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Indole 3 Carbinol - the safer, natural Tamoxifen?

Indole


Indole 3 carbinol, DIM and the treatment of cancer

In 2004/5 we told you that the Pharmaceutical company, Hoechst, had been trying to patent a number of close relatives and synthetic versions of Indole 3 carbinol (I3C). What´s the fuss, especially given that most people reading this piece have hardly heard of this compound anyway? Well, Hoechst claimed that eventually these new compounds (Indole drugs) will be used to treat all manner of illnesses from arthritis to MS to cancer and, in time, even replace Tamoxifen with a far better alternative.

 Great for patients not so good for Tamoxifen profits

In Cancer Watch (icon 2006 issue 4), we covered research that showed women on tamoxifen needed less of the drug if they supplemented with Indole 3 Carbinol, delivering the same benefits whilst reducing side effects. (Great for patients not so good for Tamoxifen profits.) Surprisingly, as we discovered when we looked into this further, this has apparently been consistently noted in a great number of studies. We wonder how many doctors and oncologists use this research?

Cruciferous Vegetables

It is often stated that Indole 3 Carbinol is found in cruciferous vegetables (the cabbage family). Strictly speaking, this is not true. Actually, the natural compound found there is Indole 3 glucosinolate (I3G), which is found in good concentrations in broccoli, kale, cabbage, bok choi, brussels sprouts, cauliflower and even turnip. I3G has minimal anti-cancer activity but upon cutting, mastication or light cooking, an enzyme (called myrosinase) is released in the vegetables and this converts indole 3 glucosinolate to indole 3 carbinol. A mass of research now indicates that the latter has significant anti-cancer properties.

Indole 3 Carbinol (I3C) is a member of the glucosinolates family. This group of compounds contains other indoles and also isothiocyanates, such as sulphoraphane. These are known antioxidants and natural detoxifying enzymes. Sulphoraphanes have also been shown to have strong anti-cancer properties.

The first recorded use of the bioactive natural compounds in cruciferous vegetables was the recommendation of Cato the Elder, a Roman Statesman around 200 BC, who wrote that, If a cancerous ulcer appears on the breast, apply a crushed cabbage leaf and it will make it well.

Between 1990 and the current time, there have been over 120 peer-reviewed scientific studies on indole 3 carbinol with cancers such as breast cancer, prostate cancer, cervical cancer and even respiratory tract cancers. For example, in one (albeit small) double blind study on women with cervical cancer, supplementation of 200 mgs to 400 mgs of I3C reversed the early stages of cancer in 8 of the 17 women. I3C is potent stuff.

So what does it actually do?

First, a caveat. I3C is unstable and much of it converts in the intestine to its metabolites Diindolymethane (DIM) and indole carbazole (ICZ). I3C, DIM and ICZ are all absorbed into the bloodstream and any or all could be active, separately or in conjunction, in the real world. 

Indeed there is an increasing amount of research on DIM - click THIS LINK for a Cancer Watch report on the latest studies. Some cancer experts believe that DIM has by far the strongest properties and is easier to use as a controlled-dose supplement. Blood levels may be pre-determined more accurately with DIM whereas I3C ingestion or supplementation may see inconsistent levels of I3C in the blood stream as it is broken down.

I3C and/or DIM seem to work at a number of levels and in several ways on cells and tissues.

1 General activities:

They are antioxidants, neutralising free-radicals. According to research covered in Cancer Watch, they can inhibit the negative action of the HPV virus, restrict carcinogenic aflatoxins and prevent them causing certain cancers. They can also denature dangerous chemicals called dioxins and prevent them from causing DNA damage.

2 Anti-cancer action involving anti-oestrogenic activity

I3C/DIM inhibit and reverse oestrogen-driven cancers, where aggressive oestradiol binds to cellular receptor sites causing havoc inside the cells.

        a) by denaturing the aggressive form of oestrogen (oestradiol) to a weaker form. 

        b) by regulating a binding protein and modifying oestrogen receptor sites on cell membranes so that oestradiol cannot bind to them and thus cause havoc inside the cell.

This is applicable in male and female cancers such as breast and prostate.

3 Anti-cancer action not involving oestrogen

        a) DIM, in particular, has been shown to restore the p21 gene activity preventing synthesis of DNA for new cancer cells. It thus stops cancers forming or growing. 

        b) It has also been shown to decrease HIF-1 alpha and stop tumours forming a blood supply (May, 2008, Biochemical Pharmacology Journal)

        c)  Orally taken supplements of I3C can cause destruction of the Cdc25A molecule, which is responsible for the rapid cell division in cancers such as breast, prostate, colorectal, oesophageal, liver and lymphoma (Ohio State Medical School, Cancer Watch, 2010)

Scientists from the Florida A&M University and Dr Stephen Safe from Texas A&M University have actually gone on record saying they believe DIM is the effective treatment for triple negative breast cancer, they are so confident in their research. Triple-negative breast cancer does not involve oestrogen, progesterone or HER-2.

From this short summary it is easy to see why pharmaceutical companies are so excited - but you can eat the cruciferous vegetable (but it is essential to avoid overcooking) or supplement with I3C, DIM, or both.

****************

The detail:

Antioxidant:

Indoles and isothiocyanates are known antioxidants and can naturally neutralise free radicals. For example, research has shown that they can inhibit free radicals which cause the oxidation of fats, for example, in the oxidation of low-density lipoprotein.

Anti-artherogenic activity:

A by-product of I3C in the body inhibits smooth muscle proliferation and would therefore inhibit some heart and artery wall problems.

Anti-cancer activity:

I3C has been shown in research to inhibit the action of some aflatoxins, which are carcinogenic. It also prevents aflatoxin-induced liver cancer, leukaemia and colon cancer.

I3C can reduce, and even reverse, breast tumour growth

In cell cultures, I3C inhibits human papilloma virus (HPV) proliferation, and the development of cysts and pre-cancerous lesions. There is some evidence that I3C may help prevent recurrences of respiratory papillomatosis.

Further research indicates that I3C may well protect your liver, but the most interesting aspect of I3C is its seeming ability to reduce, even reverse, oestrogen-driven tumour growth. The Roman was right!

I3C seems to act in five ways:


        By converting highly active oestrogen forms, and their by-products, to         much safer compounds

        By partially blocking oestrogen receptor sites on cell membranes.

        By returning alpha and beta receptor site expression to normal levels

        By blocking other cancer-enhancing receptor sites

        By directly killing cancer cells.

The Tamoxifen rival

Without getting too complicated, forms of oestrogen such as the molecules 16 alpha-hydroxyoestrone and 4-hydroxyoestrone are known carcinogens and have been shown at work in a number of cancers such as breast and prostate; however, the 2-hydroxy form is actually protective. And I3C helps raise the level of 2 whilst decreasing 16 and 4.

To put this in layman´s terms, oestrogen is a family of hormones. One, 16 alpha - by the common name of oestradiol - is known to attach to cellular receptor sites and cause havoc inside the cell (lowering oxygen levels, increasing sodium levels, and prompting a grow signal). In 1991 Researchers from the Institute for Hormone Research in New York showed that I3C helps convert it to a far less aggressive form, 2OHE, commonly called oestrone, which has much weaker cellular effects and effectively blocks the oestradiol 16 form from attaching to cellular receptor sites and passing harm messages to the inside of the cell. In one study, I3C was given to 25 women for two months. Levels of 16 AH oestradiol declined, while levels of 2OHE oestrone increased. At the same time levels of a metabolite directly associated with both breast and endometrial cancer fell.

Now, a lot is known about these cellular oestrogen receptor sites, but we do not know completely about the message transfer systems into the cell. We do know that Tamoxifen aims to sit on these same receptor sites and thus block any similar action by oestradiol. However we do not know fully the action of Tamoxifen or how/whether it transfers messages. And we know it has some less desirable side effects. For this reason some US experts dub I3C (whose simple action mechanism in converting aggressive oestrogen to the safer variety is quite clear), the ´Safer, Natural, Tamoxifen´.

Further UCLA research shows that I3C inhibits the growth of oestrogen receptor-positive breast cancer cells by 90 per cent whilst Tamoxifen only scored 60 per cent. The added benefit is that in oestrogen receptor-negative cells, I3C stopped the growth of new cells by almost 50 per cent whilst, of course, Tamoxifen had no significant effect.

But this is only a part of I3C´s action. A by-product of the metabolism of oestradiol is also a carcinogen and can also send grow signals, having been linked to prostate, breast and endometrial cancers. This by-product is especially produced by some toxins and chemicals, including some oestrogen mimics. Strang Cancer Research Institute have shown that I3C reduces the levels of these metabolites, changing them back to safer 2OHE. Again Tamoxifen has no particular effect.

The cure for modern day pollution?

If you are thinking of buying indole 3 carbinol you might like to look at the Natural Selection Product of Choice. You can do this by  clicking here.

In a separate study at New York University, researchers gave 400mgs of I3C to a number of women only to find that, whilst in most cases the bad oestrogen was converted to the safer version, in some women nothing happened. It turned out that this latter group had a genetic mutation, preventing I3C action. This group of women have an eight-fold increased risk of breast cancer.

Studies at UCLA, Berkeley show that I3C inhibits MCF7 human breast cancer cells from growing by as much as 90% in vitro. But this action did not depend on action on oestrogen receptor sites. Instead the action involved another, completely different receptor, the ah (Aryl Hydrocarbon) receptor. As yet no one knows what normally acts on this receptor, but we do know it can be hit by chemical dioxins. What are these? Formed from chlorine, they are probably the most lethal everyday chemicals and cancer promoters that surround us. Dioxins stimulate cancer by stimulating oestradiol, IGF-1 (insulin-like growth factor) and insulin itself, and tumour necrosis factor, all known cancer promoters. Dioxins are found in everything from cheap compressed wood products to bleached paper and fast foods. Most commonly they are produced by the action of chlorinated water with other chemicals for example Triclosan, which is found in some toothpastes. Dioxins are so dangerous their safe levels are measured in trillionths of a gramme. They activate cancer genes and suppress tumour suppressor genes.

So, I3C manages to block a receptor site that would otherwise be prone to chemical attack, subsequently causing serious problems inside the cell. And this is really important in this modern era. Researchers at Texas University treated breast cancer cells with I3C and dioxin simultaneously and found that I3C reduced dioxin´s negative effects by 90%. Several parallel studies on rats and mice showed I3C prevents chemically-induced breast cancer by as much as 70 to 96 per cent.

The natural cancer combatant.

I3C can also alter the activity of a number of enzymes involved in the cancer process (e.g. glutathione S-transference); it alters the chemical metabolism of carcinogens such as aflatoxin and it has even been shown to increase the death of cancer cells (apoptosis). Researchers at Strang Cancer Research Institute (Rockefeller University) showed in 1997/8 that it stops human cancer cells from growing and can provoke cancer cell death, in vitro.

I3C also restores the activity of the p21 and other tumour suppressors that act as controlling influences, preventing the synthesis of the DNA for new cancer cells.

Dosage

Research usually uses levels of 200-400mgs, although several studies have indicated the higher level to be more appropriate. Apparently the average Japanese diet consumption is over 120 mgs per day. And how much cruciferous vegetable matter are you consuming daily?

Supplementation is thus sensible as a top up, or certainly if you have an oestrogen-driven cancer or if you wish to prevent, say, breast cancer.


Precautions
Some people are actually sensitive to this naturally occurring substance. Since it is an oestrogen modulator, it is inadvisable for use if you are pregnant or nursing. Not surprisingly, it can affect the use of certain oestrogen drugs including, for example, those prescribed to women who have osteoporosis (Ed: As we repeatedly tell you for osteoporosis, come off the drugs and avoid dairy whilst you increase your magnesium levels and take in some sunshine. For natural calcium - eat more greens ...  but that´s a different story!)


In summary
Whether or not you have a hormonally-driven cancer, you really should consider eating lots of cruciferous vegetables (but also take probiotics or your body will be unable to fully release the bioactive natural goodness, especially if you have been taking drugs, antibiotics or had recent surgery). Alternatively you should seriously consider supplementing with DIM and/or I3C. 

   At last - the definitive, research-based book on how to build a diet to help beat cancer. Click here to read about it.

If you are thinking of buying indole 3 carbinol and/or DIM as a supplement, you might like to look at what they have in the Natural Selection, ´Products of Choice´ online shop; click here.

OTHER ARTICLES OF INTEREST

People who read this article also read (CLICK LINKS):

Phytomedicine, DIM and triple negative breast cancer

Natural Aromatase Inhibitors

Indole 3 carbinol in the fight against breast cancer

SOME REFERENCES:

Cover CM et al. Indole-3-carbinol and tamoxifen cooperate to arrest the cell cycle of MCF-7 human breast cancer cell.  Cancer Res. 1999; 59 1244-51

McDonnell R., Food Chain Toxicol 1998; 26.59-70.

Rosen et al Otolaryngol Head Neck Surgery 1998. 118:810-815.

Shertzer et al. Biochem Pharmacol 1988; 37. 333-8

Bradlow,  Ann. N Y Acad Science 1999; 889. 204-13
Bell et al, Gynecol oncol 2000; 78. 123-9
Wong GYC, Bradlow HL, Sepkovic DW, et al. A dose-ranging study of indole-3-carbinol for breast cancer prevention. J Cell Biol. 1988; 28:111-116
Bradlow HL, Michnovicz JJ, Wong GYC, et al. Long term responses of women to indole-3-carbinol or a high fiber diet. Cancer Epidemiol Biomarkers Prev. 1994; 3:591-595.
Bradlow HL, Sepkovic DW, Telang NT, Osborne MP. Multifunctional aspects of the action of indole-3-carbinol as an anti-tumor agent. Ann NY Acad Sci. 1999; 889:204-213.
Custodio JB, et al. 1994. Tamoxifen and hydroxytamoxifen as intramembraneous inhibitors of lipid peroxidation. Evidence for peroxyl radical scavenging activity. Biochem Phearmacol 47:1989-98.
Devanaboyina U, et al. 1997. Effects of indole-3-carbinol (I3C) and phenethyl isothiocyanate (PEITC) on 7,12-dimethylbenz[aanthracene (DMBA)-induced DNA adducts in rat mammary glands and liver (Meeting abstract). Proc Annu Meet am Assoc. Cancer Res 38:A2427.
Grubbs CJ, et al. 1995. Chemoprevention of chemically-induced mammary carcinogenesis by indole-3-carbinol. Anticancer Res 15:709-16.Guillot C, et al. 1996. Alteration of p53 damage response by tamoxifen treatment. Clin Cancer Res 2:1439-44.
He Y-H, Freisen MD, Ruch RJ, Schut HAJ. Indole-3-carbinol as a chemopreventive agent in 2-amino-1-methyl-6-phenylimidazo [4,5-b pyridine (PhIP) carcinogenesis: inhibition of PhIP-DNA adduct formation, acceleration of PhIP metabolism, and induction of cytochrome P450 in female F344 rats. Food Chem Toxicol. 2000; 38:15-23.
Michnovicz JJ, Bradlow HL. Induction of estradiol metabolism by dietary indole-3-carbinol in humans. J Natl Cancer Inst. 1990; 50:947-950.
Niwa T, Swaneck G, Bradlow HL. Alterations in estradiol metabolism in MCF-7 cells induced by treatment with indole-3-carbinol and related compounds. Steroids. 1994; 59:523-527.
Shertzer HG, et al. 1988. Intervention in free radical mediated hepatotoxicity and lipid peroxidation by indole-3-carbinol. Biochem Pharmacol 37:333-38.
Telang NT, et al. 1997. Inhibition of proliferation and modulation of estradiol metabolism: novel mechanisms for breast cancer prevention by the phytochemical I3C. Proc Soc Exp Biol Med 216:246-52.
Thangaraju M, et al. 1994. Effect of tamoxifen on lipid peroxide and antioxidative system in postmenopausal women with breast cancer. Cancer 74:78-82.

Verhagen H, et al. 1995. Reduction of oxidative DNA-damage in humans by brussels sprouts. Carcinogenesis 16:969-70.
Wattenberg LW, et al. 1978. Inhibition of polycyclic aromatic hydrocarbon-induced neoplasia by naturally occurring indoles. Cancer Res 38:1410-13.
Yang JH, et al. 1999. A malignant transformation of human cells by 2,3,7,8-tetrachlorodibenzo-p-dioxin exhibits altered expression of growth regulatory factors. Carcinogenesis 20:13-18.


Please be clear: At CANCERactive we do not consider the above compound to be a cure for cancer, despite what the research says or experts doing the research may claim. The above, is an article on the compound from published research and expert opinion in the public domain. At CANCERactive we do not believe that any single compound (drug, vitamin, whatever) is a cure for cancer. We believe that people can significantly increase their personal odds of survival by building an Integrated Programme of treatments. Equally, cancer prevention is best practiced through a width of measures.


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