Table 3.
Anti-tumor activities of I3C and DIM compounds
| Compound | Model | Response | IC50 or tested concentration | Mechanisms or molecular target | Reference |
|---|---|---|---|---|---|
| I3C | Mouse model of colitis-associated colorectal tumorigenesis (AhR +/+) | Decreased colitis-associated tumor | ND | AhR has a protective role in colitis-associated colorectal tumorigenesis. | [92] |
| I3C/DIM | ApcMin/+ mice | Suppresses intestinal carcinogenesis | ND | AhR | [93] |
| DIM | Prostate cancer |
Up regulate the expression of miRNAs (let-7, miR-34a, miR, and 150-5p) miR-92a |
ND |
Targets of those miRNAs are EZH2 Notch-1, AR, Ahr and RANKL |
[78] |
| H295R human adrenocortical carcinoma cell | Induce cytochrome P450 1A1, 1B1 and 19 | ND | Induced ethoxyresorufin-O-deethylase (EROD) activity and aromatase activity | [94] | |
| Postmenopausal American women aged 50–70 year with a history of early-stage breast cancer | DIM increased the 2-hydroxylation of estrogen urinary metabolites | Tested concentration: 108 mg DIM/day for 30 days. | DIM-treated subjects showed increased levels of 2-hydroxyestrone (2-OHE1) and cortisol. | [74] | |
| 64 patients with biopsy-proven cervical intraepithelial neoplasia (CIN) 2 or 3 | High rate of improvement in lesion number. | Oral DIM at 2 mg/kg/day for 12 days. | Improvement in confirmed CIN 2 or 3 lesions according to Pap smear, HPV, colposcopy, biopsy, and physical examination. | [95] | |
| DIM-1 and DIM-4, | Cancer cell lines | Induce apoptosis and anoikis | ND | Compounds induce morphological analysis, nuclear fragmentation, membrane integrity assay, caspase activity measurements, and modulation of pro/anti-apoptotic proteins. | [86]. |
|
2,2’-Diphenyl-3,3’-diindolylmethane (DPDIM) |
Triple-negative breast cancer | Induces apoptosis in vitro in breast cancer cells (MCF7, MDA-MB 231, and MDA-MB 468) and in vivo in 7,12-dimethylbenz[α]anthracene (DMBA) induced Sprague-Dawley (SD) rat mammary tumor | IC50 ca. 10 µmol/L; triple-negative refers to breast tumor cells lacking ER/estrogen receptor and PR/progesterone receptor, and no HER-2 overexpression | Negatively regulates the activity of EGFR and its downstream molecules like STAT3, AKT, and ERK1/2 | [96] |
| 4,4′-Dibromo-, 4,4′-dichloro-, 7,7′-dibromo-, and 7,7′-dichloro DIM |
Prostate cancer cells (LNCaP cells) |
Inhibits DHT-stimulated growth of LNCaP cells. Induced autophagy |
Tested concentrations: 10 and 30 µM and 0.3–30 µM |
Suppressed androgen receptor expression and induced apoptosis and necrosis by activating caspases-3, -8, and − 9, and induced expression of Fas, FasL, DR4, and DR5. Induced autophagy in prostate cancer cells by activation of AMP-activated kinase (AMPK) signaling and astrocyte-elevated gene 1 (AEG-1) | [97–99] |
| 1,1-Bis(3′-indolyl)-1-(p-substituted phenyl)methanes | Colon cancer cells (SW480 cells) | Inhibits the growth of SW480 tumors in vivo. Induce apoptosis in colon cancer cells. | Tested concentrations: 2.5 to 7.5 µmol/L | Induce peroxisome proliferator-activated receptor γ (PPARγ). Induce apoptosis in colon cancer cells and tumors by enhancing JNK phosphorylation that appears to be independent of activation of classical markers of endoplasmic reticulum stress | [100, 101] |
|
1,1-Bis(3′indolyl)-1-(substituted aromatic)methanes (i.e. C-DIMs) |
Breast cancer cells (MDA-MB-231) and pancreas cancer cells (BxPC-3), tumor cell lines 518A2 melanoma, KB-V1/Vbl cervix carcinoma and HT-29 colon carcinoma |
Growth inhibition Apoptosis |
IC50 < 5 µmol/L for BxPC-3 IC50 = 1.0 µmol/L for 518A2 IC50 = 3.0 µmol/L for KB-V1/Vbl, IC50 = 6.3 µmol/L for HT-29 |
DIM activates or inactivates multiple nuclear receptors, induces endoplasmic reticulum stress, decreases mitochondrial membrane potential, and modulates multiple signaling pathways, including kinases | [56] |
|
1,1-Bis(3′-indolyl)-1-(4-pyridyl)-methane (DIM-C-Pyr-4) |
Breast cancer cells (MCF-7 and ZR-75) | Contradictory results. DIM-C-Pyr-4 interacts with Chicken ovalbumin upstream promoter-transcription factor I (COUP-TFI), suppressing estrogen-induced gene expression while enhancing the motility and invasiveness of MCF-7 cells. | ND | Interacts with Chicken ovalbumin upstream promoter-transcription factor I (COUP-TFI) and activated COUP-TFI-dependent early growth response 1 (Egr-1) expression | [55, 102, 103] |
|
1,1-Bis(3′-indolyl)-1-(p-methoxyphenyl)-methane (DIM-C-pPhOCH3) |
Colon cancer cells (SW480 cells) | Inhibits tumor growth | ND | Activates extrinsic apoptosis pathway and activates Nur77-independent apoptosis. | [104] |
|
1,1-Bis(3′-indolyl)-1-(p-methoxyphenyl)-methane (DIM-C-pPhOCH3) |
Pancreatic tumors in mice and pancreatic cells (L3.6pL) |
Inhibits cell and tumor growth and induces apoptosis | Tested concentrations in mice: 25 mg/kg/day | DIM-C-pPhOCH3 induced Fas ligand and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), and induction of TRAIL was dependent on activating transcription factor 3 (ATF3). | [105] |
|
1,1-Bis(3′-indolyl)-1-(p-hydroxyphenyl)-methane (DIM-C-pPhOH) |
Breast cancer cells (MDA-MB-231 and SKBR3) and mouse xenograft model | Tumor growth inhibition. Inhibits migration and induces apoptosis | Tested concentrations in mouse: 2 mg/kg/d |
DIM-C-pPhOH is an antagonist of nuclear receptor 4A1 (NR4A1) and inhibits NR4A1-regulated pro-oncogenic pathways/genes in breast cancer cells |
[106] |
|
1,1-Bis(3′-indolyl)-1-(4-chlorophenyl)-methane (DIM-C-pPhCl) |
Pancreatic cancer cells | Inhibits migration and induces apoptosis | ND |
DIM-C-pPhCl selectively activated NR4A2 (Nurr1) and had only marginal effects on NR4A1 and NR4A3 activity |
[107] |
| DIM-C-pPhtBu | Pancreatic cancer cells | Induce apoptosis | ND | Induced ER stress included CHOP-dependent induction of death receptor DR5 and subsequent cleavage of caspase 8, caspase 3, Bid, and PARP. | [108] |
|
1,1-Bis(3′-indolyl)-1-(p-chlorophenyl)-methane (DIM-D) |
Caco-2 cells | ND | ND | Reduce permeation across caco-2 monolayer | [109] |
| Bis(triethylammonium) tris[1,1-bis(indol-3-yl)-1-(3,4-catecholate)-methane]vanadate(IV) complex. |
Cancer cell lines such as 518A2 melanoma, HCT-116 colon carcinoma (both p53-wildtype and p53-negative cells), triple-negative MDA-MB-231 breast cancer, and Panc-1 and BxPC-3 pancreas cancer cells |
Cell cycle arrest | IC50 = 1.8-3.0 µmol/L for 518A2 melanoma cells | Inhibition of tumor cell growth led to increased ROS formation and to a decrease of the mitochondrial membrane potential that caused mitochondrial damage, produced reactive oxygen species (ROS), and led to G2/M cell cycle arrest in 518A2 melanoma cells | [110] |
| Phemindole [3,3′-(4-hydroxyphenylmethylene)-bis-(7-methy-1 H-indole)] | Triple-negative breast cancer cells (TNBC, MDAMB-231). |
Apoptosis Cell migration arrest |
IC50 = 10.9 µmol/L for MDA-MB-231 | Phemindole caused mitochondrial-based apoptosis and ROS formation, and ER stress and mediated Store Operated Calcium Entry (SOCE) retardation favored the inactivation of STIM1. | [111] |
|
N-glycosylated DIM derivative (Phemindole) |
A549 (non-small cell lung carcinoma), HeLa (cervical cancer cell line), and MCF-7 (breast cancer). |
Apoptosis Inhibited migration Arrested cell cycle |
IC50 = 1.3 µmol/L for A549 lung, IC50 = 0.3 µmol/L for HeLa cervix, and IC50 = 0.9 µmol/L for MCF-7 breast cancer cells | N-glycosylated DIM derivatives induce apoptosis by upregulation of pro-apoptotic Par-4 (prostate apoptosis response 4) accompanied by suppression of Bcl-2 and GRP78 (glucose-regulated protein 78 kDa) and arrested the cell cycle in the G1 phase | [112] |
| 5,50-Dibromo DIM | Colon cancer cells | Inhibits tumor growth | Tested concentration 30 mg/kd/d | Induces Krüppel-like factor 4 and p21 | [113] |
| Breast cancer | Apoptosis | Induces caspase-dependent apoptosis, damage to mitochondrial-dependent apoptosis | [114] |
ND, No data