Indole-3-Carbinol (I3C) Revisited
New Research Underscores I3C's Anti-Cancer and Anti-Lupus Activities
By
Kimberly Pryor
Indole-3-Carbinol (I3C) is a phytonutrient derived from the cruciferous vegetables of the Brassica genus (cabbage, broccoli, cauliflower and brussels sprouts). I3C initiates a series of reactions in the body that culminates in the elimination of estrogen.
When we first reported on Indole-3-Carbinol (I3C) five years ago, research was beginning to emerge that this cruciferous vegetable-derived nutrient may reduce the risk of breast and cervical cancer as well as benefit patients with Recurrent Respiratory Papillomatosis. In the last five years, the medical literature has been filled with an unfolding array of in vitro and animal research that upholds I3C’s ability to inhibit cancer cells.
New research indicates its effects extend beyond female cancers and that it can inhibit prostate cancer and colon cancer cells as well. Furthermore, new animal studies indicate Indole-3-Carbinol may play a role in aiding Lupus patients.
Before delving into the new research that exists on I3C, it is important to review the mechanisms behind its actions.
Anti-Estrogenic Abilities
Metabolism of the natural estrogen, estradiol, occurs via one of two pathways. The “tumor enhancer” metabolic pathway, 16 alpha-hydroxylation, is elevated in patients with breast and endometrial cancer and in those at increased risk of such cancers. This increased 16 alpha-hydroxylation activity has been shown to precede clinical evidence of cancer, and it represents a significant risk factor for developing estrogen-dependent tumors.1
H. Leon Bradlow, Ph.D. has conducted numerous studies on I3C’s effect on estrogen metabolism pathways. He has observed that 16-alpha hydroxylation was 4.56-fold higher in patients undergoing mastectomy for cancer than in patients who did not have cancer.2
Conversely, when estrogen veers away from the 16-alpha pathway and takes another route out of the body, cancer incidence decreases. This alternate route—which acts as a “tumor suppressor” metabolic pathway—is called 2-hydroxylation, a process which transforms estrogen into 2-hydroxyestrone (20HEI), an antiestrogen.
Stomach acid converts I3C into products that signal the body to metabolize estrogen via the 2-hydroxylation pathway. By funneling estrogen into this “tumor suppressor” pathway, I3C essentially “vacuums” away the estrogen.3
Bradlow and a group of researchers investigated the effects of short-term oral exposure to I3C in humans. They administered 400 mg of I3C daily to test subjects for one week. After taking I3C, the extent of 2-hydroxylation jumped from 29.3 percent to 45.6 percent.4
Breast and Prostate Cancer
Indole-3-Carbinol influences the cell cycle, the process by which cells divide. Recent studies continue to confirm this effect, showing that I3C inhibits cancer cell growth and prevents cancer cell division by blocking DNA duplication. Furthermore, in cancer cells, it triggers apoptosis (cell death).
In a study in the May 2003 Anticancer Research, researchers treated rats with a chemical known to produce breast cancer in the animals. Before the rats developed breast cancer, the researchers also treated the animals with I3C (5 or 25 mg/kg of body weight) for four or 10 days. After tumors formed in the animals, cancer cell death in rats treated with I3C was 3.6 times greater than in untreated animals.5
Another study in July 2003 added to the already prolific collection of animal, in vitro and epidemiological evidence that shows I3C can cause cancer cell death. This study was conducted on both non-cancerous and cancerous human breast cells and indicated that I3C caused cell death only in the cancer cells and not in the normal cells.6
In vitro research indicates that I3C is as effective at inhibiting prostate cancer cells as it is against breast cancer cells. We first reported on the work of G.L. Firestone of the University of California at Berkeley in 1999 (Vitamin Research News, October 1999, “Indole-3-Carbinol: A Powerful Anticarcinogen”), not long after he and his colleagues investigated the effects of I3C on human breast cancer cells.
Back then, Firestone was conducting exciting research that indicated I3C could inhibit the cell cycle in breast cancer cells more effectively than tamoxifen.7 In a study reported in the journal Cancer in December 2003, Firestone and his fellow researchers once again investigated the effects of I3C—this time on human prostate cancer cells.8
Indole-3-carbinol dose-dependently suppressed the prostate cancer cell growth by stopping cancer cell progression. I3C also inhibited production of prostate specific antigen in the prostate cancer cells.
The study authors concluded, “The results of the current study demonstrated that I3C has a potent antiproliferative effect in...human prostate carcinoma cells. These findings implicate this dietary indole as a potential chemotherapeutic agent for controlling the growth of human prostate carcinoma cells.”
Colon Cancer
Researchers are stepping beyond I3C’s breast and prostate cancer boundaries into a new realm of research. In May 2002, researchers demonstrated for the first time that I3C’s benefits may extend to colon cancer. Researchers measured cell proliferation—the way cancer cells multiply—in colon cancer cells treated with I3C. The results indicated that I3C significantly reduced cell proliferation in the cancerous cells.9
Lupus
Researchers have begun to investigate whether I3C can benefit patients with systemic lupus erythematosus (SLE). The reason researchers decided to explore I3C’s effect on SLE is because women with SLE tend to metabolize estrogen through the disease-causing pathway,16 alpha-hydroxylation.
In the first study, published in 2001, 12 women with SLE took 375 mg/day of I3C for three months. After consuming I3C, the subjects’ 16 alpha-hydroxylation activity decreased while the “tumor suppressor” 2-hydroxylation activity increased. According to the researchers, “Women with SLE can manifest a metabolic response to I3C and might benefit from its antiestrogenic effects.”
Although the researchers declared that I3C had no striking effect on SLE disease activity, before treatment the disease activity index was 10.0, but declined to 6.25 at three months’ treatment. Three months after the women stopped taking I3C, the disease activity index went back up to 8.8.10
In a more recent study published in November 2003, I3C treatment in a mouse model of lupus had some interesting results (Figure 1). Mice bred to develop lupus were fed a diet with or without I3C starting soon after weaning or at five months of age. At 12 months of age, 80 percent of mice fed the I3C-supplemented diet soon after weaning were alive compared with only 10 percent of controls. When the animals were given I3C beginning at five months of age, 100 percent of I3C-fed mice and 30 percent of controls were alive a year after birth. In addition, the researchers noted that renal disease was more severe in controls compared to I3C-treated animals.11 “These findings,” the researchers wrote, “demonstrate a profound effect of dietary I3C in experimental SLE.”
Human Papilloma Virus
Human papilloma virus (HPV) infection is associated with an increased risk of cervical cancer, the second most common cancer in women and the seventh most common form of cancer worldwide. However, only a small percentage of women infected with HPV develop invasive cervical cancer. The evolution of HPV into cancer is triggered by estrogen, which increases the risk of HPV-infected cells becoming precancerous and malignant. Administration of I3C to mice bred with HPV genes has led to a significant reduction of cervical-vaginal cancer incidence compared to HPV-bred mice that did not receive the I3C.12 A study published in 2001 also confirmed that I3C can trigger cell death in precancerous cervical cells in HPV-bred mice.13
Conclusion
Indole-3-Carbinol was first investigated for its potential role in preventing breast cancer and benefiting patients infected with the human papilloma virus. New research, however, continues to reveal that this cruciferous vegetable-derived nutrient can inhibit prostate and colon cancer cells and extend the lifespan of animals with lupus, indicating I3C may have a wide role to play in health.
References
1. Fishman J., Schneider J., Hershcope RJ., Bradlow HL. Increased estrogen 16-alpha-hydroxylase activity in women with breast and endometrial cancer. J Steroid Biochem 1984; 20(4B): 1077-1081.
2. Osborne MP, Bradlow HL, Wong GY, Telang NT. Upregulation of estradiol C16 alpha-hydroxylation in human breast tissue: a potential biomarker of breast cancer risk. J National Cancer Inst 1993; 85(23): 1917-1920.
3. Michnoviez JJ, Bradlow HL. Altered estrogen metabolism and excretion in humans following consumption of indole-3-carbinol. Nutr Cancer 1991;16 (1): 59-66.
4. Michnoviez JJ, Bradlow HL. Induction of estradiol metabolism by dietary indole-3-carbinol in humans. J Natl Cancer Inst. 1990; 82(11): 947-949.
5. Effects of treatment of rats with indole-3-carbinol on apoptosis in the mammary gland and mammary adenocarcinomas. Zhang X, Malejka-Giganti D. Anticancer Res 2003 May-Jun;23(3B):2473-9.
6. Sarkar FH, Rahman KM, Li Y. Bax translocation to mitochondria is an important event in inducing apoptotic cell death by indole-3-carbinol (I3C) treatment of breast cancer cells. J Nutr 2003 Jul;133(7 Suppl):2434S-2439S.
7. Cover CM, Hsieh SJ, Cram EJ, Hong C, Riby JE, Bjeldanes LF, and Firestone GL. Indole-3-carbinol and tamoxifen cooperate to arrest the cell cycle of MCF-7 human breast cancer cells. Cancer Research 1999; 59: 1244-1251.
8. Zhang J, Hsu B A JC, Kinseth B A MA, Bjeldanes LF, Firestone GL. Indole-3-carbinol induces a G1 cell cycle arrest and inhibits prostate-specific antigen production in human LNCaP prostate carcinoma cells. Cancer 2003 Dec 1;98(11):2511-20.
9. Frydoonfar HR, McGrath DR, Spigelman AD. Inhibition of proliferation of a colon cancer cell line by indole-3-carbinol. Colorectal Dis 2002 May;4(3):205-207.
10. McAlindon TE, Gulin J, Chen T, Klug T, Lahita R, Nuite M. Indole-3-carbinol in women with SLE: effect on estrogen metabolism and disease activity. Lupus 2001;10(11):779-83.
11. Auborn KJ, Qi M, Yan XJ, Teichberg S, Chen D, Madaio MP, Chiorazzi N. Lifespan is prolonged in autoimmune-prone (NZB/NZW) F1 mice fed a diet supplemented with indole-3-carbinol. J Nutr 2003 Nov;133(11):3610-3.
12. Llang J, Mei Q, Da-Zhi C, Anderson A, Gaung-Yu Y, Arbeit J, Auborn K. Indole-3-carbinol prevents cervical cancer in human papilloma virus type 16 (HPV16) transgenic mice. Cancer Research 1999; 59: 3991-3997.
13. Chen DZ, Qi M, Auborn KJ, Carter TH. Indole-3-carbinol and diindolylmethane induce apoptosis of human cervical cancer cells and in murine HPV16-transgenic preneoplastic cervical epithelium. J Nutr 2001 Dec;131(12):3294-302.