Keap1 responds to oxidative stress signals or chemical inducers by freeing Nrf2. In addition, the transcription of Nrf2 coding gene, which was abnormally repressed through promoter DNA hypermethylation, was enhanced in mouse prostate cancer cells treated with DIM. DIM also reversed Nrf2 gene silencing in transgenic mouse prostate cancer tissues, inducing Nrf2 expression, and subsequently, NQO1 expression Figure 4.
This was accompanied by the suppression of proliferation and the induction of apoptosis in prostate cancer tissues Similar observations have been reported with I3C Endogenous estrogens are steroid hormones synthesized by humans and other mammals.
Prolonged exposure to estrogens is thought to play a role in cancer development through CYP -mediated generation of estrogen reactive metabolites that can damage DNA 24, In contrast to 2-hydroxyestrone 2HE 1 , 16HE 1 is highly estrogenic and has been found to stimulate the proliferation of several estrogen-sensitive cancer cell lines 30, However, large case-control and prospective cohort studies have failed to find significant associations between urinary 2HE 1 HE 1 ratios and risk of breast and endometrial cancer Within the nucleus , estrogen-activated ERs can bind to specific DNA sequences, known as estrogen response elements EREs , in the promoters of estrogen-responsive genes.
ERE-bound estrogen-ER complexes act as transcription factors by recruiting coactivator proteins and chromatin remodeling factors to promoters, thereby triggering the transcription of target genes I3C and condensation derivatives have been found to affect multiple signaling pathways that are often deregulated in cancer cells.
Below are some examples illustrating how I3C, DIM, or ICZ may influence cell proliferation , apoptosis , migration, invasion, angiogenesis , and immunity by targeting specific signaling pathways Once a cell divides, it passes through a sequence of stages — collectively known as the cell cycle — before it divides again.
Following DNA damage, the cell cycle can be transiently arrested at damage checkpoints, which allows for DNA repair or activation of pathways leading to cell death apoptosis if the damage is irreparable Defective cell cycle regulation may result in the propagation of mutations that contribute to the development of cancer.
In addition, unlike normal cells, cancerous cells lose their ability to respond to death signals that initiate apoptosis. The epithelial-to-mesenchymal transition EMT describes a process of epithelial cell transformation whereby cells lose their polarity and adhesion properties while gaining migratory and invasive properties through the expression of mesenchymal genes.
Inhibition of EMT by I3C and ICZ in breast cancer cells has been associated with upregulation of an epithelial marker, E-cadherin, and downregulation of vimentin, focal adhesion kinase FAK , and matrix metalloproteins MMPs — proteins and enzymes known to promote migration DIM also inhibited migration and invasion of liver cancer cells in vitro and in vivo through inactivating the FAK signaling pathway Moreover, DIM has been shown to reverse methylation -associated dysregulation of genes involved in cell adhesion, chemotaxis , and inflammation that contributes to cancer progression DIM was able to inhibit lung metastasis in mice with liver 61 or mammary tumors To fuel their rapid growth, invasive tumors must also develop new capillaries from preexisting blood vessels by a process known as angiogenesis.
I3C inhibited lipopolysaccharide LPS -induced macrophage activation and secretion of proangiogenic molecules, such as nitric oxide NO , vascular endothelial growth factor VEGF , interleukin-6 IL-6 , and MMP-9, and prevented the formation of capillary-like structures from co-cultured human umbilical endothelial cells Similarly, I3C inhibited capillary-like tube formation from phorbol myristate acetate PMA -stimulated endothelial cells Uncontrolled inflammation has been associated with several chronic diseases , including cancer.
In the mouse ear edema model, O -tetradecanoylphorbolacetate TPA -induced upregulation of pro-inflammatory mediators, such as cyclooxygenase-2 COX-2 and inducible nitric oxide synthase iNOS , has been found to be mitigated by DIM treatment The inclusion of I3C in the maternal diet was found to protect the offspring from lymphoma and lung tumors induced by dibenzo[ a ]pyrene, a polycyclic aromatic hydrocarbon 70, Polycyclic aromatic hydrocarbons are chemical pollutants formed during incomplete combustion of organic substances, such as coal, oil, wood, and tobacco However, the physiological relevance of cell culture and animal studies to human health is unclear since little or no I3C is available to tissues after oral administration see Metabolism and Bioavailability 6.
Some observational studies provide some support for the hypothesis that higher intakes of cruciferous vegetables are associated with lower risk for some types of cancer see the article on Cruciferous Vegetables 1. Cruciferous vegetables are relatively good sources of nutrients that may have protective effects against cancer, including vitamin C , folate , selenium , carotenoids , and fiber.
In addition, glucosinolates can be hydrolyzed to a variety of potentially protective isothiocyanates , in addition to indolecarbinol see the article on Isothiocyanates. Consequently, evidence for an inverse association between cruciferous vegetable intake and cancer risk provides relatively little information about the specific effects of indolecarbinol on cancer risk. Infection with certain strains of human papilloma virus HPV is an important risk factor for cervical cancer In this model, feeding I3C markedly reduced the number of mice that developed cervical cancer A small placebo -controlled trial in women examined the effect of oral I3C supplementation on the progression of precancerous cervical lesions classified as cervical intraepithelial neoplasia CIN 2 or CIN 3 HPV was present in 7 out of the 10 women in the placebo group, seven out of eight women in the mg I3C group, and eight out of nine women in the mg I3C group Although oral supplementation of I3C or DIM appears relatively safe and well tolerated, results obtained with I3C are only preliminary, and interventions with DIM failed to show preventative or therapeutic efficacy in women with precancerous lesions of the cervix.
The intravaginal administration of DIM in the form of suppositories may prove to be a more effective approach to reverse CIN in women HPV infection has also been associated with vulvar intraepithelial neoplasia VIN , a precancerous condition that may progress to vulval cancer Recurrent respiratory papillomatosis RRP is a rare disease of children and adults, characterized by generally benign growths papillomas in the respiratory tract, which are caused by HPV infection These papillomas occur most commonly on or around the vocal cords in the larynx voice box , but they may also affect the trachea, bronchi, and lungs.
The most common treatment for RRP is surgical removal of the papillomas. Since papillomas often recur, adjunct treatments may be used to help prevent or reduce recurrences In a small observational study of RRP patients, increased ratios of urinary 2HE 1 HE 1 resulting from increased cruciferous vegetable consumption were associated with less severe RRP Over a five-year follow-up period, 11 of the original 49 patients experienced no recurrence, 10 experienced a reduction in the rate of recurrence, 12 experienced no improvement, and 12 were lost to follow-up I3C given for 6 months to 3 years to five children with an aggressive form of the disease halted the growth of the papillomas in three children after two years of treatment In some patients, I3C may be an effective adjunct treatment to reduce the growth or recurrence of respiratory papillomas.
Systemic lupus erythematosus SLE is an autoimmune disorder characterized by chronic inflammation that may result in damage to the joints, skin, kidneys, heart, lungs, blood vessels, or brain Estrogen is thought to play a role in the pathology of SLE because the disorder is much more common in women than men, and its onset is most common during the reproductive years when endogenous estrogen levels are highest The potential for I3C supplementation to shift endogenous estrogen metabolism toward the less estrogenic metabolite 2HE 1 , and away from the highly estrogenic metabolite 16HE 1 see Anti-estrogenic activities , led to interest in its use in SLE In an animal model of SLE, I3C feeding decreased the severity of kidney disease and prolonged survival Controlled clinical trials are needed to determine whether I3C supplementation could have beneficial effects in SLE patients.
Glucobrassicin, the glucosinolate precursor of I3C, is found in a number of cruciferous vegetables , including broccoli, Brussels sprouts, cabbage, cauliflower, collard greens, kale, kohlrabi, mustard greens, radish, rutabaga, and turnip 91, Total glucosinolate contents of selected cruciferous vegetables are presented in Table 1. However, the amount of total glucosinolates and the amount of indolecarbinol formed from glucobrassicin in food is variable and depends, in part, on the processing and preparation of foods for more detailed information, see the article on Cruciferous Vegetables.
I3C is available without a prescription as a dietary supplement , alone or in combination products. DIM is available without a prescription as a dietary supplement , alone or in combination products. Slight increases in the serum concentrations of the liver enzyme , alanine aminotransferase ALT were observed in two women who took unspecified doses of I3C supplements for four weeks No adverse effects were reported with daily consumption of mg of I3C for four weeks 6.
In some animal models, I3C supplementation was found to enhance carcinogen -induced cancer development when given chronically after the carcinogen When administered before or at the same time as the carcinogen, oral I3C inhibited tumorigenesis in animal models of cancers of the mammary gland , , uterus , stomach , colon , , lung , and liver , Although the long-term effects of I3C supplementation on cancer risk in humans are not known, the contradictory results of animal studies have led several experts to caution against the widespread use of I3C and DIM supplements in humans until their potential risks and benefits are better understood 99 , , The acidic environment of the stomach allows I3C molecules to condense and generate a number of biologically active I3C oligomers Figure 2.
Drugs that block the production of stomach acids, like antacids, Histamine 2 H 2 receptor antagonists , and proton-pump inhibitors, would likely prevent the generation of DIM and ICZ. However, it is not known whether these drugs limit the biological activities attributed to I3C and its derivatives Originally written in by: Jane Higdon, Ph.
Updated in December by: Victoria J. Drake, Ph. Note: Content may be edited for style and length. Science News. ScienceDaily, 14 December University of California - Berkeley.
Retrieved November 11, from www. PARP inhibitors are molecular targeted cancer drugs used to The new research demonstrates that a new class of drugs called small molecule RNA inhibitors can Triple-negative breast cancers, which comprise 15 to 20 percent of all breast tumors, are a particularly deadly type of Print Email Share. Just a Game? I3C and its side-kick, DIM, may act as antioxidants to protect the body from damage caused by high blood glucose and insulin in type-2 diabetes T2DM.
Laboratory research suggests it's possible that IC3 could act similarly to metformin, a T2DM drug, but DIM could even further improve carbohydrate metabolism to keep blood sugar steady and stop the liver from converting sugar into cholesterol [9] [3]. This research is still in its early stages, but there's no harm in boosting your carbohydrate-heavy meals with lots of cruciferous veggies to support your blood sugar levels.
Yep, time for more science — when any cell divides, it passes through many stages before it divides again. A defect in these pathways may be responsible for the development of mutations leading to tumours and cancer. Laboratory research has suggested that I3C may step in at these check-points and signal the defective cell or cancer cell to undergo apoptosis [4] [5].
I3C and DIM may also prevent cancer by helping the liver to detoxify carcinogens, and by acting as an antioxidant to protect DNA from damage in healthy cells [6]. Research trials on I3C in cancer are still quite new, and researchers use huge doses of isolated indolecarbinol extracts that are highly concentrated. However, the evidence suggests that it's perfectly safe to eat a diet rich in brassica vegetables and it may help to prevent the development of many cancers [11].
Plus these veggies could also help to protect the body during chemotherapy [8]! Cooking brassicas will destroy some of the I3C content, but eating them raw has a major down-side — these raw veggies contain high levels of acids that prevent nutrients from being absorbed, compounds that interfere with thyroid hormone production and may contribute to kidney stones [14]. This is fine if you're making a meal where you'll consume the water like in soup , as that's where the nutrients are!
Otherwise, lightly steam or stir-fry your brassicas to get the most I3C and flavour out of them. Fermentation is a great way to preserve a huge dose of I3C, but it doesn't eliminate the dangerous compounds [13]. If you can't tolerate brassicas or want to boost your indolecarbinol intake to therapeutic levels, both I3C and DIM are available as supplements.
Since some I3C is converted to DIM within the stomach, some people prefer to take the end-product, while others prefer to stick to I3C. Taking DIM for 15 weeks or less appears to be safe for most people, but speak to your healthcare provider — or stick to the whole food option!
There is an enzyme called myrosinase that is stored in plant cells away from the glucosinolates. Indolecarbinol I3C 1. And research even discovered that after four weeks of daily supplementation of I3C, only DIM, not I3C, was found in the blood of the study volunteers.
DIM, on the other hand, is quite stable.
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