title: Guggulsterone sensitizes glioblastoma cells to Sonic hedgehog inhibitor SANT-1 induced apoptosis in a Ras/NFκB dependent manner.
abstract: 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.
authors.affiliation: National Brain Research Centre, Manesar, Haryana 122 050, India.
authors.forename: Deobrat
authors.initials: D
authors.lastname: Dixit
authors.forename: Ruchi
authors.initials: R
authors.lastname: Ghildiyal
authors.forename: Nikhil Ponnor
authors.initials: NP
authors.lastname: Anto
authors.forename: Sourav
authors.initials: S
authors.lastname: Ghosh
authors.forename: Vivek
authors.initials: V
authors.lastname: Sharma
authors.forename: Ellora
authors.initials: E
authors.lastname: Sen
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology*; D011282:Pregnenediones / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection; D000071676:Zinc Finger Protein GLI1; D018631:ras Proteins / Q000378:metabolism*
chemical_list: C400551:GLI1 protein, human; D053823:Hedgehog Proteins; D016328:NF-kappa B; D010879:Piperazines; D011282:Pregnenediones; D011720:Pyrazoles; C468919:SANT-1 compound; C509239:SHH protein, human; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1; C023617:pregna-4,17-diene-3,16-dione; D020169:Caspases; D018631:ras Proteins