Transfection
  • Zinc Finger Protein GLI1
  • ras Proteins / metabolism*


  • GLI1 protein, human
  • Hedgehog Proteins
  • NF-kappa B
  • Piperazines
  • Pregnenediones
  • Pyrazoles
  • SANT-1 compound
  • SHH protein, human
  • Transcription Factors
  • Zinc Finger Protein GLI1
  • pregna-4,17-diene-3,16-dione
  • Caspases
  • ras Proteins