Highlights
A recent study done in 2018 suggested that indole-3-carbinol (I3C) may have benefits as a maintenance therapy in advanced ovarian cancer patients and a previous study found significant regression of Cervical Intra-epithelial Neoplasia (CIN) in patients treated with I3C. However, well-defined studies are required to confirm the chemoprevention potential and anti-tumor effects of Indole-3-Carbinol (I3C) and its metabolite Diindolylmethane (DIM) in breast cancer, as DIM may potentially interact with the standard of care hormonal therapy, Tamoxifen. Eating a diet containing indole-3-carbinol (I3C) rich foods such as cruciferous vegetables may be preferred for reducing cancer risk, rather than randomly consuming these supplements, unless recommended with scientific explanations.
Indole-3-Carbinol (I3C) and its Food Sources
A diet rich in cruciferous vegetables has always been considered nutritious and healthy. Different observational studies have also supported the potential of these vegetables in reducing the risk of a variety of cancers.
Indole-3-carbinol (I3C) is a compound formed from a substance called glucobrassicin, which is commonly found in cruciferous vegetables such as :
- broccoli
- brussels sprouts
- cabbage
- cauliflower
- kale
- bok choy
- kohlrabi
- horseradish
- arugula
- turnips
- collard greens
- radishes
- watercress
- wasabi
- mustard
- Rutabagas
Indole-3-carbinol (I3C) is usually formed when the cruciferous vegetables are cut, chewed or cooked. Basically, cutting, crushing, chewing or cooking these vegetables damages the plant cells allowing glucobrassicin to come in contact with an enzyme called myrosinase resulting in its hydrolysis to indole-3-carbinol (I3C), glucose and thiocyanate. Taking 350 mg to 500 mg of Indole-3-carbinol (I3C) may be equivalent to eating approximately 300 grams to 500 grams of raw cabbage or Brussels sprouts.
I3C may also stimulate detoxifying enzymes in the gut and liver.
Indole-3-carbinol (I3C) is very unstable in stomach acid and is hence metabolized to a biologically- active dimer called Diindolylmethane (DIM). DIM, the condensation product of Indole-3-carbinol (I3C) is absorbed from the small intestine.
Health Benefits of Indole-3-Carbinol (I3C)
- Most of the anti-cancer, anti-inflammatory, antioxidant and anti-estrogenic properties of cruciferous vegetables may be attributed to indole-3-carbinol (I3C) and sulforaphane.
- Many previous in vitro and in vivo studies suggest the chemopreventive benefits of indole-3-carbinol (I3C) in cancers such as lung, colon, prostate, and breast cancers and may even enhance the activity of some chemotherapy drugs. However, so far, there are no human clinical trials which validated its impact on cancers.
- Few experimental/lab studies also suggest potential Indole-3-carbinol (I3C) benefits in immune functions and antiviral activities, however, human studies are lacking on this front too.
- People also use I3C to treat systemic lupus erythematosus (SLE), fibromyalgia and recurrent respiratory (laryngeal) papillomatosis, however, there is no good scientific evidence to support these uses.
Taking Indole-3-Carbinol (I3C) rich foods such as cruciferous vegetables is hence considered to have many health benefits. Apart from these Indole-3-Carbinol (I3C) rich foods, Indole-3-carbinol supplements are also available in market which is usually considered safe to take in right quantities not exceeding 400 mg daily. In some people, it can cause certain side effects such as skin rashes and diarrhea. However, avoid excess intake or higher doses of I3C as it may cause side-effects like balance problems, tremor, and nausea.
Please also note that there are few animal studies that suggested that I3C might promote tumor growth. Hence, studies are required to evaluate the impact of indole-3-carbinol (I3C) rich foods and supplements in humans. For general health benefits, consuming Indole-3-carbinol rich foods is preferred over I3C supplements.
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Use of Indole-3-carbinol (I3C) in Cancer
Different observational and dietary studies have supported the association between high dietary intake of cruciferous vegetables and lowered cancer risks. This chemo-preventive effect of these indole-3-carbinol (I3C) rich foods may possibly be attributed to the antitumor activity of I3C as well as its metabolite Diindolylmethane (DIM), and sulforaphane. However, there aren’t many studies which evaluated the association between indole-3-carbinol (I3C) and cancer risk. Below, we have provided details of some of the studies related to I3C and cancer.
Benefits of Indole-3-carbinol (I3C) and Epigallocatechin gallate (EGCG) in Advanced Ovarian Cancer Patients
Globally, ovarian cancer is the eighth most commonly occurring cancer in women and the 18th most commonly occurring cancer overall, with nearly 300,000 new cases in 2018. (World Cancer Research Fund) Approximately 1.2 percent of women will be diagnosed with ovarian cancer at some point during their lifetime. (SEER., Cancer Stat Facts, National Cancer Institute) Although the 5-year survival rate for ovarian cancer has improved in the past 30 years, overall, the prognosis for ovarian cancer still remains poor, with the 5-year relative survival rate varying between 12-42% for advanced ovarian cancers. 60–80% of these patients who are treated with the standard of care chemotherapies relapse in 6 to 24 months resulting in the need for further chemotherapy, eventually making the tumor chemo-resistant.
Hence, researchers from the Peoples’ Friendship University of Russia, Russian Scientific Center of Roentgenoradiology (RSCRR) and MiraxBioPharma in Russia and Wayne State University in the US conducted a сomparative clinical trial to evaluate the efficacy of long-term maintenance therapy with indole-3-carbinol (I3C), as well as a maintenance therapy with indole-3-carbinol (I3C) and epigallocatechin-3-gallate (EGCG) in advanced ovarian cancer patients. Epigallocatechin gallate (EGCG) is a key active ingredient present in green tea with anti-inflammatory and antioxidant properties. (Vsevolod I Kiselev et al, BMC Cancer., 2018)
The study at RSCRR included 5 groups (as defined below) of a total of 284 women aged ≥ 39 years with stage III-IV serous ovarian cancers, enrolled between January 2004 and December 2009, who received combined treatment including neoadjuvant platinum-taxane chemotherapy, surgery, and adjuvant platinum-taxane chemotherapy.
- Group 1 received combined treatment plus I3C
- Group 2 received combined treatment plus I3C and Epigallocatechin gallate (EGCG)
- Group 3 received combined treatment plus I3C and Epigallocatechin gallate (EGCG) plus long-term platinum-taxane chemotherapy
- Control group 4 combined treatment alone without neoadjuvant platinum-taxane chemotherapy
- Control group 5 combined treatment alone
Following were the key findings of the study:
- After a follow-up of five years, women who received maintenance therapy with indole-3-carbinol, or I3C with Epigallocatechin gallate (EGCG), had a significantly prolonged Progression Free Survival and Overall Survival compared to women in the control groups.
- Median Overall Survival was 60.0 months in Group 1, 60.0 months in Groups 2 and 3 who received maintenance therapy while 46.0 months in Group 4, and 44.0 months in Group 5.
- Median Progression Free Survival was 39.5 months in Group 1, 42.5 months in Group 2, 48.5 months in Group 3, 24.5 months in Group 4, 22.0 months in Group 5.
- The number of patients with recurrent ovarian cancer with ascites after combined treatment was reduced significantly in the groups which received the maintenance therapy with indole-3-carbinol or I3C with Epigallocatechin gallate (EGCG), compared to the control groups.
The researchers concluded that the long-term usage of indole-3-carbinol (I3C) and Epigallocatechin gallate (EGCG) may improve treatment outcomes (about 73.4% improvement as seen in the study) in advanced ovarian cancer patients and can be a promising maintenance therapy for these patients.
Benefits of Indole-3-carbinol (I3C) in Patients with Cervical Intra-epithelial Neoplasia (CIN)
Cervical Intra-epithelial Neoplasia (CIN) or Cervical dysplasia is a precancerous condition in which abnormal cell growths are formed on the surface lining of the cervix or the endocervical canal which is the opening between the uterus and the vagina. Cervical Intra-epithelial Neoplasia is often treated with surgery or ablative therapy to destroy the abnormal tissue.
Rather than treating cervical cancer after the cancer diagnosis, it is always better to get it detected at an earlier stage or the precancerous stage and intervene earlier using synthetic or natural compounds such as indole-3-carbinol (I3C) and prevent the development of the invasive disease. With this in mind, the researchers from the Louisiana State University Medical Center-Shreveport in the United States, evaluated indole-3-carbinol (I3C) administered orally to treat women with Cervical Intra-epithelial Neoplasia (CIN), as a therapeutic for CIN. (M C Bell et al, Gynecol Oncol., 2000)
The study included a total of 30 patients who either received placebo or 200, or 400 mg/day of oral indole-3-carbinol (I3C).
Following were the key findings of the study.
- Out of the 10 patients in the group that received placebo, none had complete regression of Cervical Intra-epithelial Neoplasia (CIN).
- 4 out of 8 patients in the group that received 200 mg/day of oral indole-3-carbinol (I3C) had complete regression of Cervical Intra-epithelial Neoplasia (CIN).
- 4 out of 9 patients in the group that received 400 mg/day of oral indole-3-carbinol (I3C) had complete regression of Cervical Intra-epithelial Neoplasia (CIN).
In short, the researchers found significant regression of Cervical Intra-epithelial Neoplasia (CIN) in patients treated with indole-3-carbinol (I3C) orally compared with those who received placebo.
Chemoprevention Potential of Indole-3-Carbinol (I3C) in Breast Cancer
According to a paper published in 1997 by the researchers from the Strang Cancer Prevention Center in New York, United States, 60 women who were at an increased risk for breast cancer were enrolled in a placebo-controlled trial to evaluate the chemoprevention potential of I3C. Out of these, 57 women with a mean age of 47 years completed the study. (G Y Won et al, J Cell Biochem Suppl., 1997)
These women were included in one of the 3 groups (detailed below) which either received a placebo capsule or an indole-3-carbinol (I3C) capsule daily for a total of 4 weeks.
- Control group received the Placebo capsule
- Low dose group received 50, 100, and 200 mg of I3C
- High dose group received 300 and 400 mg of I3C
The surrogate end-point used in this study was the urinary estrogen metabolite ratio of 2-hydroxyestrone to 16 alpha-hydroxyestrone.
The study found that the peak relative change of the surrogate end-point for women in the high dose group was significantly higher than that for women in the control and low dose groups by an amount that was inversely related to baseline ratio.
The findings from the study also suggested that indole-3-carbinol (I3C) at a minimum effective dose schedule of 300 mg per day may be a promising agent for breast cancer prevention. However, more larger well-defined clinical studies are required to validate these findings and to come up with the optimal effective dose of I3C for long-term breast cancer chemoprevention.
Diindolylmethane in Breast Cancer in Patients taking Tamoxifen
Due to the possible chemopreventive potential of cruciferous vegetables and anti-tumor effects of Indole-3-carbinol (I3C) in breast cancer, there have been interest in evaluating whether Diindolylmethane, the primary metabolite of Indole-3-carbinol (I3C), has benefits in breast cancer. (Cynthia A Thomson et al, Breast Cancer Res Treat., 2017)
Researchers from the University of Arizona, University of Arizona Cancer Center, Stony Brook University and University of Hawaii Cancer Center in the United States carried out a clinical trial to evaluate the activity and safety of combined use of Diindolylmethane (DIM) with Tamoxifen in breast cancer patients.
A total of 98 women with breast cancer who were prescribed with tamoxifen either received DIM (47 women) or placebo (51 women). The study found that daily DIM use promoted favorable changes in estrogen metabolism and circulating levels of sex hormone-binding globulin (SHBG). However, the levels of active plasma tamoxifen metabolites including endoxifen, 4-OH tamoxifen, and N-desmethyl-tamoxifen were reduced in women who received DIM, suggesting that DIM might have the potential for reducing the effectiveness of Tamoxifen.(NCT01391689).
Further research is warranted to determine whether DIM (the condensation product of Indole-3-Carbinol (I3C)) associated reduction in tamoxifen metabolites such as endoxifen, attenuates the clinical benefit of tamoxifen. Until then, since the clinical data is showing a trend of interaction between DIM and the hormonal therapy tamoxifen, breast cancer patients while on tamoxifen therapy should veer on the side of caution and avoid taking DIM supplement.
Conclusion
Indole-3-carbinol (I3C) may have anti-tumor properties as suggested by previous in vitro, in vivo and animal studies and hypothesized based on observational studies that have shown that an overall high consumption of cruciferous vegetables in the diet was significantly associated with a reduced risk of cancers. However, there aren’t many studies in humans to establish these findings.
A recent study in 2018 found that the long-term usage of indole-3-carbinol (I3C) may have benefits as a maintenance therapy and improving the treatment outcomes in advanced ovarian cancer patients and a previous study found significant regression of Cervical Intra-epithelial Neoplasia (CIN) in patients treated with I3C. However, well-defined studies are required to confirm on the chemoprevention potential and anti-tumor effects of Indole-3-Carbinol (I3C) and its metabolite Diindolylmethane (DIM) in breast cancer, as DIM may potentially interact with the standard of care hormonal therapy tamoxifen and reduce the levels of its active form endoxifen, which may possibly affect tamoxifen’s therapeutic efficacy. Hence, eating a diet containing foods like cruciferous vegetables rich in Indole-3-Carbinol (I3C) is preferred, rather than supplements, unless suggested by your healthcare provider.
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