The constitutive androstane receptor (CAR) is a xenobiotic sensor expressed in hepatocytes that activates genes involved in drug metabolism, lipid homeostasis, and cell proliferation[1].
In vitro, CAR activation accelerated intestinal epithelial wound healing by enhancing cell migration[2].
CITCO, an imidazothiazole derivative, is a selective Constitutive androstane receptor (CAR) agonist. CITCO inhibits growth and expansion of brain tumour stem cells (BTSCs) and has an EC50 of 49 nM over pregnane X receptor (PXR). CITCO (1-50 μM; 48 hours) results in a dose-dependent inhibition of viable cell count and proliferation in both T98G and U87MG glioma and BTSCs. CITCO (2.5, 5 μM; 48 hours) induces cell cycle arrest differentially in different BTSCs in culture, but not in normal astrocytes. CITCO (2.5-10 μM; 48 hours) induces apoptosis in BTSCs in culture (dose dependently), and causes the T98G and U87MG glioma and BTSCs expressing very low levels of CAR protein. CITCO (intraperitoneal; on days 22, 24, 26, 30 and 36) with 25 μg results a significant decrease in tumour growth, which further decreases to an undetectable level after treatment with 100 μg CITCO[3].
CITCO 细胞实验
Cell Line
Concentration
Treated Time
Description
References
HepG2 cells
10 µM
48 h
To investigate the effect of CAR activation on YAP nuclear translocation, results showed that CAR activation promoted YAP nuclear translocation.
Acta Pharm Sin B. 2021 Mar;11(3):727-737
HFF-1 cells
1, 2.5, 5, 10 μM
24 h
To evaluate the reversal effect of CITCO on D-galactose and doxorubicin-induced senescence, results showed CITCO reduced the area of SA-β-gal positive staining.
Adv Sci (Weinh). 2025 Mar;12(12):e2416823
Primary human hepatocytes (PHH)
1 μM
24 h
Significantly upregulated CYP2B6 mRNA expression
J Med Chem. 2023 Feb 23;66(4):2422-2456
LS174T cells
10 μM
48 h
No significant induction of CYP2B6 and CYP3A4 mRNA expression
J Med Chem. 2023 Feb 23;66(4):2422-2456
HepaRG KO CAR cells
1 μM
48 h
No significant induction of CYP2B6 and CYP3A4 mRNA expression
J Med Chem. 2023 Feb 23;66(4):2422-2456
HepaRG cells
1 μM
48 h
Induced CYP2B6 and CYP3A4 mRNA expression
J Med Chem. 2023 Feb 23;66(4):2422-2456
CD133+ BTSCs
5 μM
48 h
To investigate the effect of CITCO on CD133+ BTSCs, results showed that CITCO significantly reduced the proportion and fluorescence intensity of CD133+ cells.
Br J Cancer. 2011 Feb 1;104(3):448-59
Brain tumour stem cells (BTSCs)
2.5 μM
48 h
To investigate the effect of CITCO on the growth and expansion of BTSCs, results showed that CITCO induced increased CAR expression and inhibited the growth and expansion of BTSCs.
Br J Cancer. 2011 Feb 1;104(3):448-59
Human primary hepatocytes (HPH)
0.1, 0.5, and 1 μM
24 h
To evaluate the induction effects of CITCO on CYP2B6 and CYP3A4 mRNA and protein levels. Results showed that CITCO concentration-dependently induced CYP2B6 mRNA and protein expression, with significantly lower induction of CYP3A4 compared to CYP2B6.
Eur J Med Chem. 2019 Oct 1;179:84-99
Cardiomyocytes (H9c2)
1 μM
24 h
CITCO did not affect the expression of genes related to CHOP disposition in H9c2 cells and did not enhance CHOP toxicity in H9c2 cells.
Mol Cancer Ther. 2016 Mar;15(3):392-401
HepaRG cells (wild-type and CAR-knockout)
1 μM
24 or 72 h
In wild-type HepaRG cells, CITCO significantly enhanced CHOP cytotoxicity in SU-DHL-4 cells; this effect was abolished in CAR-knockout HepaRG cells.
Mol Cancer Ther. 2016 Mar;15(3):392-401
Lymphoma cells (SU-DHL-4, SU-DHL-6, OCI-LY-3)
1 μM
24 h
CITCO did not significantly alter the expression of genes related to CHOP disposition in lymphoma cells.
Mol Cancer Ther. 2016 Mar;15(3):392-401
Human primary hepatocytes (HPH)
1 μM
24 or 72 h
CITCO robustly induced the expression of CYP2B6 (17-fold) with moderate augmentation of CYP3A4 (4-fold), and MDR1 (4-fold), respectively.
Mol Cancer Ther. 2016 Mar;15(3):392-401
HepaRG hCAR-knockout cells
1 μM
24 h
CITCO altered the expression of 41 genes in hCAR-KO cells, mainly related to ion homeostasis and transmission of nerve impulse.
Biochem Pharmacol. 2015 Nov 1;98(1):190-202
HepaRG wild-type cells
1 μM
24 h
CITCO significantly altered the expression of 135 genes, primarily involved in drug-metabolizing enzymes, DNA damage repair, and the Nrf2 signaling pathway.
Biochem Pharmacol. 2015 Nov 1;98(1):190-202
HepaRG cells
0.1 μM
48 h
To evaluate the effect of CITCO on CYP2B6 mRNA levels, results showed CITCO significantly increased CYP2B6 mRNA levels
Drug Metab Dispos. 2021 Aug;49(8):706-717
primary cultured human hepatocytes
0.1 μM
48 h
To evaluate the effect of CITCO on CYP2B6 mRNA levels, results showed CITCO significantly increased CYP2B6 mRNA levels
Drug Metab Dispos. 2021 Aug;49(8):706-717
primary cultured mouse hepatocytes
1 μM
48 h
To evaluate the effect of CITCO on the interaction of hCAR1, hCAR2, and hCAR3 with hSRC1(RID). Results showed that CITCO significantly increased the interaction between hSRC1(RID) and hCAR1 (∼7-fold), weakly increased the interaction with hCAR2 (1.7-fold), and moderately increased the interaction with hCAR3 (∼4-fold).
Drug Metab Dispos. 2016 Apr;44(4):595-604
CITCO 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Caenorhabditis elegans
Wild-type N2 C. elegans
Administered via NGM medium
10, 25, 50, 100 μM
Daily administration until nematode death
To assess the effect of CITCO on lifespan and healthspan in nematodes, results showed CITCO significantly extended the mean lifespan and improved locomotor behaviors.
Adv Sci (Weinh). 2025 Mar;12(12):e2416823
Nude mice
Subcutaneous BTSC xenograft model
Intraperitoneal injection
25 mg and 100 mg,25μL
Administered on days 22, 24, 26, 30, and 36, continued until day 50
To investigate the effect of CITCO on BTSC xenograft tumor growth, results showed that CITCO significantly inhibited tumor volume growth.
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