Constitutive androstane receptor agonist CITCO inhibits growth and expansion of brain tumour stem cells
Constitutive androstane receptor agonist CITCO inhibits growth and expansion of brain tumour stem cells
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DOI：
10.1038/sj.bjc.6606064
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发表时间：
2011-02-01
影响因子：
8.8
通讯作者：
Bright, J. J.
中科院分区：
文献类型：
--
作者：
Chakraborty, S.;Kanakasabai, S.;Bright, J. J.
背景：脑肿瘤对传统疗法提出了独特的挑战，并在世界各地造成了重大的健康问题。脑肿瘤干细胞（BTSC）代表了一小部分肿瘤细胞，可保持生长，耐药性和复发特性。组成型雄甾烷受体（CAR）是一种核受体转录因子，调节药物代谢和体内平衡。本研究旨在探讨CAR激动剂6-（4-氯苯基）咪唑并[2，1-B][1，3]噻唑-5-碳酰二亚胺O-（3，4-二氯苄基）肟（CITCO）对BTSCs的影响。通过WST-1和H-3胸苷摄取测定确定CITCO对BTSC的抗增殖作用。通过免疫组化和流式细胞术分析CITCO对BTSC中CD I 33表达、细胞周期进展和凋亡的影响。使用皮下（s.c.）结果：我们首次发现BTSC与胶质瘤细胞相比，核受体表达水平发生了改变。BTSC中CAR mRNA和蛋白的表达较低，并且在培养物中用CITCO处理后表达增加。CITCO诱导培养物中作为胶质球的CD 133（+）BTSC的生长和扩增呈剂量依赖性下降。CITCO可诱导BTSC细胞周期阻滞和凋亡，但不能诱导正常星形胶质细胞。结论：CITCO可抑制BTSC的生长和增殖，提示CAR激动剂可用于脑肿瘤的治疗。英国癌症杂志（2011）104，448-459。doi：10.1038/sj.bjc.6606064 www.bjcancer.com在线发布2011年1月11日（C）2011英国癌症研究
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