The reaction product DIM is considered a safe and effective supplement used as an estrogen-blocker and for its anti-cancer effects.    Having benefits and safety properties not attributed to an I3C supplement.  Estrogen can be broken down to both “good” metabolites (E.g.2-hydroxy estrogen) and “bad” i.e. carcinogenic metabolites (E.g. 4-hydroxy estrogenand 16-hydroxy estrogen) – DIM supplementation promotes more of the “good” metabolites and less of the “bad”, which are affiliated with breast cancer and other health problems

DIM particularly seems to be a worthwhile supplement for:

• Any estrogen-sensitive (E.g. reproductive cancers, lung cancer) or HPV-related cancer (E.g. squamous cell lung cancer)
• Losing weight resulting from estrogen-related weight gain

The I3C reaction product DIM showing good results with cancer

• The original discoverer of the importance of cruciferous indoles for breast health advocates DIM over I3C – Leon Bradlow, Ph.D. now supports and advocates absorbable DIM, and not I3C, as the preferred supplement, even though he initiated and performed the majority of human and animal testing of I3C.
• DIM cannot be converted to undesireable ICZ in vivo (see notes on ICZ above)
• DIM blocks dioxin receptor.   Dioxin is a well-known carcinogen    Chen I et al, 1996
• DIM is not estrogenic or a growth promoter of cancer cells.   DIM exerts its control over cancer growth without inducing unwanted enzymes and their production of highly estrogenic16OHE1from I3C
• “DIM is a more effective inducer of apoptosis than I3C” Chen DZ et al, 2001
• DIM controls growth in experimental breast cancer.    Kang JS et al, 2001;   Chen I et al, 1998;

NOTE that Cell Culture studies showing DIM as a contributor to breast cancer cell growth were done in an artificial estrogen–free environment never seen in vivo.   In the article “DIM and I3C: The Real Facts on Safety” by Michael A. Zeligs, M.D., he writes:

” In the presence of estrogen, DIM is consistently anti-proliferative and reduces the growth signal provided by estrogen (2). This includes growth-inhibiting activity in both estrogen receptor positive and negative cancer cell types (3). The estrogen-independent activation pathway described by Riby et al (1) involves the increased phosphorylation of estrogen receptor proteins, and not the direct interaction of DIM with the estrogen receptor. This action may actually be of benefit in cancer control. Understood in context, this receptor activation pathway contributes to the control of abnormal cell growth in living animals through enhanced “programmed-cell-death” (apoptosis) and a reduced tendency for the metastatic spread of cancer (4). Unlike ICZ, LTR, CTR or ASG, DIM exerts its control over cancer cell growth without activating the dioxin receptor or inducing unwanted enzymes.Direct control over cancer cell growth by DIM has now been shown in breast, uterine, cervical, ovarian, and colon cancer cells.I3C has been noted to control cancer cell growth in these cell types as well. However, in cell culture media at 37 degrees Centigrade, most of the I3C is converted to DIM in 24 hours. Since no ICZ and the other condensation products formed in gastric acid occur in cell culture media, DIM may very well be responsible for much of the activity attributed to I3C in prior cell culture studies”. Riby JE et al, 2000;  Chibo et al, 2000;  Chibo et al, 2001; Platet N et al, 2000

# Study Type is Cultured (C), Animal(A) or Human (H)

*Administered BEFORE or AT THE SAME TIME as a carcinogen (required to cause cancer in most animal models)

^In what may be a previously unknown signaling pathway in the cell, its unusual mechanism promotes a sharp drop in production of the gene CDK6 (cyclin-dependent kinase 6) which encodes for the CDK6 enzyme, important in the cell’s growth cycle.

% Cdc25A occurs at abnormally high levels in cancers of the breast, prostate, liver, esophagus, endometrium and colon, and in non-Hodgkin lymphoma; it is also elevated in other diseases, including Alzheimer’s disease. The Ohio State researchers discovered that I3C causes the destruction of Cdc25A, resulting in a sudden halt to breast cancer cell growth.
About half of breast cancer cases have abnormally high levelsof Cdc24A, which is associated with a poor prognosis.”I3C can have striking effects on cancer cells”, according to Dr. Zou, one of the study’s research team, “and a better understanding of this mechanism may lead to the use of this dietary supplement as an effective and safe strategy for treating a variety of cancers and other human diseases associated with the overexpression of Cdc25A.”

I3C / DIM are likely to benefit prostate cancer and other hormone-sensitive cancers.   Which have similar contributing factors.

I3C has been used for some benign cancers and abnormal growths:    Voicebox and respiratory tract tumors caused by a virus, and cervical dysplasia (abnormal growth in cervix)

Unlike Tamoxifen, I3C / DIM work independently of the hormone estrogen.    I3C (or its reaction product DIM) could be used as a complimentary treatment with drugs that do interfere with estrogen.

Cancer prevention.   Researchers are particularly interested in supplementation of I3C or its reaction products, such as DIM, for prevention of breast, cervical, endometrial and colectoral cancers

# Study Type is Cultured (C), Animal(A) or Human (H)

+ Administered post-initiation i.e. after carcinogen (required to cause cancer in most animal models)

I3C reaction products have been shown to reduce immune system natural killer cell activity in rats.  Exon JH, South EH, 2000

I3C reaction products associated with reproductive toxicity in rats –similarly to dioxin.  Wilker C, Johnson L, 1996;   Larsen-Su SA, Williams DE, 2001

DIM is neither estrogenic or a growth promoter of cancer cells.   DIM exerts its control over cancer growth by promoting production of beneficial 2OHE1 estrogen, whilstinducing less of the unwanted enzymes that producehighly estrogenic and carcinogenic16OHE1from I3C; (see below: IC3/DIM and Hormone Balancing /Alterations in Estrogen Activity and Metabolism)

Other I3C reaction products have mixed effects

• Linear Trimer (LTR).    Anti-estrogenic, but activates dioxin receptor

• Cyclic Trimer (CTR).   Directly activates the estrogen receptor, powerfully stimulates breast cancer cell growth, whether or not estrogen is present;

•  Indole-3-acetonitrile (IAN)

  • Shown protective in animal model of stomach cancer, but it has also been found to be mutagenic and to produce DNA-damaging reaction products in the presence of nitrates (common in foods).  Yamashita K et al, 1988;    Wakabayashi K,, et al, 1985
  • IAN also found to activate inflammation-causing leukotrienes in cell membranes (via arachadonic fatty acid cascade)

The I3C reaction product ICZ (indolocarbazole) is generally undesireable.

• ICZ has both antiestrogenic and estrogenic activities.    It down-regulates estrogen receptors, but is itself estrogenic, promoting enzymes which produce the carcinogenic metabolite 4-hydroxy estrogen associated with uterine tumors
• ICZ activates the dioxin receptors just like dioxin.   Although dioxin has toxic properties, it is a powerful estrogen activity inhibitor, as is ICZ. ICZ is more quickly metabolized than dioxin, but has been shown to damage the thymus gland and immune system and to damage DNA.  d’Argy Ret al, 1989; Park JY et al, 1996;
• Another I3C condensation product, ascorbigen (ASG) is converted to ICZ in the lower intestine.   In the presence of vitamin C (naturally abundant in cruciferous vegetables), ASG is the most plentifully produced reaction product from I3C, occurring in the stomach.Some of this ASG is converted to ICZ in the lower intestine, making it available for unwanted enzyme production to promote carcinogenic 4-hydroxy estrogen.  Preobrazhenskaya MN et al, 1993
• DIM cannot be converted to the undesireable ICZ in vivo

Maybe other ingredients in cruciferous vegetables are responsible for their hypothesized lower risk for some types of cancer in epidemiological studies.   Brassica are relatively good sources of other phytonutrients including vitamin C, folate, selenium, carotenoids, fiber and other glucosinolates, in addition to I3C, that may be hydrolyzed to a variety of potentially protective isothiocyanates (E.g. Sulforaphane -“Eat Your Broccoli”).  Verhoeven DT et al, 1996