Indole-3-Carbinol
A Powerful Anticarcinogen

October 1999 Newsletter

by Kimberly Pryor
Indole-3-Carbinol (I3C) is one of the most important weapons in the anticancer arsenal. 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.

Antiestrogen

To understand why I3C is such a potent anticarcinogen, we must first look at the process involved in removing estrogen from the human body. 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, the incidence of cancer 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. Healthy individuals not at risk for breast or endometrial cancer bypass the 16-alpha route and instead metabolize estrogen through this preferable pathway.3

The process begins when I3C is ingested. Stomach acid converts it into a variety of products that ultimately induce the enzyme cytochrome P450, which signals the body to metabolize estrogen via the 2-hydroxylation pathway. By funneling estrogen into this "tumor suppressor" pathway, I3C essentially "vacuums" away the estrogen.4

Indole-3-Carbinol stimulates the rate at which the body expels estrogen through 2-hydroxylation. Bradlow and a group of researchers investigated the effects on humans of short-term oral exposure to I3C, administering 400 mg of I3C daily to test subjects for one week. After I3C was consumed, the extent of 2-hydroxylation jumped from 29.3 percent to 45.6 percent. In another study, 12 healthy volunteers ingested 6 - 7 mg of I3C per kg of body weight, per day over one-week. After exposure to I3C, the rate of 2-hydroxylation in the subjects increased by 50 percent.5-6

As I3C works to sweep the estrogen away from the tumor enhancer to the tumor suppressor pathway, it acts as an effective weapon against breast, cervical and skin cancer and respiratory papillomas.

Breast Cancer

The potent, anticarcinogen effects of I3C have been documented in a number of studies. Researchers at the University of California at Berkeley injected I3C directly into human breast cancer cells, then observed its effect on the cell cycle, the process by which cells divide. I3C halted the cell cycle process before it jumped into full gear, inhibiting the growth of the cancer cells and preventing cell division by blocking DNA duplication.7

Due to its ability to halt the cell cycle, I3C is being looked upon as a possible adjunct therapy to breast cancer. For more than 20 years, the antiestrogen Tamoxifen has remained the drug of choice to treat breast cancer sufferers. But Tamoxifen has been a double-edged sword. Although it has extended the life of many women, only half of the two-thirds of breast cancer patients with estrogen dependent tumors respond to Tamoxifen therapy. Furthermore, after 12 - 18 months of treatment, users develop a resistance to the drug, and it has been shown to stimulate the growth of breast cancer cells after prolonged use. 8-11

Research documents the effectiveness of combining I3C with Tamoxifen to eliminate the drug's potentially harmful effects and to create an even more effective antiestrogen. University of California at Berkeley researchers injected three groups of human breast cancer cells, one group with I3C, another with Tamoxifen and a third with the two substances combined. The cells injected with Tamoxifen alone experienced a 60 percent inhibition in DNA synthesis, while the cells injected with I3C experienced a 90 percent inhibition during the same time period. The combination of I3C and Tamoxifen yielded a more effective suppression of the cancer cells than either substance alone, resulting in a 95 percent inhibition after 96 hours of treatment.12

Lower doses of Tamoxifen, when combined with I3C treatment, inhibited cancer cell growth to the same extent as higher doses of either substance added individually. These results indicate that patients on a combined Tamoxifen-I3C treatment program can substantially reduce their dosage of Tamoxifen, decreasing the likelihood of resistance to the drug.13

Cervical, Vaginal and Skin Cancer

I3C plays an important role in the prevention of cervical-vaginal and skin cancer. 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, and an increased likelihood of developing skin cancer. HPV, however, is not the sole culprit behind cervical or skin cancer, and 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. 14-17

To determine whether I3C could be an effective anticarcinogen in HPV-related cases, researchers administered excessive estrogen to mice bred with HPV genes. The researchers compared mice fed a control diet with those fed a diet supplemented with 2000 ppm I3C. In the control group, 19 of 25 mice developed cervical-vaginal cancer within six months, compared to only 2 of the 24 mice in the I3C-supplemented group. In addition, researchers observed a reduction in skin cancer in the I3C-fed mice.18

Other Benefits

Besides altering estrogen metabolic pathways, I3C guards against the carcinogenic effects of two amines (IQ and PhIP) formed during the cooking process of proteinaceous foods. These amines are carcinogenic in several strains of rats, inducing mammary and liver tumors in the animals. Once activated by enzymes, PhIp and IQ yield cancer-causing DNA adducts. Indole-3-Carbinol inhibits this adduct formation by as much as 89 percent.19

Recurrent Respiratory Papillomatosis (RRP)

Recurrent Respiratory Papillomatosis (RRP) is a viral-caused disease characterized by soft tissue warts, or papillomas, that form on the larynx and vocal chords. Benign tumors which grow in clusters, the papillomas "travel" throughout the respiratory tract. There-fore, they can become extremely complicated to treat. 20

In RRP patients, there appears to be a linear relationship between the ratio of estrogen metabolism pathways and the severity of the disease, based upon urine analysis of patients participating in a Long Island Jewish Medical Center study. Ratios of less than one of the 2-hydroxylation antiestrogen byproduct 20HEI were associated with a more aggressive form of RRP. Ratios of 20HEI that were 3 or greater were connected with a milder form of the disease. 21

Because of I3C's ability to alter the estrogen metabolism pathways, research suggests it may be effective in reducing the severity of RRP or wiping out the papillomas altogether, with many RRP patients reporting either a partial or complete recovery.22-23

Vegetables Aren't Enough

For those who appreciate the anticarcinogenic effects of I3C, is it enough to increase your intake of broccoli or cabbage? According to researchers, the answer is no. In order to consume enough cruciferous vegetables to have a positive effect, research suggests that a pound or more of cabbage or cauliflower would be the required dosage, more than most people would like to consume. Bradlow recommends consuming at least 300 mg of I3C daily, the minimum dose his studies have found to be effective in human subjects.

The other disadvantage of deriving I3C directly from consumption of cruciferous vegetables is that the concentration of I3C varies greatly depending on the seed strain, climate and soil. Cabbage grown in Israel, for instance, has been found to contain virtually no I3C. Consequently, it is difficult to achieve therapeutic levels of I3C by diet alone.24

Synergistic Effect

I3C is a powerful anticarcinogen in and of itself, but studies have shown that certain substances taken in conjunction with I3C boost its effects. Some investigators have suggested that taking ascorbic acid (Vitamin C) along with I3C will produce ascorbigen, an even more crucial anticarcinogen than I3C.25

Because the digestive process assists with the breakdown of I3C, antacids are one substance that should not be taken in conjunction with this phytonutrient.26

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. Dr. Karen Auborn. Personal communication. 1999.

4. Michnoviez JJ, Bradlow HL. Altered estrogen metabolism and excretion in humans following consumption of indole-3-carbinol. Nutr Cancer. 1991;16 (1): 59-66.

5. Michnoviez JJ, Bradlow HL. Induction of estradiol metabolism by dietary indole-3-carbinol in humans. J Natl Cancer Inst. 1990; 82(11): 947-949.

6. Michnoviez JJ, Bradlow HL. Altered estrogen metabolism and excretion in humans following consumption of indole-3-carbinol. Nutr Cancer. 1991;16 (1): 59-66.

7. Cover CM, Hsieh SJ, Tran SH, Hallden G, Kim GS, Bjeldanes LF and Firestone GL. 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; 273:3838-3847.

8. Legha SS. Tamoxifen in the treatment of breast cancer. Ann Intern Med. 1988; 109: 219-228.

9. Couillard S, Gutman M, Labrie C, Belanger A, Candas B and Labrie F. Comparison of the effects of the antiestrogens EM-800 and tamoxifen on the growth of human breast ZR-75-1 cancer xenografts in nude mice. Cancer Res. 1998; 58:60-64.

10. Gottardis MM and Jordan VC. Development of tamoxifen-stimulated growth of MCF-7 tumors in athymic mice after long-term antiestrogen administration. Cancer Res. 1988; 48: 5183-5187.

11. Osborne CK, Coronado-Heinsohn EB, Hilsenbeck SG, McCue BL, Wakeling AE, McClelland RA, Manning DL, and Nicholson RI. Comparison of the effects of a pure steroidal antiestrogen with those of tamoxifen in a model of human breast cancer. J Natl. Cancer Inst. 1995; 87:746-750.

12. 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.

13. 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.

14. WHO, The World Health Report, Geneva. 1997.

15. Syrjanen KJ. Papillomavirus infections and cancer. Papillomaviruses and Human Disease, Syrjanen K, Gissmann L, and Koss LG, (eds.) Springer, New York. 1987; 467-503.

16. Czegledy J. Human papillomaviruses in non-melanoma skin cancers. Aeta Microbiol Immunol Hung. 1997; 44: 223-227.

17. Majewski S and Jabionska S. Human papillomavirus-associated tumors of the skin and mucosa. J Am Acad Dermatol. 1997; 36: 659-685.

18. 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.

19. He YH, Schut HA. Inhibition of DNA adduct formation of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine and 2-amino-3-methylimidazo[4,5-f]quinoline by dietary indole-3-carbinol in female rats. J Biochem Mol Toxicol. 1999; 13(5):239-47.

20. Lancaster C. RRP Patient Update. Recurrent Respiratory Papillomatosis Foundation Newsletter. Fall 1993. n. page.

21. Auborn K. Personal Communication. 1999.

22. Auborn K. Personal Communication. 1999.

23. Stern B. Adjuvant Therapy Survey Update. Recurrent Respiratory Papillomatosis Foundation Newsletter. Fall 1997. n. page.

24. Bradlow HL. Personal Communi-cation. 1999.

25. Preobrazhenskaya, et al. Food Chemistry. 1993; 48: 48-52

26. Additional I3C Notes. Recurrent Respiratory Papillomatosis Foundation Newsletter. Fall 1997. n. page.