Phytochemicals in Foods - 11 Health Benefits of 3,3'-Diindolylmethane

3,3'-Diindolylmethane or DIM are phytochemicals derived from the digestion of indole-3-carbinol, belonging to the group of Indoles, found abundantly in broccoli, Brussels sprouts, cabbage and kale, etc.

Health Benefits
1. Antiinflammatory and chemopreventive effects on Skin
In the examination of the effects of 3,3'-Diindolylmethane (DIM) on antiinflammatory and antitumor promotion activity in mouse skin and explored the relevant mechanism, indicated that Several lead compounds, such as genistein (from soybeans), lycopene (from tomatoes), brassinin (from cruciferous vegetables), sulforaphane (from asparagus), indole-3-carbinol (from broccoli), and resveratrol (from grapes and peanuts) are in preclinical or clinical trials for cancer chemoprevention. Phytochemicals have great potential in cancer prevention because of their safety, low cost, and oral bioavailability. In this review, we discuss potential natural cancer preventive compounds and their mechanisms of action, according to "3,3'-diindolylmethane suppresses 12-O-tetradecanoylphorbol-13-acetate-induced inflammation and tumor promotion in mouse skin via the downregulation of inflammatory mediators" by Kim EJ, Park H, Kim J, Park JH.(1)

2. Antileukemic Activity
In the study of 3,3'-diindolylmethane (DIM), one of the active products derived from Brassica plants, for it antitumor effects, showed that DIM significantly induced apoptosis in U937 human leukemia cells in dose- and time-dependent manners. These events were also noted in other human leukemia cells (Jurkat and HL-60) and primary human leukemia cells (AML) but not in normal bone marrow mononuclear cells. DIM-induced lethality is associated with caspases activation, myeloid cell leukemia-1 (Mcl-1) down-regulation, p21(cip1/waf1) up-regulation, and Akt inactivation accompanied by c-jun NH2-terminal kinase (JNK) activation. Enforced activation of Akt by a constitutively active Akt construct prevented DIM-mediated caspase activation, Mcl-1 down-regulation, JNK activation, and apoptosis, according to "3, 3'-Diindolylmethane Exhibits Antileukemic Activity In Vitro and In Vivo through a Akt-Dependent Process" by Gao N, Cheng S, Budhraja A, Liu EH, Chen J, Chen D, Yang Z, Luo J, Shi X, Zhang Z.(2)

3. Cervical Cancer
In the examination of 3,3'-Diindolylmethane (DIM) prevention or inhibition of the progression from cervical dysplasia to Human papilloma viral causes of cervical neoplasia (CIN), found that significant increases in IFN-γ serum concentrations that correlate with the percentage of CIN free mice in each group indicate that 1000 ppm of DIM in food may be the most effective dose for future studies. These results may eventually lead to new and effective vaccination strategies in women already infected with the human papilloma virus, according to '3,3'-Diindolylmethane Increases Serum Interferon-γ Levels in the K14-HPV16 Transgenic Mouse Model for Cervical Cancer" by Sepkovic DW, Raucci L, Stein J, Carlisle AD, Auborn K, Ksieski HB, Nyirenda T, Bradlow HL.(3)

4. Esophageal cancer
In the study of 3,3'-Diindolylmethane (DIM), an active metabolite of indole-3-carbinol, and its antitumor effects in experimental animals and induction of apoptosis in various cancer cells, showed that DIM significantly inhibited the proliferation of ESCC cells in a dose- and time-dependent manner. The percentage of G1 phase cells increased 48 h after being treated with DIM. DIM also reduced cyclin D1, cyclin E2, cyclin-dependent kinase (CDK) 4 and CDK 6 activities, and increased p15 and p27 levels. Additionally, DIM diminished pro-caspase-9 protein expression levels and induced increased cleaved poly (ADP-ribose) polymerase levels, accoridng to "3,3'-Diindolylmethane suppresses growth of human esophageal squamous cancer cells by G1 cell cycle arrest"by Kim SJ, Lee JS, Kim SM.(4)

5. Prostate cancer
In the stuidy of whether DIM inhibits the development of prostate cancer using the transgenic adenocarcinoma mouse prostate (TRAMP) model, showed that DIM induced a substantial reduction in the numbers of viable cells and induced apoptosis in LNCaP and DU145 cells. DIM increased the cleavage of caspase-9, -7, -3, and poly (ADP-ribose) polymerase (PARP). DIM increased mitochondrial membrane permeability and the translocation of cytochrome c and Smac/Diablo from the mitochondria. Additionally, DIM induced increases in the levels of cleaved caspase-8, truncated Bid, Fas, and Fas ligand, and the caspase-8 inhibitor Z-IETD-FMK was shown to mitigate DIM-induced apoptosis and the cleavage of caspase-3, PARP, and Bid, according to '3,3'-Diindolylmethane inhibits prostate cancer development in the transgenic adenocarcinoma mouse prostate model" by Cho HJ, Park SY, Kim EJ, Kim JK, Park JH.(5)

6. Oral Cancer
In the investigation of the antitumor activity of 3,3'-diindolylmethane (DIM), an active metabolite of the phytochemical indole-3-carbinol (I3C), in oral squamous cell carcinoma (OSCC), showed that DIM stimulated the activation of p53 via Ser-15 phosphorylation, leading to increased expression of the BH3-only proapoptotic Bcl-2 members Puma and Noxa. Together, these changes decreased the mitochondrial threshold for apoptosis. G2/M arrest might be attributable to the suppressive effect of DIM on the expression of cyclin B1 and cdc25c. As many downstream effectors of the Akt-NF-κB pathway, including glycogen synthase kinase 3β, IκB kinase α, and cyclooxygenase-2, have been shown to promote oral tumorigenesis, the ability of DIM to inhibit this signaling axis underscores its chemopreventive potential in oral cancer, according to "The dietary phytochemical 3,3'-diindolylmethane induces G2/M arrest and apoptosis in oral squamous cell carcinoma by modulating Akt-NF-κB, MAPK, and p53 signaling" by Weng JR, Bai LY, Chiu CF, Wang YC, Tsai MH.(6)

7. Ovarian cancer
In the delineation of the mechanism by which DIM suppressed the growth of SKOV3, OVCAR-3 and TOV-21G human ovarian cancer cells, found that DIM treatment also inhibited the kinase activity of ERK as observed by the down regulation of p-ELK in all the three ovarian cancer cell lines. DIM significantly suppressed the growth of ovarian tumors in vivo. Tumor growth suppressive effects of DIM in SKOV-3 tumor xenografts were associated with reduced phosphorylation of EGFR, MEK and ERK, according to "Blocking EGFR activation suppresses ovarian tumor growth in vitro and in vivo" by Kandala PK, Wright SE, Srivastava SK.(7)

8. Colon cancer
In the analyzing the expression pattern of N-myc downstream regulated gene-1 following treatment of human colonic cancer cell lines, suggested that N-myc downstream regulated gene-1 expression is enhanced by 3,3'-diindolylmethane in poorly differentiated cells and followed by induction of apoptosis. 3,3'-diindolylmethane induced apoptosis may represent a new regulator of N-myc downstream regulated gene-1 in poorly differentiated colonic cancer cells, according to "The indolic diet-derivative, 3,3'-diindolylmethane, induced apoptosis in human colon cancer cells through upregulation of NDRG1" by Lerner A, Grafi-Cohen M, Napso T, Azzam N, Fares F.(8)

9. Osteosarcoma
In the investigation of the effect of the natural product 3,3'-diindolylmethane (DIM) on cytosolic Ca(2+) concentrations ([Ca(2+) ](i) ) and viability in MG63 human osteosarcoma cells, found that DIM-evoked Ca(2+) entry was suppressed by nifedipine, econazole, SK&F96365 and protein kinase C modulators. In the absence of extracellular Ca(2+) , incubation with the endoplasmic reticulum Ca(2+) pump inhibitors thapsigargin or 2,5-di-tert-butylhydroquinone (BHQ) inhibited or abolished DIM-induced [Ca(2+) ](i) rise. Incubation with DIM also inhibited thapsigargin or BHQ-induced [Ca(2+) ](i) rise. Inhibition of phospholipase C with U73122 abolished DIM-induced [Ca(2+) ](i) rise. At concentrations of 10-50 μM, DIM killed cells in a concentration-dependent manner, according to "3,3'-Diindolylmethane Alters Ca(2+) Homeostasis and Viability in MG63 Human Osteosarcoma Cells" by Lu YC, Chen IS, Chou CT, Huang JK, Chang HT, Tsai JY, Hsu SS, Liao WC, Wang JL, Lin KL, Liu SI, Kuo CC, Ho CM, Jan CR.(9)

10. Breast cancer
in the assessment of the effects of DIM on cell-cycle regulation in both estrogen-dependent MCF-7 and estrogen receptor negative p53 mutant MDA-MB-468 human breast cancer cells,
showed that DIM inhibited the breast cancer cell growth in vitro and in vivo, and caused cell-cycle arrest by down-regulating protein levels of cell-cycle related kinases CDK1, CDK2, CDK4, and CDK6, as well as Cyclin B1 and Cdc25A. Meanwhile, it was revealed that Ser(124) phosphorylation of Cdc25A is primarily responsible for the DIM-induced Cdc25A degradation. Furthermore, treatment of MCF-7 cells with DIM increased miR-21 expression and down-regulated Cdc25A, resulting in an inhibition of breast cancer cell proliferation, according to " 3,3'-Diindolylmethane inhibits breast cancer cell growth via miR-21-mediated Cdc25A degradation' by Jin Y.(10)

11. Thyroid cancer
In the investigation of the property of a natural dietary compound found in cruciferous vegetables, 3,3'-diindolylmethane (DIM), to target the metastatic phenotype of thyroid cancer cells through a functional estrogen receptor, found that DIM inhibits estrogen mediated increase in thyroid cell migration, adhesion and invasion, which is also supported by ER-α downregulation (siRNA) studies. Western blot and zymography analyses provided direct evidence for this DIM mediated inhibition of E(2) enhanced metastasis associated events by virtue of targeting essential proteolytic enzymes, namely MMP-2 and MMP-9, according to "Estrogen induced metastatic modulators MMP-2 and MMP-9 are targets of 3,3'-diindolylmethane in thyroid cancer' by Rajoria S, Suriano R, George A, Shanmugam A, Schantz SP, Geliebter J, Tiwari RK.(11)

12. Etc.

Sources
(1) http://www.ncbi.nlm.nih.gov/pubmed/20564344
(2) http://www.ncbi.nlm.nih.gov/pubmed/22363731
(3) http://www.ncbi.nlm.nih.gov/pubmed/22351660
(4) http://www.ncbi.nlm.nih.gov/pubmed/22293900
(5) http://www.ncbi.nlm.nih.gov/pubmed/21229607
(6) http://www.ncbi.nlm.nih.gov/pubmed/22290291
(7) http://www.ncbi.nlm.nih.gov/pubmed/22205686
(8) http://www.ncbi.nlm.nih.gov/pubmed/22187533
(9) http://www.ncbi.nlm.nih.gov/pubmed/21995587
(10) http://www.ncbi.nlm.nih.gov/pubmed/21761201
(11) http://www.ncbi.nlm.nih.gov/pubmed/21267453