For Patients & Caregivers
How It Works
Indole 3-carbinol has cancer-preventive effects, but it has not been shown to treat cancer in humans.
Indole-3-carbinol, also called I3C, is a resulting compound that comes from eating vegetables such as Brussels sprouts, cabbage, cauliflower, broccoli, and kale. It is known to stimulate detoxifying enzymes in the gut and liver. Because diets high in these vegetables slow cancer growth in animals, I3C is thought to be a good candidate for cancer prevention. Laboratory studies show that I3C may have anticancer activities across a variety of tumor types, and may have added benefit with some chemotherapy drugs. However, other animal studies suggest that I3C might also promote tumor growth. Additional studies and human clinical trials are needed to determine the circumstances under which I3C might be suitable for cancer prevention.
- To prevent cancer Laboratory and animal studies suggest that indole-3-carbinol may prevent a variety of cancers, including estrogen-dependent cancers, but only one clinical trial has been performed. This small study concluded that I3C can reverse cervical intraepithelial neoplasia (CIN), a condition that can lead to cervical cancer, but these findings are too limited to draw definite conclusions. In addition, some animal studies indicate that I3C supplementation might have tumor-promoting effects. More studies including clinical trials are needed.
- To treat viral infections Preliminary studies suggest several benefits to immune function including counteracting the activity of human papiloma virus (HPV), but no studies have been conducted in humans.
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For Healthcare Professionals
Indole-3-Carbinol (I3C) is a phytochemical derived from the breakdown of glucosinolates found in cruciferous vegetables including Brussels sprouts, kale, broccoli, cabbage, and cauliflower (26). Epidemiologic studies suggest that a diet high in cruciferous vegetables is associated with a lower risk of cancer and that I3C has anticarcinogenic properties across a wide range of cancers (27).
Various in vitro and in vivo studies suggest antimicrobial (28) (29), anti-inflammatory (30) (31) (32), anti-estrogenic (33) , and antiangiogenic (21) (22) effects. Antiproliferative and anticancer effects have been demonstrated in human breast (34) (35) (36) (37), prostate (38), melanoma (39), endometrial (40) , liver (41) (42), and pancreatic cancer cells (43), as well as animal models of lung (12) (23) (44), laryngeal (45), and nasopharyngeal carcinoma (46). In addition, preliminary experiments suggest I3C may potentiate or have sensitizing effects in combination with bortezomib (25) (47), tamoxifen (48), doxorubicin (49) (50), vemurafenib (51), fludarabine (52), gemcitabine (24) (43), or acetylsalicylic acid (53), and may reverse cytotoxicity with dexamethasone (54) or cardiotoxicity with doxorubicin (50) . However, these effects have not been confirmed in humans. Studies in animal carcinogenesis models suggest that I3C may also promote tumor growth (55) (56) (57) (58) (59) (60) (61). Additional studies are needed to determine under what conditions I3C could be a suitable chemopreventive agent in humans.
Data from early phase clinical trials suggested that I3C is effective against precancerous cervical dysplasia (2) and vulvar intraepithelial neoplasia (3). In premenopausal women, a supplement containing I3C and 7-hydroxymatairesinol, a dietary ingredient, increased the urinary 2:16-hydroxyestrone ratio, a known biomarker for the reduction of breast cancer risk (4). More recently, an RCT of a diindolylmethane formulation (DIM, an active I3C metabolite) in breast cancer patients on tamoxifen suggest it encourages beneficial changes in estrogen metabolism and circulating sex hormone-binding globulin levels (67).
I3C is generally well tolerated when taken orally, but it is unclear if I3C supplementation can benefit humans due to its mixed effects in preliminary studies and its ability to induce cytochrome P450 enzymes (14) (62), which may cause interactions with several medications. In addition, a recent study to measure Brassica consumption in humans suggests that the chemopreventive effects derived from cruciferous vegetable consumption may plateau and not require eating large quantities or taking high-dose supplements (68).
Mechanism of Action
Indole-3-carbinol (I3C) is a natural indolecarbinol compound derived from the breakdown of glucobrassicin produced in cruciferous vegetables such as broccoli and Brussels sprouts (39). Some of the health-protective effects of I3C are attributed to epigenetic mechanisms such as the regulation of HDAC and HAT activities and acetylation of histones and non-histone chromatin proteins (63).
Preliminary studies suggest several benefits to immune function. I3C counteracted immune evasion mechanisms of HPV16 by antagonizing E6 repression of E-cadherin (64). It decreased pro-inflammatory cytokine production and T cell activation by acting as histone deacetylase class I (HDAC-I) inhibitors (31). Other anti-inflammatory mechanisms include regulation of TIR-domain-containing adapter-inducing interferon-β (TRIF)-dependent signaling pathways (30).
In cancer cells, I3C at higher doses (>400 μM) induced apoptosis, while lower doses (<200 μM) inihbited cell growth as well as cyclin E and CDK2 expression (27). It is among compounds that exert antiproliferative and/or proapoptotic effects through regulation of one or more microRNAs (miRNAs), short noncoding RNAs that regulate gene expression by messenger RNA (mRNA) degradation or translation repression (65).
I3C may act as a chemopreventive agent for breast cancer through its estrogen receptor (ER) modulating effect (15) or upregulation of apoptotic enzyme activities (48). It disrupted ER alpha-mediated transcription within IGF1 cascade cell signaling components (34), downregulated expression of estrogen-responsive genes pS2 and cathepsin-D, and upregulated BRAC1 (17). Other inhibitory mechanisms include suppressing epithelial-to-mesenchymal transition (EMT), blocking extracellular signal-regulated kinase (ERK)/Sp1-mediated gene transcription, reducing matrix metalloproteinase (MMP)-2 and MMP-9 activities, and decreasing aromatase expression (16) (36) (37). One randomized clinical trial suggests that the decreased risk of ER-sensitive breast and cervical cancers with I3C may be due to an increase in the 2-OH-estrone:estriol metabolite ratio (18).
In HepG2 cells, I3C induced phase II and antioxidant enzymes (41). Other hepatoprotective mechanisms include immunomodulation and inhibition of pro-inflammatory cytokines and chemokines (66). Acute hepatic inflammation was suppressed via decreased miR-31 expression and subsequent caspase-2-dependent apoptosis in T cells (32). In human lung carcinoma A549 cells, I3C significantly reduced cell proliferation and induced apoptosis and cell cycle arrest at the G0/G1 phase (12). In murine models, chemopreventive effects against lung tumors occurred via reductions in levels of proinflammatory and procarcinogenic proteins (44). In melanoma cells, I3C induced G1-phase cell-cycle arrest and apoptosis by stabilization of PTEN that express wild-type PTEN (39). In prostate cancer cells, I3C inhibits androgen-dependent pathways and appeared to block the inflammatory microenvironment (38), and caused apoptosis by inhibiting Akt activation (8).
I3C coadministration with doxorubicin potentiated cytotoxic effects compared with either agent alone in pre-B acute lymphoblastic leukemia cells (49). Chemosensitive effects were produced in gemcitabine-resistant pancreatic cancer cells via microRNA-21 downregulation (43). I3C also lowered the LD50 of gemcitabine and decreased growth of pancreatic cancer cells, possibly through reactivation of the tumor suppressor gene p16INK4a (19). I3C with genistein produced synergy of apotosis and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in endometrial cancer cells (40). It reversed dexamethasone cytotoxicity via ROS inhibition and enhanced nuclear factor erythroid 2–related factor 2 (Nrf2) expression (54).
Some animal studies suggest that I3C is both an inhibitor and promoter of carcinogenesis with strong induction of placental glutathione S-transferase foci in the liver (57), and modulatory activity that included apoptotic inhibition in colon tumors (55). In addition, I3C may promote endometrial adenocarcinoma through hepatic CYP1 induction and estrogen metabolism modulation (56).