Table 3 Anti-tumor activities of I3C and DIM compounds

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

Apc^Min/+ 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)

[97,98,99]

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]