Nutraceuticals and nootropics for anti-aging

Breast cancer runs in my family, so I’m looking for preventatives. I notice that LifeLink sells indole-3-carbinol (I3C) — an anti-cancer nutritional supplement. The Oregon State University website has an interesting page about it, but their pro-and-con discussion leaves me unsure whether to include I3C in my anti-cancer regimen. What is your opinion?

In my opinion, I3C has a lot more going for it than the LPI’s review would suggest. I don’t give medical advice in this column, but I will tell you what I know about this supplement.

The website you mentioned — at Oregon State University — is the website of the Linus Pauling Institute (LPI). I was surprised to see how lukewarm LPI’s review of I3C was, in view of the fact that I3C is usually regarded as being among the two or three most exciting and promising anti-cancer substances known today. I think the reviewer at LPI was excessively influenced by several experiments with high-dose I3C in lab animals in which cancers were induced by chemical treatments. These experiments are described below.

What is I3C?

Indole-3-carbinol (I3C) is a substance that results from cooking or crushing a wide variety of plant foods — especially ‘cruciferous vegetables’, which include broccoli, brussels sprouts, and cauliflower. Enzymes in the plants convert certain plant biochemicals into I3C. In the stomach I3C is converted into other compounds (such as ‘DIM’), some of which appear to be responsible for the anti-cancer activity of these vegetables.

Reviews

For general information about I3C, I recommend the reviews by Rogan¹, Thorne ², Stoewsand³, and Broadbent^4,5. More specialized reviews are those by Aggarwal⁶, Shertzer⁷, and Kim⁸.

History

Interest in I3C as an anti-cancer agent dates back at least to 1975⁹ when it was shown that I3C stimulates cells to produce enzymes that destroy carcinogens. Ethnic dietary surveys showed that diets high in cruciferous vegetables are correlated with lower rates of breast cancer.¹⁰ Although it was already known in 1978 (from rat experiments) that I3C inhibits the formation of breast cancer tumors,¹¹ not a single clinical study was done until the mid-1990s to determine whether this promising substance prevents or treats cancer in the human body. Throughout the 1980s, sporadic efforts were made to understand the biochemical mechanisms through which I3C affects cells. But only when I3C became available as a nutritional supplement, and women began to use it to treat cervical dysplasia, did the medical research community begin to show much interest in it. Even so, 30 years after I3C’s anti-cancer potential was first revealed, there have been no clinical trials aimed at determining directly whether I3C prevents breast cancer or causes existing breast tumors to shrink. Consequently, crucial decisions about treatment must still be based mainly on extrapolations of cell culture experiments, lab animal data, and suggestive biochemical ‘markers’.

Peter Greenwald of the U.S. National Institutes of Health has written a good review covering the history and possible future prospects for clinical trials in cancer prevention¹⁰ — a review that unintentionally illustrates the snail’s pace at which the medical research community operates.

Most other potential applications of I3C have been treated with a similar lack of urgency. These other applications include the prevention or treatment of: • prostate cancer • melanoma • non-melanoma skin cancer • lung cancer • colon cancer • recurrent respiratory papillomatosis • herpes simplex • fetal cancer • Alzheimer’s • ovulation. Only in the case of cervical dysplasia did the medical world make a concerted effort to answer the question “Does I3C work in the human body?”, and the answer turned out to be the same one arrived at earlier by supplement users: “Yes”.

Let us take a quick look at what is known about I3C’s effects on these conditions.

Cervical dysplasia, papillomatosis

Cervical dysplasia (CIN) is a precancerous condition caused by infection of the cervix by certain strains of Human Papilloma Virus. A clinical trial of I3C was reported in 2000 to cause complete regression of CIN in 50% of patients who used 200 mg/day of I3C for 12 weeks.¹²

Recurrent respiratory papillomatosis (RRP) is the repeated growth of papillomas in the larynx and trachea. In a 1998 clinical trial of I3C, one-third of RRP patients saw their papillomas stop growing; another third experienced a reduction in growth rate.¹³

I3C and cancer

In the body, I3C and its metabolites regulate certain hormonal and cell-signalling pathways, particularly those involving estrogens. Some of these pathways are involved in the development of tumors from precancerous cells.⁶ By disrupting the biochemistry of precancerous cells, I3C causes them to die before they can form tumors — and it does this without harming normal cells.¹⁴ I3C-sensitive cancers include those of the breast,^15,11,39 prostate,^16,17,18,19 cervix,²⁰ endometrium,²¹ colon,²² ovaries,³ lung,²³ white blood cells (leukemia),⁶ and skin (melanoma²⁴, and UV-induced non-melanoma skin cancer²⁵).

It was reported in 2001 that I3C inhibits the basic processes used by cancer cells to form new tumors by metastasis.²⁷

Evidence from tissue culture experiments suggests that genistein (a nutritional supplement extracted from soybeans) works synergistically with I3C to kill cancer cells.²¹

An often-overlooked cancer risk is that caused by carcinogenic substances in the diet or environment during pregnancy. The fetus can be exposed and develop cancer many years later. Recent experiments in rats have shown that I3C, taken during pregnancy, provides substantial protection against such malignancies.²⁸

Does I3C shrink existing tumors? Until recently it was thought that the anti-tumor potential of I3C supplementation would be limited to prevention. Several experiments with fish and with rats even led some researchers to believe that if I3C supplementation were started after a tumor had already developed, the growth of that tumor might actually be accelerated by I3C.^{34,35,36,37,38} This idea was largely speculative, however, since no clinical studies had been done (and still haven’t been done) on real tumors in humans. Furthermore, the dosages used in the fish and rats corresponded to higher doses than those used in humans. This issue has not yet been entirely settled. Available evidence suggests that already-existing breast and cervical tumors can be inhibited by I3C, liver tumors can be enlarged by I3C, while the data for colon, prostate, and other tumors is equivocal or nonexistent.^14,26,37.

Thus, the latest evidence suggests that when a precancerous condition is detected, the use of an I3C supplement may eliminate the precancerous cells and prevent progression to cancer. I3C supplementation may also inhibit the spread of existing tumors to other parts of the body. It may shrink existing tumors in certain tissues, but it might accelerate the growth of existing tumors in other tissues, especially the liver.

I3C and Herpes simplex (lip and genital herpes)

In 2003 it was reported that in a tissue culture experiment I3C caused a 100% inhibition of the Herpes simplex virus.^29,2 Nothing further has been reported on this subject, and apparently no clinical trials have been organized to test I3C as a treatment for herpes.

I3C prevents ovulation

I3C also has anti-ovulatory properties, as was shown in rats in 2002.³⁰ While it would be unwise to rely on I3C as one’s sole birth-control method, regular I3C supplementation might lower the risk of pregnancy due to forgetting to use one’s regular method.

Protection against toxic substances

The body produces many enzymes that inactivate substances that would be toxic if their concentrations became too high. I3C induces the production of such enzymes.³¹

I3C and Alzheimer’s Disease

A hallmark of Alzheimer’s Disease is the formation of protein tangles called ‘amyloid fibrils’ in nerve cells of the brain. These tangles disrupt the structure of the nerve cells and also collect metal ions which, in turn, promote the production of free radicals that damage and kill nerve cells. Recent Alzheimer’s research has identified I3C as a substance that inhibits the formation of amyloid fibrils.³²

Dosage

Most clinical work with I3C uses dosages from 200 mg/day to 400 mg/day.² The optimum dosage for affecting breast cancer is thought to be 400 mg/day.³³

Why take I3C as a supplement when you could instead just eat lots of broccoli or other cruciferous vegetables? There are two reasons: first, the vegetables contain many alkaloidal substances, some of them harmful; second, you have no way of knowing whether a given serving of a vegetable has a lot or only a little of the I3C-related substances you are trying to consume. Supplement capsules solve both of these problems.

Conclusion

If cancer ran in my family (which it doesn’t) — cancer of the breast, prostate, colon, skin, or reproductive organs — then I would definitely be using I3C myself. I would also use it if I knew I already had one of these cancers. But I would avoid using I3C if I had been diagnosed with liver cancer.

— Dr. Alexis Zarkov, Ph.D.

You can contact Dr. Zarkov at AskDrZarkov@yahoo.com.

Last modified 2006.Nov.29

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References

[1]  The natural chemopreventive compound indole-3-carbinol: state of the science. In Vivo. 20(2):221-8 Rogan EG

[2]  Indole-3-carbinol. Monograph. [PDF, 184KB] Altern Med Rev. 2005 Dec; 10(4):337-42

[3]  Bioactive organosulfur phytochemicals in Brassica oleracea vegetables--a review. Food Chem Toxicol. 1995 Jun; 33(6):537-43 Stoewsand GS

[4]  The chemistry and pharmacology of indole-3-carbinol (indole-3-methanol) and 3-(methoxymethyl)indole. [Part I]. Curr Med Chem. 1998 Oct; 5(5):337-52 Broadbent TA, Broadbent HS

[5]  The chemistry and pharmacology of indole-3-carbinol (indole-3-methanol) and 3-(methoxymethyl)indole. [Part II]. Curr Med Chem. 1998 Dec; 5(6):469-91 Broadbent TA, Broadbent HS

[6]  Molecular targets and anticancer potential of indole-3-carbinol and its derivatives. Cell Cycle. 2005 Sep; 4(9):1201-15 Aggarwal BB, Ichikawa H

[7]  The micronutrient indole-3-carbinol: implications for disease and chemoprevention. Drug Metabol Drug Interact 2000;17(1-4):159-88 Shertzer HG, Senft AP

[8]  Targets for indole-3-carbinol in cancer prevention. J Nutr Biochem. 2005 Feb; 16(2):65-73 Kim YS, Milner JA

[9]  Effects of dietary constituents on the metabolism of chemical carcinogens. Cancer Res. 1975 Nov; 35(11 Pt. 2):3326-31 Wattenberg LW

[10]  Clinical trials in cancer prevention: current results and perspectives for the future. J Nutr. 2004 Dec; 134(12 Suppl):3507S-3512S Greenwald P

[11]  Inhibition of polycyclic aromatic hydrocarbon-induced neoplasia by naturally occurring indoles. Cancer Res. 1978 May; 38(5):1410-3 Wattenberg LW, Loub WD

[12]  Placebo-controlled trial of indole-3-carbinol in the treatment of CIN. Gynecol Oncol 2000 Aug;78(2):123-9 Bell MC, Crowley-Nowick P, Bradlow HL, Sepkovic DW, Schmidt-Grimminger D, Howell P, Mayeaux EJ, Tucker A, Turbat-Herrera EA, Mathis JM

[13]  Preliminary results of the use of indole-3-carbinol for recurrent respiratory papillomatosis. Otolaryngol Head Neck Surg. 1998 Jun; 118(6):810-5 Rosen CA, Woodson GE, Thompson JW, Hengesteg AP, Bradlow HL

[14]  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 Chen DZ, Qi M, Auborn KJ, Carter TH

[15]  Dose-ranging study of indole-3-carbinol for breast cancer prevention. J Cell Biochem Suppl 1997;28-29:111-6 Wong GY, Bradlow L, Sepkovic D, Mehl S, Mailman J, Osborne MP

[16]  The effect of indole-3-carbinol and sulforaphane on a prostate cancer cell line. ANZ J Surg. 2003 Mar; 73(3):154-6 Frydoonfar HR, McGrath DR, Spigelman AD

[17]  Indole-3-carbinol and prostate cancer. J Nutr. 2004 Dec; 134(12 Suppl):3493S-3498S Sarkar FH, Li Y

[18]  Indole-3-carbinol (I3C) induced cell growth inhibition, G1 cell cycle arrest and apoptosis in prostate cancer cells. Oncogene 2001 May 24;20(23):2927-36 Chinni SR, Li Y, Upadhyay S, Koppolu PK, Sarkar FH.

[19]  Gene expression profiles of I3C- and DIM-treated PC3 human prostate cancer cells determined by cDNA microarray analysis. J Nutr. 2003 Apr;133(4):1011-9 Li Y, Li X, Sarkar FH

[20]  Indole-3-carbinol prevents PTEN loss in cervical cancer in vivo. Mol Med. 2005 11(1-12):59-63 Qi M, Anderson AE, Chen DZ, Sun S, Auborn KJ

[21]  Indole-3-carbinol is a negative regulator of estrogen. J Nutr. 2003 Jul;133(7 Suppl):2470S-2475S Auborn KJ, Fan S, Rosen EM, Goodwin L, Chandraskaren A, Williams DE, Chen D, Carter TH

[22]  Growth-inhibitory effects of the chemopreventive agent indole-3-carbinol are increased in combination with the polyamine putrescine in the SW480 colon tumour cell line. BMC Cancer 2003 Jan 14;3(1):2 Hudson EA, Howells LM, Gallacher-Horley B, Fox LH, Gescher A, Manson MM

[23]  Inhibition of tobacco-specific nitrosamine-induced lung tumorigenesis by compounds derived from cruciferous vegetables and green tea. Ann N Y Acad Sci. 1993 May 28; 686:186-201; discussion 201-2 Chung FL, Morse MA, Eklind KI, Xu Y

[24]  Indole-3-carbinol enhances ultraviolet B-induced apoptosis by sensitizing human melanoma cells. Cell Mol Life Sci. 2006 Nov 3; Kim DS, Jeong YM, Moon SI, Kim SY, Kwon SB, Park ES, Youn SW, Park KC

[25]  Ultraviolet radiation-induced non-melanoma skin cancer in the Crl:SKH1:hr-BR hairless mouse: augmentation of tumor multiplicity by chlorophyllin and protection by indole-3-carbinol. Photochem Photobiol Sci. 2006 May; 5(5):499-507 Cope RB, Loehr C, Dashwood R, Kerkvliet NI

[26]  Post-initiation treatment of Indole-3-carbinol did not suppress N-methyl-N-nitrosourea induced mammary carcinogenesis in rats. Cancer Lett 2001 Aug 28;169(2):147-54 Kang JS, Kim DJ, Ahn B, Nam KT, Kim KS, Choi M, Jang DD

[27]  Quantitative determination of 3,3'-diindolylmethane in urine of individuals receiving indole-3-carbinol. Nutr Cancer 2001;41(1-2):57-63 Sepkovic DW, Bradlow HL, Bell M

[28]  Indole-3-carbinol in the maternal diet provides chemoprotection for the fetus against transplacental carcinogenesis by the polycyclic aromatic hydrocarbon dibenzo[a,l]pyrene. Carcinogenesis. 2006 Oct; 27(10):2116-23 Yu Z, Mahadevan B, Löhr CV, Fischer KA, Louderback MA, Krueger SK, Pereira CB, Albershardt DJ, Baird WM, Bailey GS, Williams DE

[29]  Broccoli compound inhibits HSV. AIDS Patient Care STDS. 2003 Nov; 17(11):609

[30]  Endocrine disruption by indole-3-carbinol and tamoxifen: blockage of ovulation. Toxicol Appl Pharmacol 2002 Sep 15;183(3):179-88 Gao X, Petroff BK, Oluola O, Georg G, Terranova PF, Rozman KK

[31]  Effect of nutritional indoles on activity of xenobiotic metabolism enzymes and T-2 toxicity in rats. Bull Exp Biol Med 2001 Jun;131(6):544-7 Kravchenko LV, Avren'eva LI, Guseva GV, Posdnyakov AL, Tutel'yan VA

[32]  Inhibition of amyloid fibril formation and cytotoxicity by hydroxyindole derivatives. Biochemistry. 2006 Apr 18; 45(15):4727-35 Cohen T, Frydman-Marom A, Rechter M, Gazit E

[33]  A phase I study of indole-3-carbinol in women: tolerability and effects. Cancer Epidemiol Biomarkers Prev. 2005 Aug; 14(8):1953-60 Reed GA, Peterson KS, Smith HJ, Gray JC, Sullivan DK, Mayo MS, Crowell JA, Hurwitz A

[34]  Promotion of aflatoxin B1 carcinogenesis by the natural tumor modulator indole-3-carbinol: influence of dose, duration, and intermittent exposure on indole-3-carbinol promotional potency. Cancer Res. 1991 May 1; 51(9):2362-5 Dashwood RH, Fong AT, Williams DE, Hendricks JD, Bailey GS

[35]  Potency of dietary indole-3-carbinol as a promoter of aflatoxin B1-initiated hepatocarcinogenesis: results from a 9000 animal tumor study. Carcinogenesis. 1999 Mar; 20(3):453-8 Oganesian A, Hendricks JD, Pereira CB, Orner GA, Bailey GS, Williams DE

[36]  Biphasic modifying effect of indole-3-carbinol on diethylnitrosamine-induced preneoplastic glutathione S-transferase placental form-positive liver cell foci in Sprague-Dawley rats. Jpn J Cancer Res. 1994 Jun; 85(6):578-83 Kim DJ, Lee KK, Han BS, Ahn B, Bae JH, Jang JJ

[37]  Development of a multi-organ rat model for evaluating chemopreventive agents: efficacy of indole-3-carbinol. Carcinogenesis. 2002 Feb; 23(2):265-72 Stoner G, Casto B, Ralston S, Roebuck B, Pereira C, Bailey G

[38]  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 Yoshida M, Katashima S, Ando J, Tanaka T, Uematsu F, Nakae D, Maekawa A

[39]  3,3'-diindolylmethane and paclitaxel act synergistically to promote apoptosis in HER2/Neu human breast cancer cells. J Surg Res. 2006 May 15; 132(2):208-13 McGuire KP, Ngoubilly N, Neavyn M, Lanza-Jacoby S

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Disclaimer: The information provided in this “Ask Dr. Zarkov” article contains no medical advice whatsoever — it contains biological information. Nothing in the article constitutes an effort to persuade readers to use, or not to use, this biological information as a basis for action.