期刊
BRITISH JOURNAL OF CANCER
卷 104, 期 3, 页码 448-459出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.bjc.6606064
关键词
brain tumour stem cell; nuclear receptor; anticancer agent; cancer chemotherapy
类别
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 H-3 thymidine uptake assays. The effect of CITCO on CD I 33 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. CONCLUSION: These findings indicate that CITCO inhibits the growth and expansion of BTSCs, suggesting the use of CAR agonists for the treatment of brain tumour. British Journal of Cancer (2011) 104, 448-459. doi:10.1038/sj.bjc.6606064 www.bjcancer.com Published online 11 January 2011 (C) 2011 Cancer Research UK
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