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 3H 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.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.

Differential Regulation of CYP3A4 and CYP3A5 and its Implication in Drug Discovery

“…The mRNA of CAR is highly expressed in human liver and kidneys but is weakly expressed or not expressed at all in various other tissues [115,117]. Recent reports also indicate that CAR is expressed at varying levels in some non-small cell lung cancer and brain cancer stem cells, but the mechanism of action does not appear to involve members of the CYP family [118,119]. …”

Antiepileptic Drugs Reduce the Efficacy of Methotrexate Chemotherapy through Accelerated Degradation of the Reduced Folate Carrier by the Ubiquitin-Proteasome Pathway

“…Besides ubiquitous expression in normal tissues, Rfc is expressed in various human tumor cell lines including leukemic blasts [2]. Moreover, expression of nuclear receptor CAR was shown in various human cancer cells including brain tumor stem cells [58] and hepatoma or colon carcinoma cells [59]. Concerning the clinical relevance for patients with ALL receiving MTX and PB, recent studies demonstrated expression of CAR in human peripheral blood mononuclear cells [60] as well as expression and inducibility of CYP 2B6 by PB-type CYP450 inducers in the human leukemia HL-60 cell line [61].…”

Anticancer Drug Metabolism: Chemotherapy Resistance and New Therapeutic Approaches

“…Indeed, a recent study showed that CAR is a positive regulator of MDR1 (Pgp), MRP2 and BCRP expression in rat and mouse brain capillaries (Wang, B. et al, 2010). Moreover, another study demonstrated that CITCO inhibits the growth and expansion of brain tumor cancer stem cells by inducing cell cycle arrest and apoptosis in vitro (Chakraborty et al, 2011). Although the CAR-mediated antineoplastic effect is not known, these results support the use of CAR agonists as a new therapy to target brain tumor cancer stem cells for the treatment of glioma.…”