The orphan nuclear receptor NR4A1 (nuclear receptor 4A1) exhibits pro-oncogenic activity in cancer cell lines. NR4A1 activates mTOR signaling, regulates genes such as thioredoxin domain containing 5 and isocitrate dehydrogenase 1 that maintain low oxidative stress, and coactivates specificity protein 1 (Sp1)-regulated pro-survival and growth promoting genes. DIM-C-pPhOH binds NR4A1 and act as antagonists. DIM-C-pPhOH (20 μM; 18 hr) inhibited growth and induced apoptosis in ACHN and 786-O cells, and the functional and genomic effects of it were comparable to those observed after NR4A1 knockdown. Moreover, treatment of these cells with 0–20 μM of the NR4A1 antagonist DIM-C-pPhOH also significantly decreased cell proliferation. IC50 values for DIM-C-pPhOH were 13.6 μM and 13.0 μM in ACHN cells and 786-O cells, respectively. Moreover, treatment of athymic nude mice bearing ACHN cells as xenografts with DIM-C-pPhOH (30 mg/kg/d) for 50 days also resulted in a significant inhibition of tumor growth and complemented results of the in vitro studies. In addition, researchers also observed decreased expression of survivin, bcl-2, EGFR and induced PARP cleavage in tumor lysates from nude mice bearing ACHN cells as a xenograft and treated with DIM-C-pPhOH (30 mg/kg/d)[1].
DIM-C-pPhOH 细胞实验
Cell Line
Concentration
Treated Time
Description
References
A549 cells
10 µM and 20 µM
24 hours
Caused G0/G1 phase arrest in A549 cells, resulting in 74.46±0.66% and 81.66±0.22% of cells accumulating in G1 phase at 10 μM and 20 μM concentrations, respectively.
Eur J Pharm Sci. 2013 Oct 9;50(2):227-41.
Panc-1 cells
25 µM
24 hours
Induces ER stress-mediated apoptosis by increasing ROS production
Mol Cancer Res. 2014 Apr;12(4):527-538.
MCF-7 breast cancer cells
15 or 20 µM
24 hours
To investigate the effect of DIM-C-pPhOH on MCF-7 cell migration, results showed that DIM-C-pPhOH significantly inhibited cell migration.
Mol Cell Biol. 2016 Apr 15;36(9):1383-94.
MDA-MB-231 breast cancer cells
15 or 20 µM
24 hours
To investigate the effect of DIM-C-pPhOH on MDA-MB-231 cell migration, results showed that DIM-C-pPhOH significantly inhibited cell migration.
Mol Cell Biol. 2016 Apr 15;36(9):1383-94.
SKBR3 breast cancer cells
15 or 20 µM
24 hours
To investigate the effect of DIM-C-pPhOH on SKBR3 cell migration, results showed that DIM-C-pPhOH significantly inhibited cell migration.
Mol Cell Biol. 2016 Apr 15;36(9):1383-94.
Rh30 cells
20 µM
24 hours
Induced ROS accumulation and IL-24 expression, inhibited cell proliferation and migration, and induced apoptosis
Mol Cancer Res. 2019 Nov;17(11):2221-2232.
RD cells
20 µM
24 hours
Induced ROS accumulation and IL-24 expression, inhibited cell proliferation and migration, and induced apoptosis
Mol Cancer Res. 2019 Nov;17(11):2221-2232.
MDA-MB-231 cells
20 µM
24 hours
DIM-C-pPhOH induced the expression of SERPINB5, GADD45α, and p21 proteins.
Breast Cancer Res Treat. 2019 Aug;177(1):29-40.
SKBR3 cells
20 µM
24 hours
RNAseq analysis showed that compared to control (DMSO) cells, DIM-C-pPhOH treatment altered the expression of 1823 genes.
Breast Cancer Res Treat. 2019 Aug;177(1):29-40.
Colon cancer cells (RKO, SW480)
15 and 20 µM
24 hours
Decreased β1-integrin expression, inhibited cell migration and adhesion
Mol Carcinog. 2017 Sep;56(9):2066-2075.
Pancreatic cancer cells (Panc1, L3.6pL, MiaPaCa2)
15 and 20 µM
24 hours
Decreased β1-integrin expression, inhibited cell migration and adhesion
Mol Carcinog. 2017 Sep;56(9):2066-2075.
786-O cells
0-20 µM
24 hours
Inhibited cell proliferation, IC50 value was 13.0 μM
PLoS One. 2015 Jun 2;10(6):e0128308.
ACHN cells
0-20 µM
24 hours
Inhibited cell proliferation, IC50 value was 13.6 μM
PLoS One. 2015 Jun 2;10(6):e0128308.
H1299 cells
20 µM
3 days
DIM-C-pPhOH inhibited H1299 cell proliferation and induced apoptosis by inactivating the TR3/p300/Sp1 complex.
Oncogene. 2012 Jul 5;31(27):3265-76.
H460 cells
20 µM
3 days
DIM-C-pPhOH inhibited H460 cell proliferation and mTORC1 signaling through activation of the p53/sestrin2/AMPK α axis.
Oncogene. 2012 Jul 5;31(27):3265-76.
A549 cells
20 µM
3 days
DIM-C-pPhOH inhibited A549 cell proliferation and mTORC1 signaling through activation of the p53/sestrin2/AMPK α axis.
Oncogene. 2012 Jul 5;31(27):3265-76.
L3.6pl cells
15.61 µM (IC50)
48 hours
Inhibited cell proliferation and induced apoptosis, accompanied by decreased Bcl-2 and survivin expression, and increased caspase-3 and PARP cleavage
Cancer Res. 2010 Sep 1;70(17):6824-36.
MiaPaCa-2 cells
13.87 µM (IC50)
48 hours
Inhibited cell proliferation and induced apoptosis, accompanied by decreased Bcl-2 and survivin expression, and increased caspase-3 and PARP cleavage
Cancer Res. 2010 Sep 1;70(17):6824-36.
Panc1 cells
11.35 µM (IC50)
48 hours
Inhibited cell proliferation and induced apoptosis, accompanied by decreased Bcl-2 and survivin expression, and increased caspase-3 and PARP cleavage
Cancer Res. 2010 Sep 1;70(17):6824-36.
A549 cells
10 µM and 20 µM
48 hours
Induced apoptosis in A549 cells, resulting in 26±1.05% and 25.5±2.40% apoptosis at 10 μM and 20 μM concentrations, respectively.
Eur J Pharm Sci. 2013 Oct 9;50(2):227-41.
DIM-C-pPhOH 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Nude mice (NCr-nu/nu)
Orthotopic model of pancreatic cancer
Oral gavage
30 mg/kg
Once daily for 4 weeks
Inhibited tumor growth and induced apoptosis, accompanied by decreased Bcl-2 and survivin expression, and increased caspase-3 and PARP cleavage
Cancer Res. 2010 Sep 1;70(17):6824-36.
Nude mice
Orthotopic and metastatic lung cancer models
Oral gavage
30 mg/kg
3 times per week for 4 weeks
DIM-C-pPhOH significantly inhibited tumor growth in orthotopic and metastatic lung cancer models and induced tumor cell apoptosis.
Oncogene. 2012 Jul 5;31(27):3265-76.
Athymic nude mice
ACHN cell xenograft model
Oral gavage
30 mg/kg
Once daily for 50 days
Significantly inhibited tumor growth
PLoS One. 2015 Jun 2;10(6):e0128308.
Nu/Nu mice
A549 cell lung metastasis model
Inhalation
5 mg/ml
Alternate days for 4 weeks
Significantly inhibited lung tumor growth, reduced tumor nodules, and decreased VEGF and CD31 expression, demonstrating anti-angiogenic and anti-metastatic activities.
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