Indole-3-Carbinol

Purported Benefits, Side Effects & More
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Indole-3-Carbinol

Purported Benefits, Side Effects & More
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Indole-3-Carbinol

Common Names

  • I3C
  • Indole-3-methanol
  • 3-(Hydroxymethyl)indole
  • 3-Indolylcarbinol
  • Indolylmethanol

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For Patients & Caregivers

Tell your healthcare providers about any dietary supplements you’re taking, such as herbs, vitamins, minerals, and natural or home remedies. This will help them manage your care and keep you safe.

What is it?

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.

Lab studies suggest that I3C may have activity across various tumor types, or enhance activity of 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.

What are the potential uses and benefits?
  • To prevent cancer
    Lab studies suggest that I3C may protect against a variety of cancers, but some animal studies suggest that I3C supplementation might have tumor-promoting effects. More studies including clinical trials are needed.
  • To treat viral infections
    Lab studies suggest immune function and antiviral effects, but no studies have been conducted in humans.
What are the side effects?
  • Skin rash
What else do I need to know?

Do Not Take if:

  • You are taking cytochrome P450 1A2 substrate drugs: Lab studies suggest I3C may reduce the effectiveness of these drugs. Clinical relevance has yet to be determined.
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For Healthcare Professionals

Scientific Name
Indole-3-Methanol, 1H-Indole-3-methanol
Clinical Summary

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 protective effects and lower cancer risk (27).

Preclinical studies suggest antimicrobial (28) (29), anti-inflammatory (30) (31) (32), anti-estrogenic (33) , and antiangiogenic (21) (22) effects. Potential activity against 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) have also been exhibited. In addition, preliminary experiments suggest I3C may enhance effects of vorinostat (69), bortezomib (25) (47), tamoxifen (48), doxorubicin (49) (50), vemurafenib (51), fludarabine (52), gemcitabine (24) (43), or acetylsalicylic acid (53), and may reverse toxicities of dexamethasone (54) or doxorubicin (50). However, these effects have not been confirmed in humans and some 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).

Food Sources

Broccoli, Brussels sprouts, cabbage, cauliflower, collards, kale, kohlrabi, mustard greens, rapeseed, rutabaga, turnips

Purported Uses and Benefits
  • Cancer prevention
  • Detoxification
  • Viral infections
Mechanism of Action

I3C is derived from the breakdown of glucobrassicin produced in cruciferous vegetables (39). Some health-protective effects are attributed to epigenetic mechanisms (63). I3C counteracted HPV16 immune evasion by antagonizing E6 repression of E-cadherin (64). It decreased proinflammatory cytokine production and T-cell activation by acting as histone deacetylase class I inhibitors (31). Hepatoprotective mechanisms include immunomodulation and inhibition of proinflammatory cytokines and chemokines (66), decreased miR-31 expression, and subsequent T-cell apoptosis (32).

In cancer cells, I3C at higher doses induced apoptosis, while lower doses inhibited cell growth and cyclin E and CDK2 expression (27). Antiproliferative effects may occur by regulating microRNAs that regulate gene expression (65) and upregulation of apoptotic enzymes (48). Other observed activities include estrogen receptor modulation (15) (34) and reductions in MMP-2/9 and aromatase expression (16) (36) (37). In lung carcinoma cells, I3C induced G0/G1 apoptosis and cell cycle arrest (12). In gemcitabine-resistant pancreatic cancer cells, chemosensitizing occurred via downregulated microRNA-21 (43), lower LD50 of gemcitabine, and reactivation of the p16INK4a tumor suppressor gene (19). In melanoma cells, G1 apoptosis/arrest occurred via stabilization of wild-type PTEN expression (39). In prostate cancer cells, I3C inhibits Akt activation, androgen-dependent pathways, and inflammation (8) (38). In murine models, it reduced proinflammatory and procarcinogenic proteins (44).

I3C coadministration with doxorubicin potentiated cytotoxic effects compared with either agent alone in pre-B acute lymphoblastic leukemia cells (49). Along with vorinostat, it modulated re-expression of critical receptors in certain triple negative breast cancer subtypes (69). I3C with genistein produced synergy of apoptosis and TRAIL in endometrial cancer cells (40). It reversed dexamethasone cytotoxicity via ROS inhibition and enhanced 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).

Adverse Reactions

Skin rash (5) (15)

Herb-Drug Interactions
  • Cytochrome P450 1A2 substrates: Laboratory studies suggest I3C induces CYP 1A2 (14) (62). Clinical relevance has yet to be determined.
Herb Lab Interactions

In rare cases, small increases in ALT have occurred (5) (15).

Dosage (OneMSK Only)
References
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  2. Bell MC, et al. Placebo-controlled trial of indole-3-carbinol in the treatment of CIN. Gynecol Oncol 2000;78:123-9.
  3. Naik R, Nixon S, Lopes A, et al. A randomized phase II trials of indole-3-carbinol in the treatment of vulvar intraepithelial neoplasia. Int J Gynecol Cancer 2006;16(2):786-90.
  4. Laidlaw M, Cockerline CA, Sepkovic DW. Effects of a breast-health herbal formula supplement on estrogen metabolism in pre- and post-menopausal women not taking hormonal contraceptives or supplements: a randomized controlled trial. Breast Cancer. 2010 Dec 16;4:85-95.
  5. Indole-3-Carinol(I3C). National Toxicology Program. NIEHS. Accessed August 14, 2020.
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  7. Cover CM, et al. Indole-3-carbinol inhibits the expression of cyclin-dependent kinase-6 and induces a G1 cell cycle arrest of human breast cancer cells independent of estrogen receptor signaling. J Biol Chem 1998;273:3838-47.
  8. Chinni SR, Sarkar FH. Akt inactivation is a key event in indole-3-carbinol-induced apoptosis in PC-3 cells. Clin Cancer Res 2002;8:1228-36.
  9. Chen DZ, et al. Indole-3-carbinol and diindolylmethane induce apoptosis of human cervical cancer cells and in murine HPV16-transgenic preneoplastic cervical epithelium. J Nutr 2001;131:3294-302.
  10. Hong C, et al. Bcl-2 family-mediated apoptotic effects of 3,3’-diindolylmethane (DIM) in human breast cancer cells. Biochem Pharmacol 2002 Mar 15;63(6):1085-97.
  11. Nachshon-Kedmi M, et al. Indole-3-carbinol and 3,3’-diindolylmethane induce apoptosis in human prostate cancer cells. Food Chem Toxicol 2003 Jun;41(6):745-52.
  12. Choi HS, Cho MC, Lee HG, et al. Indole-3-carbinol induces apoptosis through p53 and activation of caspase-8 pathway in lung cancer A549 cells. Food Chem Toxicol. 2010 Mar;48(3):883-90.
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  14. Yoshida M, Katashima S, Ando J, et al. Dietary indole-3-carbinol promotes endometrial adenocarcinoma development in rats initiated with N-ethyl-N’-nitro-N-nitrosoguanidine, with induction of cytochrome P450s in the liver and consequent modulation of estrogen metabolism. Carcinogenesis. 2004 Nov;25(11):2257-64.
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  18. Bradlow HL, et al. Long-term responses of women to indole-3-carbinol or a high fiber diet. Cancer Epidemiol Biomarkers Prev 1994;3:591-5.
  19. Lyn-Cook BD, Mohammed SI, Davis C, et al. Gender differences in gemcitabine (Gemzar) efficacy in cancer cells: effect of indole-3-carbinol. Anticancer Res. 2010 Dec;30(12):4907-13.
  20. Rosen CA, et al. Preliminary results of the use of indole-3-carbinol for recurrent respiratory papillomatosis. Otolaryngol Head Neck Surg 1998;118:810-5.
  21. Jin L, et al. Indole-3-carbinol prevents cervical cancer in human papilloma virus type 16 (HPV16) transgenic mice. Cancer Res 1999;59:3991-7.
  22. Wang ML, Shih CK, Chang HP, Chen YH. Antiangiogenic activity of indole-3-carbinol in endothelial cells stimulated with activated macrophages. Food Chem. 2012 Sep 15;134(2):811-20.
  23. Qian X, Melkamu T, Upadhyaya P, Kassie F. Indole-3-carbinol inhibited tobacco smoke carcinogen-induced lung adenocarcinoma in A/J mice when administered during the post-initiation or progression phase of lung tumorigenesis. Cancer Lett. 2011 Dec 1;311(1):57-65.
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  25. Taylor-Harding B, Agadjanian H, Nassanian H, et al. Indole-3-carbinol synergistically sensitises ovarian cancer cells to bortezomib treatment. Br J Cancer. 2012 Jan 17;106(2):333-43.
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  27. Chen L, Cheng PH, Rao XM, et al. Indole-3-carbinol (I3C) increases apoptosis, represses growth of cancer cells, and enhances adenovirus-mediated oncolysis. Cancer Biol Ther. Sep 2014;15(9):1256-1267.
  28. Monte J, Abreu AC, Borges A, et al. Antimicrobial Activity of Selected Phytochemicals against Escherichia coli and Staphylococcus aureus and Their Biofilms. Pathogens. 2014;3(2):473-498.
  29. Julliard W, De Wolfe TJ, Fechner JH, et al. Amelioration of Clostridium difficile Infection in Mice by Dietary Supplementation With Indole-3-carbinol. Ann Surg. 2017 Jun;265(6):1183-1191.
  30. Jiang J, Kang TB, Shim do W, et al. Indole-3-carbinol inhibits LPS-induced inflammatory response by blocking TRIF-dependent signaling pathway in macrophages. Food Chem Toxicol. Jul 2013;57:256-261.
  31. Busbee PB, Nagarkatti M, Nagarkatti PS. Natural indoles, indole-3-carbinol and 3,3’-diindolymethane, inhibit T cell activation by staphylococcal enterotoxin B through epigenetic regulation involving HDAC expression. Toxicol Appl Pharmacol. Jan 1 2014;274(1):7-16.
  32. Busbee PB, Nagarkatti M, Nagarkatti PS. Natural indoles, indole-3-carbinol (I3C) and 3,3’-diindolylmethane (DIM), attenuate staphylococcal enterotoxin B-mediated liver injury by downregulating miR-31 expression and promoting caspase-2-mediated apoptosis. PLoS One. 2015;10(2):e0118506.
  33. Enriquez J, Velazquez-Cruz R, Parra-Torres A, et al. The anti-estrogenic activity of indole-3-carbinol in neonatal rat osteoblasts is associated with the estrogen receptor antagonist 2-hydroxyestradiol. J Endocrinol Invest. 2016 Oct;39(10):1149-58.
  34. Marconett CN, Singhal AK, Sundar SN, et al. Indole-3-carbinol disrupts estrogen receptor-alpha dependent expression of insulin-like growth factor-1 receptor and insulin receptor substrate-1 and proliferation of human breast cancer cells. Mol Cell Endocrinol. Nov 5 2012;363(1-2):74-84.
  35. Caruso JA, Campana R, Wei C, et al. Indole-3-carbinol and its N-alkoxy derivatives preferentially target ERalpha-positive breast cancer cells. Cell Cycle. 2014;13(16):2587-2599.
  36. Ho JN, Jun W, Choue R, et al. I3C and ICZ inhibit migration by suppressing the EMT process and FAK expression in breast cancer cells. Mol Med Rep. Feb 2013;7(2):384-388.
  37. Licznerska BE, Szaefer H, Murias M, et al. Modulation of CYP19 expression by cabbage juices and their active components: indole-3-carbinol and 3,3’-diindolylmethene in human breast epithelial cell lines. Eur J Nutr. Aug 2013;52(5):1483-1492.
  38. Kim EK, Kim YS, Milner JA, et al. Indole-3-carbinol and 3’,3’-diindolylmethane modulate androgen’s effect on C-C chemokine ligand 2 and monocyte attraction to prostate cancer cells. Cancer Prev Res (Phila). Jun 2013;6(6):519-529.
  39. Aronchik I, Kundu A, Quirit JG, et al. The antiproliferative response of indole-3-carbinol in human melanoma cells is triggered by an interaction with NEDD4-1 and disruption of wild-type PTEN degradation. Mol Cancer Res. Nov 2014;12(11):1621-1634.
  40. Parajuli B, Shin SJ, Kwon SH, et al. The synergistic apoptotic interaction of Indole-3-Carbinol and Genistein with TRAIL on endometrial cancer cells. J Korean Med Sci. Apr 2013;28(4):527-533.
  41. Krajka-Kuzniak V, Paluszczak J, Szaefer H, et al. The activation of the Nrf2/ARE pathway in HepG2 hepatoma cells by phytochemicals and subsequent modulation of phase II and antioxidant enzyme expression. J Physiol Biochem. Jun 2015;71(2):227-238.
  42. Wang X, He H, Lu Y, et al. Indole-3-carbinol inhibits tumorigenicity of hepatocellular carcinoma cells via suppression of microRNA-21 and upregulation of phosphatase and tensin homolog. Biochim Biophys Acta. Jan 2015;1853(1):244-253.
  43. Paik WH, Kim HR, Park JK, et al. Chemosensitivity induced by down-regulation of microRNA-21 in gemcitabine-resistant pancreatic cancer cells by indole-3-carbinol. Anticancer Res. Apr 2013;33(4):1473-1481.
  44. Song JM, Qian X, Molla K, et al. Combinations of indole-3-carbinol and silibinin suppress inflammation-driven mouse lung tumorigenesis by modulating critical cell cycle regulators. Carcinogenesis. Jun 2015;36(6):666-675.
  45. Wang YQ, Chen C, Chen Z, et al. Indole-3-carbinol inhibits cell proliferation and induces apoptosis in Hep-2 laryngeal cancer cells. Oncol Rep. Jul 2013;30(1):227-233.
  46. Chen Z, Tao ZZ, Chen SM, et al. Indole-3-carbinol inhibits nasopharyngeal carcinoma growth through cell cycle arrest in vivo and in vitro. PLoS One. 2013;8(12):e82288.
  47. Taylor-Harding B, Agadjanian H, Nassanian H, et al. Indole-3-carbinol synergistically sensitises ovarian cancer cells to bortezomib treatment. Br J Cancer. Jan 17 2012;106(2):333-343.
  48. Malejka-Giganti D, Parkin DR, Bennett KK, et al. Suppression of mammary gland carcinogenesis by post-initiation treatment of rats with tamoxifen or indole-3-carbinol or their combination. Eur J Cancer Prev. Apr 2007;16(2):130-141.
  49. Safa M, Tavasoli B, Manafi R, et al. Indole-3-carbinol suppresses NF-kappaB activity and stimulates the p53 pathway in pre-B acute lymphoblastic leukemia cells. Tumour Biol. May 2015;36(5):3919-3930.
  50. Adwas AA, Elkhoely AA, Kabel AM, et al. Anti-cancer and cardioprotective effects of indol-3-carbinol in doxorubicin-treated mice. J Infect Chemother. Jan 2016;22(1):36-43.
  51. Kundu A, Quirit JG, Khouri MG, et al. Inhibition of oncogenic BRAF activity by indole-3-carbinol disrupts microphthalmia-associated transcription factor expression and arrests melanoma cell proliferation. Mol Carcinog. 2017 Jan;56(1):49-61.
  52. Perez-Chacon G, Martinez-Laperche C, Rebolleda N, et al. Indole-3-Carbinol Synergizes with and Restores Fludarabine Sensitivity in Chronic Lymphocytic Leukemia Cells Irrespective of p53 Activity and Treatment Resistances. Clin Cancer Res. Jan 1 2016;22(1):134-145.
  53. Poindexter KM, Matthew S, Aronchik I, et al. Cooperative antiproliferative signaling by aspirin and indole-3-carbinol targets microphthalmia-associated transcription factor gene expression and promoter activity in human melanoma cells. Cell Biol Toxicol. Apr 2016;32(2):103-119.
  54. Lin H, Gao X, Chen G, et al. Indole-3-carbinol as inhibitors of glucocorticoid-induced apoptosis in osteoblastic cells through blocking ROS-mediated Nrf2 pathway. Biochem Biophys Res Commun. May 1 2015;460(2):422-427.
  55. Suzui M, Inamine M, Kaneshiro T, et al. Indole-3-carbinol inhibits the growth of human colon carcinoma cells but enhances the tumor multiplicity and volume of azoxymethane-induced rat colon carcinogenesis. Int J Oncol. Nov 2005;27(5):1391-1399.
  56. Yoshida M, Katashima S, Ando J, et al. Dietary indole-3-carbinol promotes endometrial adenocarcinoma development in rats initiated with N-ethyl-N’-nitro-N-nitrosoguanidine, with induction of cytochrome P450s in the liver and consequent modulation of estrogen metabolism. Carcinogenesis. Nov 2004;25(11):2257-2264.
  57. Stoner G, Casto B, Ralston S, et al. Development of a multi-organ rat model for evaluating chemopreventive agents: efficacy of indole-3-carbinol. Carcinogenesis. Feb 2002;23(2):265-272.
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  67. Thomson CA, Chow HHS, Wertheim BC, et al. A randomized, placebo-controlled trial of diindolylmethane for breast cancer biomarker modulation in patients taking tamoxifen. Breast Cancer Res Treat. Aug 2017;165(1):97-107.
  68. Fujioka N, Ransom BW, Carmella SG, et al. Harnessing the Power of Cruciferous Vegetables: Developing a Biomarker for Brassica Vegetable Consumption Using Urinary 3,3’-Diindolylmethane. Cancer Prev Res (Phila). Oct 2016;9(10):788-793.
  69. Nouriemamzaden F, Word B, Cotton E, et al. Modulation of Estrogen α and Progesterone Receptors in Triple Negative Breast Cancer Cell Lines: The Effects of Vorinostat and Indole-3-Carbinol In Vitro. Anticancer Res. Jul 2020;40(7):3669-3683.
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