Article

Dose-ranging study of Indole-3-Carbinol for breast cancer prevention

Authors:
To read the full-text of this research, you can request a copy directly from the authors.

Abstract

Sixty women at increased risk for breast cancer were enrolled in a placebo-controlled, double-blind dose-ranging chemoprevention study of indole-3-carbinol (I3C). Fifty-seven of these women with a mean age of 47 years (range 22-74) completed the study. Each woman took a placebo capsule or an I3C capsule daily for a total of 4 weeks; none of the women experienced any significant toxicity effects. The urinary estrogen metabolite ratio of 2-hydroxyestrone to 16 alpha-hydroxyestrone, as determined by an ELISA assay, served as the surrogate endpoint biomarker (SEB). Perturbation in the levels of SEB from baseline was comparable among women in the control (C) group and the 50, 100, and 200 mg low-dose (LD) group. Similarly, it was comparable among women in the 300 and 400 mg high-dose (HD) group. Regression analysis showed that peak relative change of SEB for women in the HD group was significantly greater than that for women in the C and LD groups by an amount that was inversely related to baseline ratio; the difference at the median baseline ratio was 0.48 with 95% confidence interval (0.30, 0.67). No other factors, such as age and menopausal status, were found to be significant in the regression analysis. The results in this study suggest that I3C at a minimum effective dose schedule of 300 mg per day is a promising chemopreventive agent for breast cancer prevention. A larger study to validate these results and to identify an optimal effective dose schedule of I3C for long-term breast cancer chemoprevention will be necessary.

No full-text available

Request Full-text Paper PDF

To read the full-text of this research,
you can request a copy directly from the authors.

... pekinensis) is a relatively rich source of these chemicals, particularly gluconasturtiin (aromatic glucosinolate), glucobrassicin (indolyl glucosinolate), and progoitrin (aliphatic glucosinolate) (Daxenbichler et al., 1979). Gluconasturtiin and glucobrassicin are precursors to phenethlyisothiocyanate (PEITC) and indole-3-carbanol (I3C), strong inhibitors of carcinogenesis in mammalian systems (Bell et al., 2000;Hecht, 2000;Wong et al., 1997). In contrast hydrolyzed products of progoitrin have demonstrated goitrogenic activity in animals, but in most cases this appears to be limited to situations of iodine deficiency (Jongen, 1996). ...
... Based on epidemiological, cell culture, and animal model studies, PEITC and I3C are currently undergoing clinical trials, and appear to slow or prevent several forms of cancer successfully (Bell et al., 2000;Wong et al., 1997). I3C, derived from glucobrassicin in cruciferous vegetables, has been shown to the lower incidence of hormone-dependent cancers by altering estrogen metabolism (Fowke et al., 2000;Keck and Finley, 2004). ...
... In the stomach, I3C is transformed into various bioactive compounds that can influence estrogen metabolism and promote hydroxylated metabolites at the C-2 position of the estrogen molecule and prevent hydroxylation at the C-16 position. Several investigations suggest that women who metabolize a large proportion of their estrogens in the form of 2-OH estrone as opposed to the 16-OH estrone have lower breast cancer risk (Badithe et al., 2001;Michnovicz et al., 1997;Wong et al., 1997). This research suggests that women whose diets are high in glucobrassicin content would be at less risk of developing breast cancer. ...
Article
Full-text available
Strong evidence exists to suggest that increased consumption of glucosinolates from Brassica vegetables is associated with reduced risk of cancer induction and development. Development of elite germplasm of these vegetables with enhanced levels of glucosinolates will putatively enhance health promotion among the consuming public. To evaluate levels of glucosinolate phenotypic variation in Chinese cabbage tissue and partition the total phenotypic variation into component sources (genotype, environment, and genotype-by-environment interaction), a set of 23 Brassica rapa L. var. pekinensis genotypes were grown in two different environments (field plots and greenhouse ground beds). Gluconasturtiin and glucobrassicin were found to account for ≈80% of total head glucosinolate content Significant differences were found in glucosinolate concentrations between the lowest and highest genotypes for glucobrassicin (6-fold) and for gluconasturtiin (2.5-fold). Analysis of variance showed that for the three major glucosinolates (gluconasturtiin, glucobrassicin, and progoitrin), the geneiypic effects described most of the phenotypic variation (62% averaged over the three compounds). The next most important factor was genotype x environment interaction (29%), whereas variation affiliated with the environment was found to be relatively minor (8%). These results suggest that genetic manipulation and selection can be conducted to increase glucosinolate content and the putative health promotion associated with consumption of Chinese cabbage.
... Нарушение баланса эстрогенов и прогестерона, в результате чего развивается абсолютная или относительная гиперэстрогения, а также дисбаланс процессов пролиферации и апоптоза являются одними из основных причин гиперпластических процессов репродуктивных органов [4,14,29,35,36]. Поэтому назначение гестагенов -патогенетически обоснованный метод лечения гиперэстрогении. ...
... Именно с регулярным употреблением в пищу некоторых из этих продуктов ученые связывают низкую заболеваемость РМЖ на Востоке (Китай, Япония) [8,20,28,30]. С 1995 года овощи семейства крестоцветных, по рекомендации Всемирного фонда исследования рака (World Cancer Research Fund International), считаются источником биологически активных веществ, обладающих наибольшей антиканцерогенной, антипролиферативной и антимутагенной активностью, и включены в перечень растительных групп, абсолютно необходимых для правильного жизнеобеспечения организма [9,10,18,30,36]. ...
... Терапевтические концентрации фитонутриентов оказывают выраженный положительный эффект на гиперпластические процессы. Они способствуют избирательному ингибированию роста опухолевых клеток и индукции апоптоза [26,29,36]. Одним из таких веществ является индол-3-карбинол, который получают из овощей семейства крестоцветных (это все виды капустыброкколи, цветная, белокочанная, брюссельская). ...
Article
Benign breast hyperplasia is a diseases of civilization associated in women with hormonal disorders, estrogen dominance syndrome. Risk of developing breast cancer for women with proliferative forms of benign breast disease increased tenfold. Absolutely all patients seek medical attention, regardless of pathology, must undergo breast examination and obtain recommendations for the prevention and the multiplicity of diagnostic tests. An important role in the pathogenesis of benign breast hyperplasia plays an increase prolactin levels. Hyperprolactinemia is a frequent cause of menstrual and generative dysfunctions, as well as benign breast hyperplasia, which negatively affects the quality of women life. Quite often there is not a permanent but temporary (latent or hidden) increase prolactin secretion. Occasional bursts of prolactin levels, combined with hyperestrogenemia cause bloating, breast tenderness (mastalgia). Hyperprolactinemia induced menstrual dysfunction causes abnormal steroidogenesis in the ovaries, which also exacerbates the morphological and functional abnormalities in the mammary glands, promotes dishormonal breast diseases and increases the risk of breast cancer. Due to the increase of cancer incidence in all countries is increased emphasis on early tumors diagnosis and prevention. Special nutrition and various diets are considered as one of the variants of the anti-tumor protection. Numerous studies in recent years devoted phytonutrients – substances of plant origin. Phytopreparation that can be used in these disorders is Epigalin Brest® that contained indole-3-carbinol, epigallocatechin-3-gallate and Vitex agnus castus extract. Indole-3-carbinol and epigallocatechin-3-gallate are biologically active substances with a well-deserved popularity among clinicians in Europe and the United States. Herbal drug Epigalin Brest® regulates the metabolism of estrogen by blocking the synthesis of its “aggressive” forms, reduces the level of prolactin, inhibits the abnormal proliferation in hormone-dependent organs (mammary gland) and tissues of the reproductive system. Also Epigalin Brest® has antiproliferative effects.
... Indoles may help increase this ratio; in particular, indole-3-carbinol (I3C), a natural compound derived by hydrolysis from glycobrassicin produced in cruciferous vegetables such as cabbage, broccoli, and Brussels sprouts, and its natural diindole condensation product 3-3'-diindolylmethane (DIM) [6]. Several studies provide evidence that both of these indoles can improve the 2-HE/16alpha-HE ratio when given in the appropriate dose [7]. DIM, can induce estrogenic responses through a ligand-independent activation of estrogen receptors or disrupt estrogen responsiveness through its interaction with the aryl hydrocarbon receptor [8,9]. ...
... In that study, the maximal increase was observed with the 400 mg daily of I3C, with no further increase found at 800 mg daily. In a related study, Wong et al. demonstrated in 57 women that 300 mg per day of I3C significantly increased the 2-HE/ 16alpha-HE ratio [7]. Additionally, the other indole, DIM has antitumorogenesis effects [23] in breast cancer. ...
Article
Full-text available
Gynecological cancers are among the most common in women and are directly related to a variety of hormonal factors. One potential risk factor associated with developing a gynecological malignancy is the ratio of two hormone metabolites, 2-Hydroxyestrone (2-HE) and 16alpha-Hydroxyestrone (16alpha-HE). A number of botanical constituents such as indoles, flavonoids, and resveratrol have been shown to have a favorable effect on the metabolic pathways that affect this ratio. The present study was designed to evaluate if a multi-nutrient supplement containing targeted botanical constituents would affect the 2-HE/16 alpha-HE ratio in middle-aged women. A retrospective analysis was performed on 76 female patients (mean age 54 years) who received 2-HE/16 alpha-HE ratio assessments at two separate time points. The ratio assessment was part of standard care for women who presented with risk indicators associated with a high proliferative state. All patients who completed pre and post assessments were included. Sixty-five of the patients received a multi-nutrient supplement, Lucentia Peak(R), during the study period. Eleven patients chose not to take the supplement, but did receive ratio assessments at similar time points as the treatment group, allowing for between group comparisons. Paired t-tests were used to compare the changes in the 2-HE and 16alpha-HE measures as well as their ratio, both within groups and between groups. The results demonstrated a significant increase in the 2-HE/16alpha-HE ratio in the treated group (pre 0.38 to post 0.57, p<0.0001), and was significantly different (p=0.02) compared to the change in the control group (pre 0.65 to post 0.64). This change appears to be mediated primarily by an increase in the 2-HE level. Individually, 54 patients given Lucentia Peak(R) had increased ratios while 11 patients had a decrease. In the control group, 3 patients had an increase in their ratio and 8 patients had a decrease. The results demonstrated that women receiving the Lucentia Peak(R) multi-nutrient supplement had significant increases in their 2-HE:16alpha-HE ratio, which appears to be mediated primarily by increasing the 2-HE levels. These results suggest further research on phytonutrients that might positively affect estrogen metabolism is warranted.
... I3C has been found in fruits and vegetables, including members of the cruciferous family and, particularly, members of the genus Brassica. Its anticancer effects in experimental animals [21][22][23][24] and humans [25,26] have led to its use as a possible chemopreventive agent [27]. In cruciferous vegetables, I3C is derived from the hydrolysis of glucobrassicin, a glucosinolate. ...
... The National Research Council, Committee on Diet, Nutrition, and Cancer has recommended increased consumption of cruciferous vegetables as means to reduce cancer incidence. Epidemiological findings have shown that consumption of cruciferous vegetables protects against cancer more effectively than the total intake of fruits and vegetables [33], and this effect of cruciferous vegetable is attributed to the presence of I3C [24][25][26]34]. The beneficial anticancer effects of I3C were first recognized by 'Cato the Elder', a Roman statesman (234-149 BC) who said -"If a cancerous ulcer appears upon the breast, apply a crushed cabbage leaf, and it will make it well" [5]. ...
Article
Full-text available
Indole compounds, found in cruciferous vegetables, are potent anti-cancer agents. Studies with indole-3-carbinol (I3C) and its dimeric product, 3,3'-diindolylmethane (DIM) suggest that these compounds have the ability to deregulate multiple cellular signaling pathways, including PI3K/Akt/mTOR signaling pathway. These natural compounds are also effective modulators of downstream transcription factor NF-κB signaling which might help explain their ability to inhibit invasion and angiogenesis, and the reversal of epithelial-to-mesenchymal transition (EMT) phenotype and drug resistance. Signaling through PI3K/Akt/mTOR and NF-κB pathway is increasingly being realized to play important role in EMT through the regulation of novel miRNAs which further validates the importance of this signaling network and its regulations by indole compounds. Here we will review the available literature on the modulation of PI3K/Akt/mTOR/NF-κB signaling by both parental I3C and DIM, as well as their analogs/derivatives, in an attempt to catalog their anticancer activity.
... They were able to induce the activity of cytochrome P450 isoenzyme CYP1A2, and increase the ratio of 2-OHE1:16α-OHE1. A similar beneficial shift in estrogen metabolites was also observed in early studies on women with increased risk for breast cancer [97][98][99] and a more detailed study on postmenopausal women with a history of early-stage breast cancer [100] . Based on the preclinical evidence which indicated that I3C and DIM may offer benefit for diseases caused by HPV, two studies explored the effect on cervical intraepithelial neoplasia (CIN). ...
Article
Full-text available
Cancer prevention research has drawn much attention worldwide. It is believed that some types of cancer can be prevented by following a healthy life style. Cancer chemoprevention by either natural or synthetic agents is a promising route towards lowering cancer incidence. In recent years, the concept of cancer chemoprevention has evolved greatly. Experimental studies in animal models demonstrate that the reversal or suppression of premalignant lesions by chemopreventive agents is achievable. Natural occurring agents such as dietary phytochemicals, tea polyphenols and resveratrol show chemopreventive activity in animal models. Moreover, clinical trials for testing the safety and efficacy of a variety of natural agents in preventing or treating human malignancy have been ongoing. Here, we summarize experimental data on the chemopreventive or tumor suppressive effects of several natural compounds including curcumin, (-)-epigallocatechin-3-gallate, resveratrol, indole-3-carbinol, and vitamin D.
... Fat and fiber may also play roles in determining the composition and activities of gut bacteria (36)(37)(38), which can deconjugate and facilitate reabsorption of a certain pathway EM via enterohepatic recycling (39)(40)(41)(42). Furthermore, many cytochrome P450 1A1 enzymes that are involved in hydroxylation of parent estrogens are inducible, and phytochemicals may play roles in determining their expression and activity (43,44). Dietary fat intake may also contribute to sex steroid hormone synthesis and hormone balance (20). ...
Article
Full-text available
Interindividual differences in the bioavailability of potentially carcinogenic estrogen and estrogen metabolites (EMs) may play a role in the risk of breast cancer. We examined whether dietary intake of fiber and fat influences premenopausal EM profiles through effects on estrogen synthesis, metabolism, or excretion. We conducted a cross-sectional analysis of 598 premenopausal women who participated in a reproducibility study (n = 109) or served as controls in a nested case-control study of breast cancer (n = 489) within the Nurses' Health Study II. Dietary intake of fiber and fat was assessed via semiquantitative food frequency questionnaires in 1995 and 1999. Midluteal urine samples were collected between 1996 and 1999 and EMs were quantified with the use of HPLC-tandem mass spectrometry. Linear mixed models were used to estimate creatinine-adjusted geometric means for individual EMs and their pathway groups across categories of dietary intake while controlling for total energy intake and potential confounders. Higher total dietary fiber intake (>25 g/d vs. ≤15 g/d) was associated with significantly higher concentrations of 4-methoxyestradiol (50% difference, P-difference = 0.01, P-trend = 0.004) and lower concentrations of 17-epiestriol (-27% difference, P-difference = 0.03, P-trend = 0.03), but was not associated with any other EMs. The associations did not vary by fiber intake from different sources. Total fat intake (>35% energy vs. ≤25% energy) was suggestively positively associated with 17-epiestriol (22.6% difference, P-difference = 0.14, P-trend = 0.06); the association was significant for polyunsaturated fatty acids (37% difference, P-difference = 0.01, P-trend = 0.01) and trans fat (36.1% difference, P-difference = 0.01, P-trend = 0.01) intake. Fiber and fat intake was not strongly associated with patterns of estrogen metabolism in premenopausal women. Our data suggest estrogen metabolism is not a major mechanism through which dietary intake of fiber and fat may act upon breast or other hormone-related cancer risks. © 2015 American Society for Nutrition.
... Moreover, BIMs have also been found to be potent anticancer derivatives, and clinical studies have demonstrated that they could be potentially used as chemotherapeutic agents against various forms of cancer. BIM suppresses the proliferation of estrogen dependent reproductive cancers of breast [3], ovarian [4], cervical [5], and prostate [6] but also thyroid [7], neck and head [8], melanoma or blood cells (leukemia) [9]. BIMs is a potent radioprotector against UV and ionizing radiation acting by a unique mechanism of sudden activation of a nuclear kinase which regulates the response to DNA damage, repair, or apoptosis and oxidative stress [10]. ...
Article
Full-text available
Herein we report crystallographic comparison of some geometrical and structural features for a series of biologically relevant bis-indole derivatives. Selected bond distances and bond angles of interest in a series of bis-indole derivatives have been discussed in detail. The biological activity of the substances has been correlated with based the structure-activity relationships (SAR) base which provides the different possibility of activity (Pa) and possibility of inactivity (Pi). For a better understanding of the packing interactions existing among these derivatives, an overview of crystal structure analysis with emphasis on the intramolecular hydrogen bonding in some bis-indole derivatives is presented. The role of hydrogen bonding in the crystal structure assembly of bis-indole derivatives has been found to be predominant and this observation reveals significant impact of hydrogen bonding in high value of drug-likeness of these bio-molecules.
... Indole-3carbinol (I-3-C) is a breakdown product of the glucosinolate glucobrassicin, also known as indole-3-glucosinolate[207]. Indole-3-carbinol may have cancer chemopreventive activity[208,209]. Glucosinolates themselves have minimal anticancer activity. ...
... Research shows that I3C has potential value as an anticancer agent for breast cancer through its effect on estrogen receptors. (Wong 1997) Several studies have also shown that I3C can promote cancer cell death (apoptosis), including prostate cancer cells. For example, a study at Wayne State University examined the molecular mechanisms by which DIM has an effect on prostate cancer cells. ...
Article
Indole-3-carbinol (I3C) is a phytonutrient found in high levels in cruciferous vegetables, such as broccoli, cabbage, and cauliflower. Indole-3-carbinol is the precursor to another indole and phytonutrient, diindolylmethane (DIM). Significant amounts of DIM are released in the body when gastric acid acts on I3C during digestion. I3C and DIM are frequently taken to promote metabolism of estrogen and to help manage estrogen-related conditions, such as cancer. However, DIM has been identified as the safest and most active and effective of the two indoles. As men age, they experience a decline in testosterone and, in many cases, increases in estrogen levels. The result is a testosterone/estrogen imbalance that directly causes many of the debilitating health problems associated with normal aging. Estrogen is metabolized into several different post-estrogen hormones, namely 2-hydroxy, 4-hydoxy and 16-hydroxy estrogens. Research has shown 4-hydroxy and 16-hydroxy estrogens to be powerful growth and inflammation promoters, with direct connections to cancer, especially in estrogen-sensitive tissues such as the prostate. Obesity is also associated with unfavorable estrogen metabolites. (Schneider 1983) On the other hand, 2-hydroxy estrogens have been shown to be powerfully protective of those same tissues, helping to prevent cancer and resolve disorders including elevated PSA from prostate tissue. (Le 2003) Balanced estrogen levels in men are essential to encourage a healthy libido, improved brain function, protect the heart and strengthen the bones. However, aging, body fat, hormone replacement, pesticides, prescription medications, and excessive alcohol intake can lead to high estrogen levels, which in turn can cause reduced testosterone levels, fatigue, loss of muscle tone, increased body fat, loss of libido and sexual function, and an enlarged prostate.
... The observed changes in estrogen metabolism is consistent with our prior clinical study that showed an induction of 1A2 and inhibition of 3A4 activity after 4 weeks of 1 gm daily resveratrol dosing [22]. Prior studies have shown that putative cancer preventive compounds derived from cruciferous vegetables, indole-3-carbinol and 3,3′diindolylmethane, also increased the urinary 2-OHE 1 /16α-OHE 1 ratio [30][31][32]. Some observation studies have demonstrated a correlation between a low urinary 2-OHE 1 /16α-OHE 1 ratio and increased breast cancer risk, whereas others have not shown the same correlation [9,10]. ...
Article
Full-text available
Background Breast cancer risk is partially determined by several hormone-related factors. Preclinical and clinical studies suggested that resveratrol may modulate these hormonal factors.Methods We conducted a pilot study in postmenopausal women with high body mass index (BMI¿¿¿25 kg/m2) to determine the clinical effect of resveratrol on systemic sex steroid hormones. Forty subjects initiated the resveratrol intervention (1 gm daily for 12 weeks) with six withdrawn early due to adverse events (AEs). Thirty-four subjects completed the intervention.ResultsResveratrol intervention did not result in significant changes in serum concentrations of estradiol, estrone, and testosterone but led to an average of 10% increase in the concentrations of sex steroid hormone binding globulin (SHBG). Resveratrol intervention resulted in an average of 73% increase in urinary 2-hydroxyestrone (2-OHE1) levels leading to a favorable change in urinary 2-OHE1/16¿-OHE1 ratio. One participant had asymptomatic Grade 4 elevation of liver enzymes at the end of study intervention. Two subjects had Grade 3 skin rashes. The remaining adverse events were Grade 1 or 2 events. The most common adverse events were diarrhea and increased total cholesterol, reported in 30% and 27.5% of the subjects, respectively.Conclusion We conclude that among overweight and obese postmenopausal women, daily 1 gm dose of resveratrol has favorable effects on estrogen metabolism and SHBG. Further placebo-controlled studies are needed to confirm our findings on these hormone-related breast cancer risk factors and the attribution of the adverse effects observed in the study population.Trial registrationClinicalTrials.gov: NCT01370889.
... Nrf2 activators are also a well-established product available in the market as an antioxidant and a detoxification support formula. Some clinical studies have reported anticancer and antihyperlipidemic activity of broccoli sprouts (10 g/d), which has proven clinically feasible in the treatment of communicable and non-communicable diseases (Wong et al., 1997). ...
Article
Full-text available
This study investigated the protective effect of extracts from flowers of Brassica oleracea L. var. italica Plenck on type 2 diabetes mellitus and its associated disorders. Three different doses of each extract (petroleum ether, ethanol, and aqueous) were administered orally for 42 days. Biochemical parameters, behavioral studies, and histological studies were measured at different periods. Mortality was found to be nil up to 2,000 mg/kg. Statistically significant (P<0.001) improvement in serum glucose level was observed in the groups receiving 400 mg/kg of petroleum ether, aqueous, or ethanol extracts compared with the negative control group. Insulin level was decreased by aqueous extracts, whereas lipid profiles were improved by aqueous and ethanol extracts. A reduction in transfer latency was observed in treatments of all three extract types. Ethanol extract treatment (400 mg/kg) showed maximum percentage inhibition in a lipid peroxidation assay. Additionally, the aqueous and ethanol extract treatments markedly reduced tumor necrosis factor-α, interleukin-6, and glycosylated hemoglobin levels. Histological results showed that high doses of extracts alleviated the damages induced by type 2 diabetes mellitus in various organs and bones. Based on the results of this study, it can be concluded that B. oleracea has the potential to alleviate type 2 diabetes mellitus.
... The amount of I3C found in the diet can vary greatly, ranging from 20 and 120 mg daily, and is dependent on dietary intake of cruciferous vegetables and their changeable concentrations [10]. Its anti-carcinogenic effects in experimental animals [11-14] and humans [15,16] are well-documented and, therefore, I3C has received special attention as a possible chemopreventive agent [17]. ...
Article
Full-text available
Indole compounds, obtained from cruciferous vegetables, are well-known for their anti-cancer properties. In particular, indole-3-carbinol (I3C) and its dimeric product, 3,3´-diindolylmethane (DIM), have been widely investigated for their effectiveness against a number of human cancers in vitro as well as in vivo. These compounds are effective inducers of apoptosis and the accumulating evidence documenting their ability to modulate multiple cellular signaling pathways is a testimony to their pleiotropic behavior. Here we attempt to update current understanding on the various mechanisms that are responsible for the apoptosis-inducing effects by these compounds. The significance of apoptosis-induction as a desirable attribute of anti-cancer agents such as indole compounds cannot be overstated. However, an equally intriguing property of these compounds is their ability to sensitize cancer cells to standard chemotherapeutic agents. Such chemosensitizing effects of indole compounds can potentially have major clinical implications because these non-toxic compounds can reduce the toxicity and drug-resistance associated with available chemotherapies. Combinational therapy is increasingly being realized to be better than single agent therapy and, through this review article, we aim to provide a rationale behind combination of natural compounds such as indoles with conventional therapeutics.
... 51 These doses of I3C clearly shift the metabolism of estradiol away from its 16-alpha-hydroxyestrone metabolite and toward the more benign 2-hydroxyestrone. 52 Side effects at these doses of I3C have been minimal. ...
Article
Full-text available
This article provides a review of the many facets of interactions between herbal constituents and cytochrome P450 (CYP450) enzymes. While stressing potential drug-herb interactions, the article also reviews information about how CYP450 enzymes participate in activating (for better or for worse) botanical constituents, and suggests circumstances in which the individual expression of patients' CYP450 enzymes can influence the activity of botanical medicines affected by these enzymes. The article reviews the effect of Hypericum perforatum (St. John's wort) and Citrus decumana (grapefruit) on CYP3A4, and the potential influence of this effect on the metabolism of certain drugs. The article discusses the toxic activation by CYP3A4 of unsaturated pyrrolizidine alkaloids from plants such as Symphytum officinale (comfrey) and of alkylbenzenes such as safrole from Sassafras spp. (sassafras) and Areca catechu (areca or betel nut), and estragole from Foeniculum vulgare (fennel), Pimpinella anisum (anise), Ocimum basilicum (basil), and Artemisia dracunculus (tarragon). The effects of piperine from Piper nigrum (black pepper) and Piper longum (long pepper) on CYP3A4, as well as its interactions with Curcuma longa (turmeric), are surveyed. The effect of cruciferous vegetables, including Nasturtium officinale (watercress), and their isothiocyanate constituents (sulforaphane, phenylethyl isothiocyanate [PEITC], and most notably indole-3-carbinole) with CYP1A1, 1A2, and 2E1 are discussed in the context of carcinogenesis, induction of beneficial estrogen metabolism, and the ways in which the individual patient's glutathione enzyme systems can alter the efficacy of these vegetables and isothiocyanates. The pharmacokinetics of Artemisia annua (sweet Annie, qing hao) and artemisinin are discussed in light of CYP450 interactions. The article also presents minor relationships involving plants and plant constituents and CYP450 enzymes, such as that of grapefruit with CYP2A6, the activation of resveratrol to its more active metabolite piceatannol, and interactions of artemisinin and Ginkgo biloba with CYP2C19.
... Some patients who take indoles therapeutically may experience a slight increase in alanine aminotransferase (ALT). 19 In a study of 60 women who were at an increased risk for developing breast cancer, subjects were given either 50, 100, 200, 300, or 400 mg doses of indole-3-carbinol. The minimum effective dose per day as a possible chemopreventive agent against breast cancer was 300 mg. ...
... 65 In another double-blind, placebo-controlled study of 57 women at increased risk for breast cancer, supplementation with I3C (300-400 mg/d for 4 weeks) proved to be a promising chemopreventive agent as measured by the increased 2-OH:16α-OH ratio. 69 Not only does I3C promote healthier estrogen metabolism, but it may also act as a "weak," or anti-estrogen. Through competitive inhibition, I3C has been shown to prevent the receptor binding of "stronger," more stimulating estrogens. ...
Article
It is now well known that one of the most promi- nent causes of breast cancer, as well as many other hormone related health problems in both men and women, is excessive estrogen exposure from both endogenous and exogenous sources. Improving estrogen metabolism can be of benefit in women with various conditions and family histories, including a family history of breast, uterine, or ovarian cancer, and condi- tions such as endometriosis, premenstrual syndrome, uterine fibroid tumors, fibrocystic or painful breasts, cervical dysplasia, and systemic lupus erythematosis. Beneficial modulation of estrogen metabolism can be accomplished through dietary and lifestyle modifications such as increasing fiber and reducing fat, increasing phytoestrogen intake, losing weight, and increasing exercise. In addition, many nutrients effectively reduce estrogen load by supporting preferred pathways of estrogen metabolism and detoxification, including indole-3-carbinol, B vitamins, magnesium, limonene, calcium D-glucarate, and antioxidants. The influences of these nutrients on estrogen metabolism may have profound significance for diseases in which these hor- mones may play a role in clinical expression.
... Literature is mixed in its results. Different clinical studies find I3C to be safe and to have anticancer properties (Wong et al., 1997;Weng et al., 2008), although there remains a considerable concern about whether dietary I3C prevents or enhances carcinogenesis. This compound can induce either phase I (activation) or phase II (detoxification) enzymes, depending on the metabolic pathway it takes, and it can, therefore, either activate or deactivate some carcinogens. ...
... Several prior reports have shown that the ratio of 2-hydroxy E2 to 16-hydroxy E2 can be used as a biomarker that correlates with carcinogenicity as well as tumor follow-up, and the ratio was described as more representative of the intrinsic tissue estrogen milieu than each metabolite separately (Fishman et al., 1995;Kabat et al., 1997;Meilahn et al., 1998;Muti et al., 2000;Lord et al., 2002). This was described in several types of cancer in various anatomical sites, such as breast cancer, mammary tumor, head and neck cancer as well as endometrial cancer (Persson, 1985;Taioli et al., 1996;Wong et al., 1997;Auborn et al., 1998;Ursin et al., 1999;Yoo et al., 2001;Lord et al., 2002). ...
... I3C is found in some fruits and vegetables, including members of the cruciferous family, and, in particular, members of the genus Brassica. Its anticarcinogenic effects in experimental animals 30e33 and humans 34,35 are well established. In cruciferous vegetables, I3C is produced by the hydrolysis of glucobrassicin, a glucosinolate. ...
Article
Indole compounds, obtained from cruciferous vegetables, are known to possess potent anticancer properties. Studies with indole-3-carbinol (I3C) and its dimeric product, 3,3' diindolylmethane (DIM), have indicated the efficacy of these compounds against a number of human cancers, which is related to their ability to interfere with and modulate multiple cellular signaling pathways. The nuclear factor-kappa B (NF-κB) pathway plays an important role in the control of cell proliferation, metastasis, angiogenesis, and drug resistance. Emerging evidence points to an effective inhibition of NF-κB signaling by I3C and DIM. This seems to be central to most of the observed anticancer properties of these compounds. Here, we summarize our current understanding of regulation of NF-κB signaling by I3C and DIM and the resulting biological effects. Breast, prostate, and pancreatic cancers are relatively better characterized in terms of modulation of NF-κB signaling by indoles, and it is our intent that this review incites similar studies in other human cancer models as well.
... Several molecular targets have been identified for I3C and its metabolites, such as the primary acid condensation product diindolylmethane (DIM). I3C and DIM can bind several cytosolic receptors and alter several important signaling pathways including the aryl hydrocarbon receptor (AhR), estrogen receptor (ER), androgen receptor (AR), and nuclear factor-kappa B (NF-κB) (6)(7)(8)(9)(10). A complex signaling cascade is likely induced following I3C exposure due to crosstalk between these pathways including physical interaction of the ligand-bound AhR with NF-κB (10,11) and the ER (12)(13)(14). ...
Article
Full-text available
Due to the severe adverse effects that can accompany conventional therapies for Crohn's disease, the search for natural complementary therapies has increased dramatically in recent years. Indole-3-carbinol (I3C), a constituent of cruciferous vegetables, possesses anti-inflammatory properties; however, its effects on intestinal inflammation have yet to be evaluated. To test the hypothesis that I3C dampens intestinal inflammation, C57BI/6 mice were treated with I3C and exposed to 2,4,6-trinitrobenzenesulfonic acid (TNBS) to induce colitis. Several parameters of disease severity and inflammation were subsequently evaluated. I3C dampened the disease severity, as indicated by decreased body weight loss and decreased severity of clinical signs. Interestingly, this effect was observed in female but not male mice, which displayed a trend towards exacerbated colitis. Differential effects were observed in the profiles of cytokine production, as the production of pro-inflammatory cytokines was increased in males. The sex-specific effect of I3C in TNBS-induced colitis is a novel finding and warrants further investigation since this is a common dietary compound and is also available commercially.
... Literature is mixed in its results. Different clinical studies find I3C to be safe and to be anti-cancer properties (Wong et al. 1997;Weng et al. 2008) although there remains a considerable concern about whether dietary I3C prevents or enhances carcinogenesis. This compound can induce either phase I (activation) or phase II (detoxification) enzymes, depending on the metabolic pathway it takes, and it can, therefore, either activate or deactivate some carcinogens. ...
... 23,24 Οι διοξίνες υπεισέρχονται στα ορμονικά σήματα, μιμούνται τη δράση της θυροξίνης, αναστέλλουν τη βιταμίνη Α, και μπλοκάρουν τους υποδοχείς των οιστρογόνων, γεγονός που οδήγησε στην παρασκευή πειραματικών φαρμάκων για τη θεραπεία του ορμονο-εξαρτώμενου καρκίνου του μαστού. 14,25,26 Μελέτες σε ζώα έδειξαν ότι οι διοξίνες ευθύνονται για ανωμαλίες της νεφρικής λειτουργίας στα νεογέννητα, αποβολές και θνησιγενή έμβρυα. 14,27 Το TCDD δημιουργεί ισχυρό σύμπλεγμα με την α-φετοπρωτεΐνη, μεταφέρεται πιο εύκολα στους εμβρυϊκούς ιστούς, με αποτέλεσμα εμβρυοτοξικότητα και τερατογενέσεις. ...
Article
Full-text available
Tuberculous meningitis (TBM) is a serious extrapulmonary form of tuberculosis and its rapid diagnosis is of vital importance for an optimum outcome for the patients. The aim of this study to evaluate the contribution of PCR amplification in the early diagnosis of TBM in parallel to the classical diagnostic methods. A total of 66 CSF samples were assessed from adult patients (34-71 years) with suspected TBM based on clinical data. Cytological and biochemical CSF examination, demonstration of the Mycobacterium tuberculosis by Ziehl-Neelsen (ZN) staining, and culture on Lowenstein Jensen slope were performed in all CSF samples. Mycobacterial DNA from all samples was amplified using an IS6110 gene-specific PCR (insertion sequence). This region is specific for all species of the M. tuberculosis complex. In addition, 7 CSF samples from patients with microbial meningitis were examined by PCR. All the 66 CSF samples were negative by ZN staining, but from 8 samples M. tuberculosis was isolated (12.1%). PCR was positive in 18 samples (27.2%). PCR confirmed the diagnosis of TBM in 18 patients while the CSF culture waw positive only in 8 patients. In the total of 18 patients with confirmed TBM the culture was positive in 44.4%. The samples from the microbial meningitis cases were all negative by PCR. The CSF PCR is a rapid, sensitive and specific diagnostic test in comparison to conventional procedures, and it contributes to the early diagnosis of TBM.
... Unlike DIM, there are warnings regarding the wide-spread use of I3C supplementation for cancer prevention and other roles until sufficient clinical data established regarding their potential risks and benefits. [62][63][64][65][66][67] The wide range of research outputs, marketing as a supplement, and other media publicity on I3C and DIM health benefits have evoked to review the existing human clinical-based literature in connection to DIM interventions. Therefore, the principal goal of this review was to review the human clinical trial published studies on DIM clinical efficacy towards prevention and treatment of diseases including the mechanism, and consistency of clinical trial scientific results. ...
Article
Full-text available
Dagnachew Eyachew Amare Department of Environmental and Occupational Health and Safety, Institute of Public Health, College of Medicine and Health Sciences, University of Gondar, Gondar, EthiopiaCorrespondence: Dagnachew Eyachew AmareDepartment of Environmental and Occupational Health and Safety, Institute of Public Health, College of Medicine and Health Sciences, University of Gondar, P.O. Box 196, Gondar, EthiopiaTel +251-939406194Email dagnachew.eyachew@gmail.comObjective: To systematically review the human clinical trial published studies regarding a dietary compound 3,3ʹ-diindolylmethane (DIM) clinical efficacy towards the prevention and treatment of cancer and other diseases, its bioavailability, safety, and consistency of the results.Methods: An electronic literature search of PubMed database (14), Cochrane Clinical Trials library (3), and Google Scholar (5) from inception to Feb 2020 was conducted. All the in vitro, animal, epidemiological, and review studies of DIM were excluded. Twenty-two randomized or controlled human clinical trials with prospective/retrospective studies published in the English language and that involved DIM intervention on human participants were extracted.Results: DIM has increased estrogen metabolism, decreased androgen-specific antigen, up-regulated BRCA1 expression, and increased androgen hormone-binding globulin. This suggests that DIM may have a promising beneficial role as a chemo-preventive supplement for breast and prostate cancers. DIM has shown some clinical efficacy to treat cervical/prostate dysplasia, human papilloma-virus, and warts.Conclusion: The absence of clinical evidence about DIM efficacy to treat prostate or breast cancer patients is the concern as this dietary compound is being advocated as a supplement in the market to treat these disease conditions. The maximum DIM intervention time for breast and prostate cancer patients was 28 days and 12 months, respectively, and most of the prospective trials were targeting DIM biological fate, than adequately addressing DIM efficacy in treating breast or prostate cancer.Keywords: 3,3ʹ-diindolylmethane, cancer, cruciferous vegetables, human clinical trials, indole-3-carbinol, supplementation
... Immunofluorescence analysis of tumor xenograft sections demonstrated that concomitant with the in vivo inhibition of tumor growth, I3C injected animals showed a strong down-regulation of MITF-M protein relative to vehicle treated control animals ( Figure 1B, left panels). Similar down regulation of MITF-M protein was observed by immunofluorescence analysis of cultured G-361 melanoma cells treated for 48h with or without 200 μM I3C ( Figure 1B, right panels), which is the optimal I3C concentration for the anti-proliferative effect in cultured human cancer cells [36]. This result indicated that the I3C down regulation of MITF-M levels observed in vivo is a direct effect in the melanoma cells, rather than an indirect consequence of other tissues conceivably producing a factor in response to I3C that acts on the melanoma-derived tumor xenografts. ...
Article
Indole-3-carbinol (I3C), an anti-cancer phytochemical derived from cruciferous vegetables, strongly inhibited proliferation and down-regulated protein levels of the melanocyte master regulator micropthalmia-associated transcription factor (MITF-M) in oncogenic BRAF-V600E expressing melanoma cells in culture as well as in vivo in tumor xenografted athymic nude mice. In contrast, wild type BRAF-expressing melanoma cells remained relatively insensitive to I3C anti-proliferative signaling. In BRAF-V600E-expressing melanoma cells, I3C treatment inhibited phosphorylation of MEK and ERK/MAPK, the down stream effectors of BRAF. The I3C anti-proliferative arrest was concomitant with the down-regulation of MITF-M transcripts and promoter activity, loss of endogenous BRN-2 binding to the MITF-M promoter, and was strongly attenuated by expression of exogenous MITF-M. Importantly, in vitro kinase assays using immunoprecipitated BRAF-V600E and wild type BRAF demonstrated that I3C selectively inhibited the enzymatic activity of the oncogenic BRAF-V600E but not of the wild type protein. In silico modeling predicted an I3C interaction site in the BRAF-V600E protomer distinct from where the clinically used BRAF-V600E inhibitor Vemurafenib binds to BRAF-V600E. Consistent with this prediction, combinations of I3C and Vemurafenib more potently inhibited melanoma cell proliferation and reduced MITF-M levels in BRAF-V600E expressing melanoma cells compared to the effects of each compound alone. Thus, our results demonstrate that oncogenic BRAF-V600E is a new cellular target of I3C that implicate this indolecarbinol compound as a potential candidate for novel single or combination therapies for melanoma. © 2016 Wiley Periodicals, Inc.
... 27 I3C may reduce the risk of hormone-related cancers, such as prostate, breast and cervical cancers. 8,28,29 The inhibitory effects of I3C and its metabolites have been investigated through cancer cellcycle/survival regulation such as Akt-NF-kB signaling involved pathways, caspase activation, estrogen metabolism, and cyclindependent kinase activities. 30 The availability of I3C was significantly enhanced with grinding (14.86-25.08 ...
Article
Full-text available
This study evaluated the effects of grinding and chopping with/without microwaving on the health-beneficial components, and antioxidant, anti-inflammation and anti-proliferation capacities of commercial kale and broccoli samples. The availability of indole-3-carbinol (I3C) was evaluated using high performance liquid chromatography. The total phenolic contents, the scavenging activities against DPPH, oxygen, hydroxyl and ABTS cation radicals, and cell-based antioxidant activities were determined for the antioxidant capacities. The results indicated that chopping released the least nutraceutical components and antioxidant capacities. Microwaving had no effect on I3C release from kale, but resulted in an elevated (more than 2-fold) release of I3C from broccoli. In addition, the choice of a blender affected the availability of anti-proliferative capacity from the vegetables, while had no effect on the availability of their anti-inflammatory activity. In summary, different food preparation methods could strongly impact the availability of bioactive factors in the selected vegetables. These findings suggest that choosing an appropriate food processing method for each vegetable might be critical to obtain desirable health-beneficial effects.
... Thus a higher ratio of 2-hydroxy estrone to 16-hydroxy estrone may determine the cancer preventive status. Consumption of 300 mg of I3C per day caused an increase in the ratio of 2 α-hydroxy estrone to 16 α-hydroxy estrone in woman who are at a risk of developing breast cancer [62]. Metabolism of estrogen favouring 2-hydroxy estrone is influenced by race, ethnicity, and dietary factors (increased consumption of fiber, polyphenols, crucifer vegetables, fruits) [63]. ...
Article
Full-text available
A unique feature of bioactive food ingredients is their broad antioxidant function. Antioxidants having a wide spectrum of chemical structure and activity beyond basic nutrition; display different health benefits by the prevention and progression of chronic diseases. Functional food components are capable of enhancing the natural antioxidant defense system by scavenging reactive oxygen and nitrogen species, protecting and repairing DNA damage, as well as modulating the signal transduction pathways and gene expression. Major pathways affected by bioactive food ingredients include the pro-inflammatory pathways regulated by nuclear factor kappa B (NF-κB), as well as those associated with cytokines and chemokines. The present review summarizes the importance of plant bioactives and their roles in the regulation of inflammatory pathways. Bioactives influence several physiological processes such as gene expression, cell cycle regulation, cell proliferation, cell migration, etc., resulting in cancer prevention. Cancer initiation is associated with changes in metabolic pathways such as glucose metabolism, and the effect of bioactives in normalizing this process has been provided. Initiation and progression of inflammatory bowel diseases (IBD) which increase the chances of developing of colorectal cancers can be downregulated by plant bioactives. Several aspects of the potential roles of microRNAs and epigenetic modifications in the development of cancers have also been presented.
... The results of this study suggested that the minimum effective dose schedule of 300mg/day is optimal for breast cancer prevention, although should be confirmed by long term breast cancer prevention trial [Wong et al. 1997]. ...
Chapter
Indole-3-carbinol (I3C), a common phytochemical in cruciferous vegetables, and its condensation product, 3,3?-diindolylmethane (DIM) exert several biological activities on cellular and molecular levels, which contribute to their well-recognized chemoprevention potential. Initially, these compounds were classified as blocking agents that increase drug-metabolizing enzyme activity. Now it is widely accepted that I3C and DIM affect multiple signaling pathways and target molecules controlling cell division, apoptosis, or angiogenesis deregulated in cancer cells. Although most of the current data support the role of I3C and DIM in prevention of hormone-dependent cancers, it seems that their application in prevention of the other cancer as well as cardiovascular disease, obesity, and diabetes reduction is also possible. This chapter summarizes the current experimental data on the I3C and DIM activity and the results of clinical studies indicating their role in prevention of chronic diseases.
... In many studies, I3C has shown prophylactic potential against several conditions owing to its condensation reaction. Wong et al. (1997) evaluated I3C's ability to prevent breast cancer in a double-blind, dose-ranging, placebo-controlled trial. The study included 60 women between the ages of 22 and 74 years, who received I3C capsules daily for approximately 30 days. ...
Article
Indole-3-carbinol (I3C) is a plant-derived phytochemical produced when raw cruciferous vegetables are chopped, and their plant cells are damaged. I3C is an orally bioactive compound formed upon the hydrolysis of glucosi-nolate by the plant enzyme myrosinase. Cruciferous vegetables belong to the Brassicaceae family and include many genera and species with potential biomedical applications. I3C is more abundant in certain cruciferous vegetables, such as broccoli, cabbage, green peas, cauliflower, and brussels sprouts, and has multiple biological activities, including antimicrobial, antioxidant, antiviral, anti-inflammatory, and anti-cancer activities. Most recent studies indicate that regular consumption of I3C-containing vegetables decreases the rate of various types of cancer. This review focuses on the general biomedical applications of I3C and its role in human wellness.
... Indole-3-carbinol (I3C) is the second product of hydrolysis glucobrassicin (3-indolylmethl glucosinolate), which is found in cruciferous vegetables such as broccoli, cabbages, brussels sprouts, collard greens, kale, cauliflower, kohlrabi, mustard greens, radishes, rutabaga and turnips [1,2]. Epidemiological and clinical studies suggest that indole-3-carbinol is a potential agent in blocking tumour initiation, oestrogen metabolism, inhibition of cell proliferation and induction of apoptosis [3,4,5,6,7]. So far, many studies have shown indole-3-carbinol is a bioactive component that plays an important anti-cancer role against breast [8], liver [9], prostate [10], lung and colon cancers [11,12]. ...
Article
Full-text available
Indole-3-carbinol is a potential anti-cancer agent, and it has been found rich in Brassica vegetables. However, there was few good extraction method of indole-3-carbinol in cabbage and broccoli. In this work, the wavelength and the ration of mobile phase in determination method, as well as different temperature and pH values in extraction method were all investigated some cultivars of cabbage and broccoli were collected and validated the determination method. A sensitive and rapid high-performance liquid chromatography method has been established and used for the determination of indole-3-carbinol in cabbage (Brassica oleracea L. var. capitata) and broccoli (Brassica oleracea L. var. italica). The method was proved to be sensitive, selective, rapid and reproducible, with a good recovery of 99.25%. There was a fast retention time (4.88 min) and good linearity (R 2 =0.9991) in the system. Meanwhile, significant differences of indole-3-carbinol contents were detected among all the materials (P<0.05). Finally a simple extracting method of indole-3-carbinol was established, at the same time, the determination method was shown accurate, reliable and stable. So the determination method could be proposed application in medical and industrial area.
Article
Full-text available
Cruciferous vegetables, such as cabbage, cauliflower, and broccoli, have been cultivated since antiquity as medicinal plants. Once ingested, the Cruciferae release unique phytochemical constituents able to modify the activity of cellular enzymes effecting carcinogen clearance and estrogen metabolism. The most active of these phytochemicals with regard to estrogen is the dietary indole, diindolylmethane. Understanding the dietary influences of cruciferous phytochemicals on estrogen status provides a basis for nutritional approaches to estrogen-related concerns that accompany aging in women and men.
Article
Cruciferous vegetables contain glucosinolates, minor substances that have anti-carcinogenic and detoxifying effects, increasing the adaptive capacity of the body. In case of insufficient consumption of cruciferous with food, some glucosonolates or their derivatives, such as inol‑3-carbinol, can be additionally introduced into the diet. The article discusses the mechanisms of action and the role of indole‑3-carbinol in supporting the reproductive system and adaptive reserves of the body.
Article
The overall objective of our research proposal is nonparametric inference of the joint survival function S(x1, ..., xd) =Pr(X1 > x1, ..., Xd > xd) of d (>= 2) correlated time-to-event variables X1, ..., Xd, each of which is subject to interval censoring. The standard estimator of S is the generalized maximum likelihood estimator (GMLE) S. However, S cannot be expressed in a closed-form expression and its statistical properties have not been studied in the multivariate case. The technical objectives of this pioneer methodological research proposal are to develop asymptotic generalized maximal likelihood (GML) inference of S and to derive efficient computational algorithms for the GML procedure. In our fourth and final year of research, we have implemented a computer software for asymptotic inference of GMLE p of the correlation coefficient p between a pair of the X' variables. When the censoring distribution is continuous, we have numerically established p is not asymptotically normal and we have implemented a bootstrap method for obtaining interval estimator of p. Thus in our four years of research, we have successfully completed the tasks we proposed. The results will be useful to breast cancer researchers pursuing chemoprevention intervention trials involving multiple surrogate endpoint biomarkers, and genetic epidemiologists conducting studies on familial aggregation of breast cancer and related cancers.
Article
Introduction. Amidst a steady increase in hyperplastic processes in uterus and mammary glands, numerous studies have shown that women with dyshormonal pathology of mammary glands had a range of gynecological diseases: external or internal endometriosis, hyperplastic processes of the endometrium and myometrium, polyps, polycystic ovary syndrome (PCOS), etc. Objective. To assess the mammary gland condition in premenopausal women with endometrial hyperplasia during indole-3-car-binol (I3C) therapy. Materials and methods. A total of 42 premenopausal patients aged 45-52 years (48.54 ± 1.83) were enrolled in an open-label prospective study. All patients received I3C 400 mg a day for 12 months. The examination included clinical laboratory, ultrasound imaging and mammographic examination of the mammary glands, cytologic examination of a nipple discharge. The examinations were carried out at the baseline, 6 and 12 months after starting treatment. The study findings were evaluated using descriptive statistics. Differences were considered significant at p <0.05. Results and discussion . All patients were diagnosed as having mastalgia before starting treatment. Mammary gland ultrasound imaging showed that the frequency of BI-RADS 2 was 9.5 times higher than that of BI-RADS 1 (90.5% and 9.5%, respectively, p <0.05). Mammography revealed that the frequency of BI-RADS 2 was 9.26 times higher than that of BI-RADS 1 (88% and 9.5%, respectively, p <0.05). After 6-month therapy, 59.5% of patients reported the disappearance of pain syndrome, the number of patients with ONE1/16a-ONE1 deviations decreased by 22%, 7.1% of patients showed improvement of ultrasound picture in BI-RADS. After 12-month therapy, the number of patients with ONE1 / 16a-ONE1 deviations decreased by 92.86% compared with the figures before starting treatment, ultrasound imaging showed improvement in the BI-RADS picture in 19% of patients, mammography findings - in 28.5% of patients. I3C is an effective and safe method to treat benign breast diseases in premenopausal women. Conclusion . Indole-3-carbinol therapy can be assessed as the treatment having an influence on the general components of pathogenesis of endometrial hyperplasia and benign hyperplastic processes in mammary glands. It is advisable to consider the use of indole-3-carbinol combined with antioxidant resveratrol in clinical practice.
Research
Full-text available
Green and red cabbage vegetables (Brassica oleracea var.capitata) are called "drug of the poor" due to their health benefits including curing the constipation, stomach ulcers, headache, excess weight, skin disorders, eye disorders, heart diseases, ageing, and Alzheimer's disease. Cabbage is cheap source of nutrient, healthful characteristics and cultivated in large scales in Egypt. The main object of the present investigation is using two types of cabbage to produce some preserved of green and red cabbage products. Also study the effect of storage on the properties of these products include of cooled, frozen, dried and prickled products. Chemical composition such as moisture, protein, carbohydrates, fat, fibers and minerals were measured. Also, indoles, chlorophyll (A& B), carotenoindes and anthocyanin in green and red cabbage and their products were estimated. High level of indoles was recorded in the inner layers of green and red cabbage. The methods used such as cooling, drying and pickling led to raise indoles concentration. Shelf life indicated that, dried were preserved products for consumption during 360 days, while the frozen was 312 days but cooled products recorded from one moth to 3 months of shelf life. Also, noticed that, the shelf life of red cabbage preserved in saline solution were 270 days. The sensory evaluation indicated that the dried products recorded slightly differences between color, taste, odor, texture, and appearance. On the other hand, prickled products recorded the highest value of organoleptic evaluation.
Chapter
Key Points Dietary habits are instrumental in about 40% of cancers in men and 60% in women. Fruit and vegetable consumption is associated with decreased risk of several cancers. Fruits and vegetables contain many non-nutritive as well as nutritive compounds including carotenoids, dithiolthiones, flavonoids, glucosinolates, indoles, isothiocyanates, monoterpenes, phenols, sterols, sulfhydryls, and vitamins including folate, C, and E. Anticarcinogenic actions from dietary components in fruits and vegetables include the induction of detoxification enzymes, blockage of carcinogen formation (such as nitrosamines), shifts in hormone homeostasis, slowing of cell division, induction of apoptosis, depression in angiogenesis, and several others. There are critical interrelationships between diet, environment, and genetics that affect cancer risk. In addition to fruits and vegetables, teas, spices, and herbs consumed in the diet have been associated with reducing cancer risk in cell culture and animal models; epidemiological studies show similar associations, but there are very few intervention studies to date.
Article
1. Recent studies have shown that vegetables of the Brassica species can contribute to the prevention of cancer. The Brassica vegetables include broccoli, bok choy, cabbage, and Brussels sprouts, to name a few. 2. Brassica-derived compounds tend to induce the expression of batteries of genes involved in cytoprotection, repress the expression of genes involved in carcinogenesis, improve access to DNA, and induce apoptosis. 3. Cruciferous vegetables are known to contain bioactive compounds that activate Nrf2, a possible tumor suppressor, in various cellular models. 4. Isothiocyanates have been found to inhibit the activity of oncogenic transcription factors such as activator protein-1 (AP-1) and nuclear factor kappa B (NFκB). AP-1 is a protein dimer consisting of either Jun-related proteins or heterodimers of Jun and Fos-related proteins. In its active state, AP-1 can bind to the TPA-response element (TRE). Once bound to the TRE, AP-1 recruits factors to regulate the transcription of genes involved in proliferation, differentiation, apoptosis, and angiogenesis. 5. Researchers have started to explore the ability of isothiocyanates and indoles to inhibit COX-2 activity and inflammation in general. In particular, sulforaphane (SUL) has been noted to block inflammatory responses in both cultured RAW 264.7 macrophages (via NFκB inhibition) and mouse BV-2 microglial cells. 6. Cruciferous vegetables intake appears to reduce the risk for colorectal, prostate and possibly renal cancers. To date the available evidence is not as strong for lung, breast, and oral cancers.
Article
In our pursuit to develop new potential anticancer leads, we designed a combination of structural units of indole and substituted triazole; and a library of 1-{1-methyl-2-[4-phenyl-5-(propan-2-ylsulfanyl)-4H-1,2,4-triazol-3-yl]-1H-indol-3-yl}methanamine derivatives was synthesized and characterized. Cytotoxic evaluations of these molecules over a panel of three human cancer cell lines were carried out. Few molecules exhibited potent growth inhibitory action against the treated cancer cell lines at lower micro molar concentration. An in vitro assay investigation of these active compounds using recombinant human SIRT1 enzyme showed that one of the compounds (IT-14) inhibited the deacetylation activity of the enzyme. The in vivo study of IT-14 exemplified its promising action by reducing the prostate weight to the body weight ratio in prostate hyperplasia animal models. A remarkable decrease in the disruption of histoarchitecture of the prostate tissues isolated from IT-14 treated animal compared to that of the positive control was observed. The molecular interactions with SIRT1 enzyme were also supported by molecular docking simulations. Hence this compound can act as a lead molecule to treat prostatic hyperplasia.
Article
The present study describes the synthesis, characterization and biological evaluation of N-benzyl indole aldehydes. The biological activities of the newly synthesized compounds were examined by investigating their antioxidant and anti-inflammatory activities. The potential of these compounds as an antioxidant was determined by 2,2-diphenylpicrylhydrazyl, Nitric oxide, Superoxide, peroxide radical scavenging methods. We found that aldehydes 4a, 4b, 4c, and 4e and shows promising in vitro DPPH scavenging antioxidant activity while aldehyde 4b and 4e show good in vitro anti-inflammatory activity.
Article
Epidemiological studies have demonstrated that a significant difference exists in the incidence of cancer among different ethnic groups. This difference is known to be partly attributed to dietary factors. Indole-3-carbinol (I3C) and its in vivo dimeric product 3,3′-diindolylmethane (DIM) are produced from naturally occurring glucosinolates in the family Cruciferae. They have received much attention as dietary components that have an inhibitory affect on cancer. I3C and DIM up-regulate the expression of phase I and phase II enzymes, suggesting an increased role in the detoxification and inhibition of carcinogens. They also inhibit the growth of cancer cells through the modulation of genes that are related to the control of cell proliferation, cell cycle, apoptosis, signal transduction, oncogenesis, transcription regulation and protein phosphorylation. Moreover, I3C and DIM inactivate NF-κB, Akt and MAPK signalling pathways, all of which are believed to be potential targets in cancer prevention and therapy. Collectively, several studies have provided evidence for pre-clinical and clinical activities of I3C and DIM against some cancers. Hence, significant advances have been made to date that show I3C and DIM as promising agents for cancer chemoprevention and/or treatment. This review summarises the well accepted inhibitory effects of I3C and DIM on cancer cells and provides a comprehensive view on their molecular mechanism(s) of cancer chemoprevention.
Article
This article has been withdrawn at the request of the editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal.
Chapter
Estrogens and men - this is a topic which has been neglected for quite some time and it is only relatively recently that discussion of it has intensified remarkably. The discussion has not been restricted to the scientific community. In former times, the role of estrogens in male physiology received little attention since androgens clearly have a dominant role. It is now becoming more and more evident that estrogens are far more important in the male than we had supposed (HABENICHT 1998).
Article
Background: Glucosinolates (GLSs) are dietary plant secondary metabolites occurring in the order Brassicales with potential health effects, in particular as anti-carcinogenic compounds. GLSs are converted into a variety of breakdown products (BPs) upon plant tissue damage and by the gut microbiota. GLS biological activity is related to BPs rather than to GLSs themselves. Methods: we have reviewed the most recent scientific literature on the metabolic fate and the biological effect of GLSs with particular emphasis on the epidemiological evidence for health effect and evidence from clinical trials. An overview of potential molecular mechanisms underlying GLS biological effect is provided. The potential toxic or anti-nutritional effect has also been discussed. Results: Epidemiological and human in vivo evidence point towards a potential anti-cancer effect for sulforaphane, indole-3-carbinol and 3,3-diindolylmethane. A number of new human clinical trials are on-going and will likely shed further light on GLS protective effect towards cancer as well as other diseases. BPs biological effect is the results of a plurality of molecular mechanisms acting simultaneously which include modulation of xenobiotic metabolism, modulation of inflammation, regulation of apoptosis, cell cycle arrest, angiogenesis and metastasis and regulation of epigenetic events. BPs have been extensively investigated for their protective effect towards cancer but in recent years the interest also includes other diseases. Conclusion: It appears that certain BPs may protect against and may even represent a therapeutic strategy against several forms of cancer. Whether this latter effect can be achieved through diet or supplements should be investigated more thoroughly.
Chapter
Many people still do not know or place obliquely the importance of other risk factors which are different from the classic ones (menstrual-reproductive history, family history of cancer). As a consequence, the former ones could appear as inexistent. Despite any kind of purpose of such attitude – a fact that we will not analyze here – we should remark that it has an important weight for the public opinion and also at an individual level, especially if comments proceed from specialists who can be considered as opinion leaders.
Article
Three experimental techniques 1H-14N NQDR, 13C CP/MAS NMR and X-ray and Density Functional Theory (GGA/BLYP with PBC) and Hirshfeld surfaces were applied for the structure-activity oriented studies of two phyto-antioxidants and anticarcinogens: indole-3-carbinol, I3C, and 3,3′-diindolylmethane, DIM, (its bioactive metabolite). One set of 14N NQR frequencies for DIM (2.310, 2.200 and 0.110 MHz at 295 K) and I3C (2.315, 1.985 and 0.330 MHz at 160 K) was recorded. The multiplicity of NQR lines recorded at RT revealed high symmetry (chemical and physical equivalence) of both methyl indazole rings of DIM. Carbonyl 13C CSA tensor components were calculated from the 13C CP/MAS solid state NMR spectrum of I3C recorded under fast and slow spinning. At room temperature the crystal structure of I3C is orthorhombic: space group Pca21, Z = 4, a = 5.78922(16), b = 15.6434(7) and c = 8.4405(2) Å. The I3C molecules are aggregated into ribbons stacked along [0 0 1]. The oxygen atoms are disordered between the two sites of different occupancy factors. It implies that the crystal is built of about 70% trans and 30% gauche conformers, and apart from the weak OH⋯O hydrogen bonds (O⋯O = 3.106 Å) the formation of alternative O′H⋯O bonds (O′⋯O = 2.785 Å) is possible within the 1D ribbons. The adjacent ribbons are further stabilised by O′H⋯O bonds (O′⋯O = 2.951 Å). The analysis of spectra and intermolecular interactions pattern by experimental techniques was supported by solid (periodic) DFT calculations. The knowledge of the topology and competition of the interactions in crystalline state shed some light on the preferred conformations of CH2OH in I3C and steric hindrance of methyl indole rings in DIM. A comparison of the local environment in gas phase and solid permitted drawing some conclusions on the nature of the interactions required for effective processes of recognition and binding of a given anticarcinogen to the protein or nucleic acid.
Article
Full-text available
Glucobrassicin in Brassica vegetables gives rise to indole-3-carbinol, a compound with potent anti-cancer effects in preclinical models. We previously showed that the urinary metabolite 3,3'-diindolylmethane (DIM) could discriminate between volunteers fed high and low doses of Brassica vegetables. However, the quantitative relationship between glucobrassicin exposure and urinary DIM level is unclear. We conducted a clinical trial to examine the hypotheses that a range of glucobrassicin exposure from Brassica vegetables is reflected in urinary DIM, and that this effect plateaus. Forty-five subjects consumed vegetables, a mixture of Brussels sprouts and/or cabbage, at 1 of 7 discrete dose levels of glucobrassicin ranging from 25 to 500 μmol, once daily for two consecutive days. All urine was collected for 24 hours after each vegetable-eating session. Urinary DIM was measured using our published liquid chromatography-electrospray ionization-tandem mass spectrometry-selected reaction monitoring (LC/ESI-MS/MS-SRM) method. Urinary DIM excretion increased predictably with increasing glucobrassicin dose and plateaued between 200 and 300 μmol of glucobrassicin. The association between glucobrassicin dose and urinary DIM was strong and positive (R(2)=0.68). The majority of DIM was excreted in the first 12 hours after vegetable consumption. We conclude that urinary DIM is a reliable biomarker of glucobrassicin exposure and I3C uptake, and that feeding glucobrassicin beyond 200 μmol did not consistently lead to more urinary DIM, suggesting a plateau in potential chemopreventive benefit.
Book
The book is the first one published exclusively on the field of nutritional epidemiology of breast cancer. It summarizes the currently existing knowledge, with an updated and comprehensive international bibliography (1.000 references). The authors also performed a review on the epidemiological studies on nutrition and breast cancer carried out in Uruguay between 1994 and 2011, which allowed exploring and identifying the main risk and protective factors for the disease in this high-risk country. Epidemiologists, Nutritionists, Public Health managers and breast specialists from the prevention to the treatment fields will find in this book a unique source of technical information, which will contribute in expanding their knowledge and view of the disease. © Springer Science+Business Media B.V. 2012. All rights reserved.
Article
Phytoestrogens are highly bioactive compounds that modulate a wide range of signalling pathways. Among these are the aryl hydrocarbon receptor pathway and potential processes that are mediated by an activated aryl hydrocarbon receptor signalling cascade. Isoflavones and indoles have been reported to be dual modulators of the aryl hydrocarbon receptor and the estrogen receptor. The effect of these compounds on the aryl hydrocarbon receptor still requires further investigation, but both in vitro and in vivo studies have demonstrated modulation of this pathway. Implications are difficult to derive because this field requires more research but could include modulation of cell cycle regulation, hormone receptor pathways and reproduction, chemoprevention and cancer, and xenobiotic metabolism. Various studies have presented the aryl hydrocarbon receptor as a modulator of all of these functions, and this could be also caused by isoflavones and indoles as selective aryl hydrocarbon receptor modulators.
Article
Epidemiological studies suggest that broccoli can decrease risk for cancer. Broccoli contains many bioactives, including vitamins C and E, quercetin and kaempferol glycosides and, like other members of the Brassicaceae, several glucosinolates, including glucobrassicin (3-indolylmethyl glucosinolate) and glucoraphanin (4-methylsulphinylbutyl glucosinolate). A key bioactive component responsible for much of this activity may be sulforaphane (1-isothiocyanato-4-methylsulfinylbutane), a hydrolysis product of glucoraphanin. Sulforaphane not only upregulates a number of phase II detoxification enzymes involved in clearance of chemical carcinogens and reactive oxygen species, but has anti-tumorigenic properties, causing cell cycle arrest and apoptosis of cancer cells. The bioequivalency of sulforaphane and whole broccoli have not been fully evaluated, leaving it unclear whether whole broccoli provides a similar effect to purified sulforaphane, or whether the presence of other components in broccoli, such as indole-3-carbinol from glucobrassicin, is an added health benefit. Dietary indole-3-carbinol is known to alter estrogen metabolism, to cause cell cycle arrest and apoptosis of cancer cells and, in animals, to decrease risk for breast cancer. Recent research suggests that both dietary broccoli and the individual components sulforaphane and indole-3-carbinol may offer protection from a far broader array of diseases than cancer, including cardiovascular and neurodegenerative diseases. A common link between these oxidative degenerative diseases and cancer may be aggravation by inflammation. A small body of literature is forming suggesting that both indole-3-carbinol and sulforaphane may protect against inflammation, inhibiting cytokine production. It remains to be seen whether cancer, cardiovascular disease, dementia and other diseases of aging can all benefit from a diet rich in broccoli and other crucifers.
Article
Full-text available
In this report, we describe our findings on the relationship between estradiol 16 alpha-hydroxylation and mammary tumor incidence. A close correlation between the two has been demonstrated with 16-hydroxylation being elevated in strains with a high incidence of tumors, such as RIII and C3H, and low in strains with a low incidence of cancer, such as C57BL. The extent of reaction is highly reproducible and unaffected by age or presence of overt mammary tumors. Studies on the inheritance of estradiol 16 alpha-hydroxylase showed that it is inherited as an autosomal dominant and is not correlated with estradiol 2-hydroxylase or androgen and progestin 16 alpha-hydroxylases. In addition, the reaction was shown to be markedly enhanced by the presence of murine mammary tumor virus and diminished in the absence of the virus. These studies establish a relationship between genetics, hormonal factors, and murine mammary tumor virus, the three key factors in mammary tumorigenesis.
Article
Full-text available
We test the hypothesis that the estrogen metabolite ratio 2-OH-estrone:estriol can be raised via dietary indole-3-carbinol (I3C) and that this higher ratio can be sustained over a 3-month test period. We also explore the possible role of pure fiber on estradiol metabolism. Using a randomized clinical trial with three arms, each containing 20 subjects, arm 1 received 400 mg/day of I3C daily for 3 months, arm 2 received 20 g of alpha-cellulose daily for the same time period as a source of added fiber, and arm 3 received a placebo dose. Blood levels of a variety of biochemical parameters were measured. The urinary 2-OH-estrone:estriol estrogen metabolite ratio was measured monthly at the same time of the menstrual cycle. While no changes were observed in the control and alpha-cellulose-treated arms, a substantial mean increase in the ratio was observed in the I3C-treated arm at month 1; that increase was maintained over the 3-month time period. Three of the 20 subjects in this I3C-treated group differed from the others in that no significant change in the metabolite ratio was observed at any time point. The results suggest that I3C can serve to increase the 2-OH-estrone:estriol metabolite ratio in a sustained manner without detectable side effects and that some individuals may be resistant to such change.
Article
A collaborative program is exploring potential endocrine biomarkers of breast cancer risk and the effects of omega-3 fatty acids and levothyroxine on these biomarkers.
Article
Indole-3-carbinol, 3,3'-diindolylmethane, and indole-3-acetonitrile, three indoles occurring in edible cruciferous vegetables, have been studied for their effects on 7,12-dimethylbenz(a)anthracene-induced mammary tumor formation in female Sprague-Dawley rats and on benzo(a)pyrene-induced neoplasia of the forestomach in female ICR/Ha mice. When given by p.o. intubation 20 hr prior to 7,12-dimethylbenz(a)anthracene administration, indole-3-carbinol and 3,3'-diindolylmethane had an inhibitory effect on mammary tumor formation, but indole-3-acetonitrile was inactive. Indole-3-carbinol when added to the diet for 8 days prior to challenge with 7,12-dimethylbenz(a)anthracene inhibited mammary tumor formation, whereas indole-3-acetonitrile did not. Dietary administration of all three indoles inhibited benzo(a)pyrene-induced neoplasia of the forestomach in ICR/Ha mice. The identification of dietary constituents that can inhibit chemical carcinogens ultimately may be of value in understanding the balance of factors that determines the neoplastic response to these cancer-producing agents in the environment.
Article
Estrogens are potent mammary tumor promoters influencing post-initiation events via epigenetic mechanisms. The upregulation (i.e., induction) of the C16 alpha-hydroxylation pathway during 17 beta-estradiol (E2) biotransformation has been associated with mammary cell transformation. The action of E2 metabolites on tumorigenic transformation, however, is poorly understood. The newly established mammary epithelial cell line C57/MG, derived from the C57BL mouse strain, was used to examine whether E2 or its metabolites, 16-hydroxyestrone (16 alpha-OHE1) and estriol (E3), function as initiators of mammary cell transformation. DNA repair (hydroxyurea-insensitive thymidine uptake), estrogen metabolism (3H exchange to form 3H2O), hyperproliferation (increased cell number), and acquisition of anchorage-independent growth (soft-agar colonies) were used as quantitative end points to measure the relative extent of transformation. Treatment of cells with 200 ng/mL 16 alpha-OHE1 resulted in a 55.2% increase in DNA repair synthesis, a 23.09% increase in proliferative activity, and a 18-fold increase in the number of soft-agar colonies, relative to the solvent controls (P less than .0001). The extent of upregulation of the three end points was similar to that induced by the genotoxic mammary carcinogen 7, 12-dimethylbenz[a]anthracene (DMBA, positive control). DMBA treatment also upregulated the ratio of 16 alpha/C2 hydroxylation of E2 leading to increased formation of 16 alpha-OHE1. E2 and E3 were not effective in upregulating these markers for transformation. These results demonstrate that in nontransformed C57/MG cells, 16 alpha-OHE1 may function as an initiator, perturbing the intermediate biomarkers for preneoplastic transformation.
Article
Indole-3-carbinol (I3C) is a potent inducer of cytochrome P450 enzymes in many species, including humans. We therefore studied alterations in the cytochrome P450-dependent metabolism of estradiol in different strains of mice consuming I3C in semisynthetic powdered diets at doses ranging from 250 to 5000 p.p.m. (34-700 mg/kg/day) for different periods of time. In short-term metabolic studies (3 weeks), wet liver weight increased in SW and C3H/OuJ mice in a dose-responsive manner. Dietary I3C increased the cytochrome P450 content measured in hepatic microsomes, as well as the extent of estradiol 2-hydroxylation, up to 5-fold. In a long-term feeding experiment (8 months), female C3H/OuJ mice consumed synthetic diets containing I3C at 0, 500 or 2000 p.p.m. Mammary tumor incidence and multiplicity were significantly lower at both doses of I3C, and tumor latency was prolonged in the high-dose group. We conclude that I3C is an inducer of hepatic P450-dependent estrogen metabolism in mice, and that it is chemopreventive in the C3H/OuJ mouse mammary tumor model. This protective effect may be mediated in part by the increased 2-hydroxylation and consequent inactivation of endogenous estrogens.
Article
Dietary indoles in cruciferous vegetables induce cytochrome P450 enzymes and have prevented tumors in various animal models. Because estradiol metabolism is also cytochrome P450 mediated and linked to breast cancer risk, indoles may similarly reduce estrogen-responsive tumors in humans. We examined several indoles in female Sprague-Dawley rats for induction of hepatic estradiol 2-hydroxylation. The most potent inducer, indole-3-carbinol, was administered to humans (500 mg daily for 1 wk). It significantly increased the extent (mean +/- SEM) of estradiol 2-hydroxylation from 29.3% +/- 2.1% to 45.6% +/- 2.1% (P less than .001). These results indicate that indole-3-carbinol strongly influences estradiol metabolism in humans and may provide a new chemopreventive approach to estrogen-dependent diseases.
Article
Indole-3-carbinol, a component of cruciferous vegetables, was evaluated for it efficacy in the prevention of chemically-induced mammary tumors using three different protocols. Because this compound was unstable, it was administered by gavage rather than in the diet. A preliminary dose range study revealed that dose levels of 100 and 50 mg/day, 5x/week, were not toxic to female Sprague-Dawley rats. Initial studies in the DMBA model showed that administering indole-3-carbinol during the initiation and promotion phases were highly effective chemopreventive methods (91-96% reduction in cancer multiplicity). Subsequent studies showed that the administration of indole-3-carbinol only during the initiation phase (7 days prior to until 7 days post DMBA) was also highly effective as a chemopreventive agent. Determination of enzyme levels in the livers of animals treated long-term with indole-3-carbinol showed high levels of induction of various phase I and phase II drug metabolizing enzymes. Finally, indole-3-carbinol when administered both prior to and after MNU (a direct acting carcinogen) caused a significant decrease (65%) in mammary tumor multiplicity. These results support previous studies that indole-3-carbinol can prevent mammary carcinogenesis by direct and indirect acting carcinogens. Therefore, indole-3-carbinol might be a good candidate for chemoprevention of breast cancer in women.
Article
In mammals, estradiol (E2) metabolism primarily involves mutually exclusive hydroxylation at either C-2 or C-16 alpha. We have previously reported a consistent increase in the C-16 alpha hydroxylation activity in human breast cancer and in mouse strains with high levels of mammary tumors. Here we show that the dietary compound indole-3-carbinol (I3C) increases C-2 hydroxylation five-fold in MCF-7 cells in culture but has minimal effect on the reaction at C-16 alpha. Because I3C-induced changes in E2 metabolism result in a metabolite ratio inverse to that observed in women with breast cancer we have separately examined whether this shift conferred an anti-tumorigenic advantage to estrogen target cells. The preferential changes induced by I3C on estradiol metabolism in MCF-7 cells parallel its anti-tumorigenicity in mice. These results suggest that changes in the metabolism of estradiol via the C-2 pathway might play a significant role in decreasing risk for breast cancer in women. Indole-2-carbinol is readily available as a chemical and as a dietary component of cruciferous vegetables. Feasible dietary changes show promise of having clinical utility in the prevention of breast cancer and other hormone-dependent cancers.
Article
Indole-3-carbinol (I3C), a compound found in cabbage, broccoli, and brussels sprouts, inhibits the growth of mammary tumors when fed to certain strains of mice. The chemopreventive and antitumor effects of I3C depend on the species and tissue type. The mechanism of action and specific human cell types that respond to I3C are not known. Our purpose was to study the mechanism of action of I3C in estrogen-responsive (MCF-7) and estrogen-nonresponsive (MDA-MB-231) human breast cancer cell lines. Estrogen responsiveness was determined by the ability of estradiol to stimulate the growth of breast cancer cells deprived of estrogen. The effect of I3C was measured on cell growth, estradiol metabolism, and level of cytochrome P-4501A1. Growth was measured by cell counts and soft-agar assay, estrogen metabolism was examined by a radiometric assay, and the level of cytochrome P-4501A1 was measured by Western blots with a polyclonal antibody. I3C inhibits the growth of estrogen-responsive cell line MCF-7 but has little effect on estrogen-nonresponsive cell line MDA-MB-231. Specific C-2 hydroxylation of estrogen and induction of cytochrome P-4501A1 was enhanced by I3C in the MCF-7 but not in the MDA-MB-231 cells. I3C has specific antigrowth effects in human breast cancer cells. The inhibitory effects of I3C may involve selective induction of estradiol metabolism and the related cytochrome P-450 system that may be limited to estrogen-sensitive cells.
Article
The polycyclic aromatic hydrocarbon 7,12-dimethylbenz(a)anthracene (DMBA) is a metabolism-dependent procarcinogen whose tumorigenicity is modified by dietary and endocrine manipulations in vivo. DMBA initiates molecular and cellular alterations in the mammary tissue, while dietary components and estrogens affect the post-initiational phase of tumorigenic transformation. The mechanism(s) responsible for modulation of tumorigenic transformation remain unclear. This study examines the effects of selected tumor suppressing agents and estradiol (E2) metabolites on in vitro DMBA carcinogenesis utilizing a newly established mouse mammary epithelial cell line C57/MG. Alteration in DNA repair synthesis, metabolism of E2 via the C2- and C16 alpha-hydroxylation pathways, and acquisition of anchorage-independent growth were utilized as molecular, endocrine, and cellular biomarkers to quantitate the cellular transformation by DMBA and its modulation by tumor suppressing agents and E2 metabolites. A single 24 hr exposure of 0.78 microM DMBA to C57/MG cells resulted in a 193.9% increase in DNA repair synthesis and a 73.1% decrease in C2/C16 alpha hydroxylation of E2. The DMBA treated C57/MG cells also exhibited increased anchorage-independence in vitro prior to tumorigenesis in vivo. A simultaneous treatment of cells with DMBA and with the highest noncytotoxic doses of the tumor suppressing agents 5 microM N-(4-hydroxyphenyl) retinamide (HPR), 50 microM indole-3-carbinol (I3C), or 1 microM tamoxifen (TAM) resulted in a 35.6% to 63.9% decrease in DNA repair synthesis, a 23.8% to 1347.6% increase in C2/C16 alpha hydroxylation of E2, and a 53.8% to 72.4% decrease in anchorage-independent growth. The E2 metabolites at the highest non-cytotoxic doses of 0.76 microM estrone (E1), 0.69 microM 2-hydroxyestrone (2-OHE1), and 0.66 microM 2-methoxyestrone (2-MeOHE1) suppressed DMBA-induced DNA repair synthesis by 56.0% to 68.8%. These tumor suppressing agents and E2 metabolites also effectively suppressed post-initiational, anchorage-independent growth by 24.9% to 72.4%. These results indicate that DMBA induces cellular transformation in part by causing DNA damage, altering C2/C16 alpha hydroxylation in favor of C16 alpha-hydroxylation, and inducing anchorage-independent growth prior to tumor development. Effective downregulation of these genotoxic, endocrine and proliferative end points by prototypic tumor suppressing agents and by E2 metabolites generated via the C2-hydroxylation pathway suggest that these agents may influence mammary tumorigenesis by inhibiting early occurring initiational and/or post initiational events.
Article
Work from Strang and other laboratories has established that the 2-/16 alpha-hydroxyestrone ratio is inversely correlated with the risk for breast and cervical cancer. In order to measure these metabolites in urine samples, it is essential to have an assay for these compounds that is both sensitive and reproducible. The present paper describes such an ELISA assay, which overcomes problems that existed in prior approaches to measuring these compounds. The new ELISA procedure supplies greater sensitivity and reproducibility than earlier assay procedures. The ELISA assay has also been found to correlate well with the GC-MS procedure of Adlercreutz.
Cyp1A1 genotype, estradiol metabolism and breast cancer in African-Americans
  • E Taioli
  • Bradlow Hl
  • Sv
  • Sepkovic Dw
  • Mp
  • J Trachman
  • S Ganguly
  • Garte
  • Sj
Taioli E, Bradlow HL, Garbers SV, Sepkovic DW, Os-borne MP, Trachman J, Ganguly S, Garte SJ (1998): Cyp1A1 genotype, estradiol metabolism and breast cancer in African-Americans. Cancer Prev Detect (in press).