3,3'-Diindolylmethane(DIM) is a strong, pure androgen receptor (AR) antagonist. DIM exhibits potent antiproliferative and antiandrogenic properties in androgen-dependent human prostate cancer cells. DIM suppresses cell proliferation of LNCaP cells and inhibits dihydrotestosterone (DHT) stimulation of DNA synthesis. Moreover, DIM inhibited endogenous PSA transcription and reduced intracellular and secreted PSA protein levels induced by DHT in LNCaP cells. Also, DIM inhibited, in a concentration-dependent manner, the DHT-induced expression of a prostate-specific antigen promoter-regulated reporter gene construct in transiently transfected LNCaP cells[3]. DIM significantly inhibited the proliferation of human gastric cancer cells in a dose-dependent manner. The percentage of G1 phase cells increased 24 h following DIM treatment. DIM reduced CDK2, CDK4, CDK6 and cyclin D1 protein levels, while increasing p53 protein levels[4]. After intraperitoneal injection of 3,3'-diindolylmethane, skin erythema and edema in mice were significantly alleviated. Furthermore, 3,3'-diindolylmethane reduced immune activation, probably by inhibiting the secretion of thymic stromal lymphopoietin by keratinocytes. 3,3'-Diindolylmethane also promoted the differentiation of regulatory T cells and inhibited the activation of T helper 2 and T helper 17 cells to reduce atopic dermatitis-related immune responses[5].
3,3'-Diindolylmethane/3,3'-亚甲基二吲哚 细胞实验
Cell Line
Concentration
Treated Time
Description
References
Prdx-2 mutants
100 µM
24 hours
Reduced mitochondrial ROS levels
Antioxidants (Basel). 2022 May 11;11(5):950.
MCF-7 human breast cancer cells
10 µM
1 hour
To study the genome-wide binding profiles of DIM on ERα and AHR. DIM–ERα-bound regions were enriched for an AHRE motif, suggesting co-recruitment of ERα and AHR to target genes.
Int J Mol Sci. 2023 Sep 26;24(19):14578.
H1975 non-small cell lung cancer cells
20 and 50 µM
1, 2, and 3 days
DIM inhibited the growth of non-small cell lung cancer cells expressing the L858R+T790M EGFR mutation and reduced EGFR phosphorylation.
Cancer Lett. 2010 Sep 1;295(1):59-68.
H1650 non-small cell lung cancer cells
20 and 50 µM
1, 2, and 3 days
DIM inhibited the growth of non-small cell lung cancer cells expressing the delE746-A750 EGFR mutation and reduced EGFR phosphorylation.
Cancer Lett. 2010 Sep 1;295(1):59-68.
U87MG glioma cells
20 and 30 µM
1, 2, and 3 days
DIM inhibited the growth of EGFRvIII-expressing glioma cells and reduced the expression of EGFRvIII and Met.
Cancer Lett. 2010 Sep 1;295(1):59-68.
H4 glioma cells
20 and 30 µM
1, 2, and 3 days
DIM inhibited the growth of EGFRvIII-expressing glioma cells and reduced the expression of EGFRvIII and Met.
Cancer Lett. 2010 Sep 1;295(1):59-68.
MCF-7 breast cancer cells
10 and 20 µM
1, 2, and 3 days
DIM inhibited the growth of EGFRvIII-expressing breast cancer cells, but the effect was less pronounced than in MDA-MB-361 cells.
Cancer Lett. 2010 Sep 1;295(1):59-68.
MDA-MB-361 breast cancer cells
10 and 20 µM
1, 2, and 3 days
DIM inhibited the growth of EGFRvIII-expressing breast cancer cells and reduced the expression of EGFRvIII and ErbB2.
Cancer Lett. 2010 Sep 1;295(1):59-68.
Primary HSCs
10 μg/mL
15 days
To evaluate the effect of DIM on primary HSC activation, results showed that DIM inhibited the TGF-β/Smad signaling pathway by down-regulating miR-21 expression, thereby suppressing the self-activation process of primary HSCs.
Br J Pharmacol. 2013 Oct;170(3):649-60.
Wild-type N2 worms
100 µM
24 hours
Reduced oxidative stress and maintained mitochondrial function
Antioxidants (Basel). 2022 May 11;11(5):950.
HSC-T6 cells
10 μg/mL
24 hours
To evaluate the effect of DIM on HSC-T6 cell activation, results showed that DIM inhibited the TGF-β/Smad signaling pathway by down-regulating miR-21 expression, thereby suppressing HSC-T6 cell activation.
Br J Pharmacol. 2013 Oct;170(3):649-60.
Peritoneal macrophages
10 µM
24 hours
To investigate the effect of DIM on LPS-induced peritoneal macrophage activation. Results showed that DIM pretreatment significantly reduced LPS-induced TNF-α secretion.
Br J Pharmacol. 2015 Apr;172(8):2133-47.
RAW264.7 macrophages
10 µM
24 hours
To investigate the effect of DIM on LPS-induced macrophage activation. Results showed that DIM pretreatment significantly reduced LPS-induced TNF-α secretion and expression of macrophage activation markers (CD80, CD86, and CD40).
Br J Pharmacol. 2015 Apr;172(8):2133-47.
Huh7 cells
0, 20, 40, 60, 80, 120 µM
24 hours
DIM significantly suppressed Huh7 cell growth and proliferation in a concentration-dependent manner.
Cells. 2021 May 12;10(5):1178.
Hep3B cells
0, 20, 40, 60, 80, 120 µM
24 hours
DIM significantly suppressed Hep3B cell growth and proliferation in a concentration-dependent manner.
Cells. 2021 May 12;10(5):1178.
Human endometrial Ishikawa cancer cells
0.1 µM
24 hours
Restrained E2 or CYP-induced cell invasion
Int J Mol Sci. 2018 Jan 8;19(1):189.
Human endometrial Ishikawa cancer cells
0.1 µM
24 hours
Inhibited E2 or CYP-induced cell migration
Int J Mol Sci. 2018 Jan 8;19(1):189.
Human endometrial Ishikawa cancer cells
0.1 µM
24 hours
Suppressed E2 or CYP-induced epithelial-mesenchymal transition (EMT)
Int J Mol Sci. 2018 Jan 8;19(1):189.
MDA-MB-231
5, 10, 25, 40 µM
24-72 hours
DIM alone or in combination with Taxotere significantly inhibited the growth of breast cancer cells, with inhibition rates reaching 75-90%.
To evaluate the effect of DIM on the viability of RA-FLSs, results showed DIM inhibited cell viability in a dose-dependent manner after 48h
Front Immunol. 2019 Jul 23;10:1620.
SGC-7901 gastric cancer cells
0-120 µM
24hours to 48 hours
DIM significantly inhibited the proliferation of SGC-7901 gastric cancer cells and activated STIM1-mediated SOCE by upregulating STIM1 and decreasing ER Ca2+ level, inducing apoptosis and autophagy.
Int J Biol Sci. 2021 Mar 19;17(5):1217-1233.
BGC-823 gastric cancer cells
0-120 µM
24hours to 48 hours
DIM significantly inhibited the proliferation of BGC-823 gastric cancer cells and activated STIM1-mediated SOCE by upregulating STIM1 and decreasing ER Ca2+ level, inducing apoptosis and autophagy.
Int J Biol Sci. 2021 Mar 19;17(5):1217-1233.
HT-22 cells
10–80 µM
30 minutes
DIM protected hippocampal neuronal cells against oxidative stress-induced apoptosis by regulating the expression of apoptosis-related proteins.
Antioxidants (Basel). 2019 Dec 18;9(1):3.
BM-derived MDSCs
10 µM, 20 µM, 40 µM, 80 µM
4 days
DIM suppressed the induced ratio of BM-MDSCs in a concentration-dependent manner, including both G-MDSCs and M-MDSCs subsets. Additionally, DIM treatment decreased the mRNA levels of Arg1 and iNOS in BM-MDSCs and partially abrogated the inhibitory effect of BM-MDSCs on the proliferation of CD4+ and CD8+ T cells.
Chin Med. 2022 Jun 30;17(1):81.
HepG2 cells
1-50 µM
4 hours
To investigate the effect of DIM on HIF-1α protein levels under hypoxic conditions. Results showed that DIM was effective at concentrations as low as 1 μM and completely inhibited HIF-1α expression at 50 μM.
Biochem Pharmacol. 2008 May 1;75(9):1858-67.
MDA-MB-231 cells
1-50 µM
4 hours
To investigate the effect of DIM on HIF-1α protein levels under hypoxic conditions. Results showed that DIM was effective at concentrations as low as 1 μM and completely inhibited HIF-1α expression at 50 μM.
Biochem Pharmacol. 2008 May 1;75(9):1858-67.
Human umbilical cord mesenchymal stem cells (hucMSCs)
50 µM
48 hours
To evaluate the effect of DIM on the stemness of hucMSCs, results showed that DIM dose-dependently induced the expression of Oct4, Nanog, Sox2, and Sall4.
Theranostics. 2017 Apr 10;7(6):1674-1688.
KYSE150 cells
0, 20, 40, 60 µM
48 hours
DIM inhibited migration and invasion of KYSE150 cells, downregulated mesenchymal cell markers β-Catenin, Vimentin and Slug, and upregulated epithelial cell marker Claudin-1
J Exp Clin Cancer Res. 2020 Jun 16;39(1):113.
TE1 cells
0, 20, 40, 60 µM
48 hours
DIM inhibited migration and invasion of TE1 cells, downregulated mesenchymal cell markers β-Catenin, Vimentin and Slug, and upregulated epithelial cell marker Claudin-1
J Exp Clin Cancer Res. 2020 Jun 16;39(1):113.
Human endometrial Ishikawa cancer cells
0.1 µM
6 days
Inhibited E2 or CYP-induced cell proliferation
Int J Mol Sci. 2018 Jan 8;19(1):189.
MCF-7 human breast cancer cells
10 µM
6 hours
To study the transcriptomic changes regulated by DIM via ERα and AHR. DIM treatment resulted in 446 differentially expressed genes, including upregulation of AHR target genes CYP1A1 and CYP1B1.
Int J Mol Sci. 2023 Sep 26;24(19):14578.
Mouse primary hippocampal cells
0.01, 0.1, 1, 10 µM
6 hours ischoursemia followed by 18 hours reoxygenation
DIM exhibited neuroprotective effects by inhibiting ischemia-induced apoptosis and autophagy, accompanied by a decrease in AhR/CYP1A1 signaling and an increase in HDAC activity.
Apoptosis. 2019 Jun;24(5-6):435-452.
Mouse primary hippocampal cells
0.01-10 µM
6 hours ischoursemia followed by 18 hours reoxygenation
DIM inhibited ischemia-induced apoptosis and autophagy, decreased AhR/CYP1A1 signaling, and increased HDAC activity
To evaluate the effect of DIM on migration and invasion of RA-FLSs, results showed DIM significantly reduced migratory and invasion capacity of RA-FLSs
Front Immunol. 2019 Jul 23;10:1620.
SKBR3
25 or 40 µM
72 hours
DIM treatment significantly reduced FoxM1 mRNA levels and inhibited cell growth.
Int J Cancer. 2011 Oct 1;129(7):1781-91.
MDA-MB-468
25 or 40 µM
72 hours
DIM treatment significantly reduced FoxM1 mRNA levels and inhibited cell growth.
Int J Cancer. 2011 Oct 1;129(7):1781-91.
MCF-7
25 or 40 µM
72 hours
DIM treatment significantly reduced FoxM1 mRNA levels and inhibited cell growth.
Int J Cancer. 2011 Oct 1;129(7):1781-91.
Human endometrial Ishikawa cancer cells
0.1 µM
72 hours
Suppressed E2 or CYP-induced metastasis-related gene expression
Int J Mol Sci. 2018 Jan 8;19(1):189.
Human endometrial Ishikawa cancer cells
0.1 µM
72 hours
Inhibited E2 or CYP-induced EMT-related gene expression
Int J Mol Sci. 2018 Jan 8;19(1):189.
3,3'-Diindolylmethane/3,3'-亚甲基二吲哚 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Wistar rats
Perinatal asphyxia model
Intraperitoneal injection
0.1, 10 or 100 mg/kg
First administration 30 minutes after HI, followed by additional doses at 24, 48 and 72 hours
DIM reduces brain damage induced by perinatal asphyxia by inhibiting AhR and NMDA signaling, restores brain weight and neuronal number, and inhibits apoptosis and oxidative stress
Apoptosis. 2020 Oct;25(9-10):747-762
C57BL/6 mice
Adjuvant-induced arthritis (AIA) model
Oral gavage
10 mg/kg
Once daily for 31 consecutive days
To evaluate the effect of DIM on arthritis severity in AIA mice, results showed DIM alleviated arthritis severity and pathological features
Front Immunol. 2019 Jul 23;10:1620.
BALB/C nude mice
Esophageal squamous cell carcinoma model
Gavage
10 mg/kg/day
Once daily for 4 weeks
DIM inhibited tumor growth and metastasis, downregulated AHR, RhoA, ROCK1, COX2 and mesenchymal cell markers, and upregulated epithelial cell marker Claudin-1
J Exp Clin Cancer Res. 2020 Jun 16;39(1):113.
ICR mice
Scopolamine-induced memory impairment model
Oral
10 or 20 mg/kg
Once daily for three consecutive days
DIM improved scopolamine-induced memory impairment by protecting hippocampal neuronal cells against oxidative damage.
Antioxidants (Basel). 2019 Dec 18;9(1):3.
Caenorhabditis elegans
Reproductively aged model
Oral feeding
100 μM
24 hours
Maintained oocyte quality and reproductive capacity
Antioxidants (Basel). 2022 May 11;11(5):950.
BALB/c mice
4T1 breast cancer model
Intraperitoneal injection
2, 5, 10 mg/kg
Three times a week for two weeks
DIM treatment significantly inhibited tumor growth and tumor weight in a dose-dependent manner and reduced the percentage of MDSCs in bone marrow, blood, spleen, and tumor tissues. Furthermore, DIM treatment increased the percentage of CD4+ and CD8+ T cells in blood, spleen, and tumor, and elevated the level of IFN-γ in tumor tissue.
Chin Med. 2022 Jun 30;17(1):81.
Female C57BL/6 mice
Unpredictable chronic mild stress (UCMS)-induced depressive-like behaviors model
Oral (mixed in peanut butter)
20 mg/kg
Daily administration for 3 weeks (prevention experiment) or 4 weeks (reversal experiment)
To evaluate the preventive and reversal effects of DIM and 1,4-DHNA on UCMS-induced depressive-like behaviors. Results showed that DIM and 1,4-DHNA could prevent and reverse UCMS-induced anhedonia-like behavior with little to no effect on anxiety levels and spatial learning.
J Affect Disord. 2022 Jul 15;309:201-210
ICR SCID mice
Breast cancer xenograft model
Oral gavage
3.5 mg/day/animal
Once daily for 3 weeks
DIM alone or in combination with Taxotere significantly inhibited tumor growth, with inhibition rates of 40% and 80%, respectively.
Int J Cancer. 2011 Oct 1;129(7):1781-91.
C57BL/6 mice
D-galactosamine/Lipopolysaccharide (GalN/LPS)-induced acute liver failure model
Intraperitoneal injection
40 mg/kg
Two doses, 24 hours and 2 hours before GalN/LPS injection
To investigate the protective effect of DIM on GalN/LPS-induced acute liver failure. Results showed that DIM pretreatment significantly improved survival rate, reduced serum ALT levels and liver tissue damage, and decreased levels of pro-inflammatory cytokines (TNF-α, IL-6, and CCL2).
Br J Pharmacol. 2015 Apr;172(8):2133-47.
BALB/c mice
RFP-expressing orthotopic breast cancer model derived from 4T1 CSCs
Intratumoral injection
5 mg/kg
Once daily for 10 days
E-DDMSNP significantly inhibited tumor growth and metastasis, prolonging survival time
J Nanobiotechnology. 2024 May 25;22(1):285.
ICR mice
Thioacetamide-induced hepatic fibrosis model
Intraperitoneal injection
50 mg/kg
Twice weekly for 8 weeks
To evaluate the therapeutic effect of DIM on thioacetamide-induced hepatic fibrosis, results showed that DIM attenuated liver fibrosis by down-regulating miR-21 expression and inhibiting the TGF-β signaling pathway.
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