title: Constitutive androstane receptor agonist CITCO inhibits growth and expansion of brain tumour stem cells.
abstract: BACKGROUND
  Brain tumours present unique challenges to conventional therapies and pose major health problems around the world. Brain tumour stem cells (BTSCs) represent a small fraction of tumour cells that maintain growth, drug resistance and recurrence properties. Constitutive androstane receptor (CAR) is a nuclear receptor transcription factor that regulates drug metabolism and homoeostasis. In this study, we examined the effect of CAR agonist, 6-(4-chlorophenyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehydeO-(3,4-dichlorobenzyl)oxime (CITCO) on BTSCs.
  
  
  METHODS
  The expression of CAR in BTSCs was detected by quantitative RT-PCR and western blot. The antiproliferative effect of CITCO on BTSCs was determined by WST-1 and (3)H thymidine uptake assays. The effect of CITCO on CD133 expression, cell cycle progression and apoptosis in BTSCs was analysed by immunostaining and flow cytometry. The in vivo effect of CITCO was studied using subcutaneous (s.c.) BTSC xenograft in nude mice.
  
  
  RESULTS
  We show for the first time that BTSCs express altered levels of nuclear receptors compared with glioma cells. The expression of CAR mRNA and protein was low in BTSCs and that increased following treatment with CITCO in culture. CITCO induced a dose-dependent decrease in growth and expansion of CD133(+) BTSCs as gliospheres in culture. Cell cycle arrest and apoptosis in BTSCs were induced by CITCO, but not in normal astrocytes. Growth of s.c BTSC xenograft in nude mice was also inhibited by CITCO.
  
  
  CONCLUSIONS
  These findings indicate that CITCO inhibits the growth and expansion of BTSCs, suggesting the use of CAR agonists for the treatment of brain tumour.
authors.affiliation: Neuroscience Research Laboratory, Methodist Research Institute, 1800 N. Capitol Avenue, Noyes Bldg E504C, Indianapolis, IN 46202, USA.
authors.forename: S
authors.initials: S
authors.lastname: Chakraborty
authors.forename: S
authors.initials: S
authors.lastname: Kanakasabai
authors.forename: J J
authors.initials: JJ
authors.lastname: Bright
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001932:Brain Neoplasms / Q000188:drug therapy*; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D000090702:Constitutive Androstane Receptor; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D014411:Neoplastic Stem Cells; D010091:Oximes / Q000494:pharmacology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000090702:Constitutive Androstane Receptor; D010091:Oximes; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; C475093:6-(4-chlorophenyl)imidazo(2,1-b)(1,3)thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl)oxime