Broccoli and Tomato Found to Be More Effective in Inhibiting Prostate Cancer Cells Than Leading Drug for Prostate Cancer

Below is an abstract of a very interesting publication that came out about the combination of broccoli and tomatoes. Scientists believe that the active ingredients that explain these results are: DIM (Diindolylmethane), Sulforaphane, Selenium and Lycopene among other phytochemicals.

Combinations of Tomato and Broccoli Enhance Antitumor Activity in Dunning R3327-H Prostate Adenocarcinomas. Canene-Adams K, Lindshield B, Wang S, Jeffery E, Clinton S, Erdman J., Cancer Res 2007; 67: (2). January 15, 2007

The consumption of diets containing 5 to 10 servings of fruits and vegetables daily is the foundation of public health recommendations for cancer prevention, yet this concept has not been tested in experimental models of prostate cancer. We evaluated combinations of tomato and broccoli in the Dunning R3327-H prostate adenocarcinoma model. Male Copenhagen rats (n=206) were fed diets containing 10% tomato, 10% broccoli, 5% tomato plus 5% broccoli (5:5 combination), 10% tomato plus 10% broccoli (10:10 combination) powders for approximately 22 weeks starting 1 month prior to receiving s.c. tumor implants. We compared the effects of diet to surgical castration (2 weeks before termination) or finasteride (5 mg/kg body weight orally, 6 d/wk). Castration reduced prostate weights, tumor areas, and tumor weight (62%, P<0.001), whereas finasteride reduced prostate weights (P<0.0001), but had no effect on tumor area or weight. Tomato reduced tumor weight by 34% (P<0.05). Broccoli decreased tumor weights by 42% (P<0.01) whereas the 10:10 combination caused a 52% decrease (P<0.001). Tumor growth reductions were associated with reduced proliferation and increased apoptosis, as quantified by proliferating cell nuclear antigen immunohistochemistry and the ApopTag assay. The combination of tomato and broccoli was more effective at slowing tumor growth than either tomato or broccoli alone and supports the public health recommendations to increase the intake of a variety of plant components.

DIM Acts Synergistically With the Most Widely Used Cancer Drug Paclitaxel (Taxol)

Scientists have recently discovered that DIM synergizes with the most widely used cancer drug-Taxol.

Here is an overview of the abstract published on Medline:

3,3′-Diindolylmethane and Paclitaxel Act Synergistically to Promote Apoptosis in HER2/Neu Human Breast Cancer Cells. Journal of Surgical Research, 2006 May 15;132(2):208-13. K. McGuire, N. Ngoubilly, M. Neavyn, S. Lanza-Jacoby Department of Surgery, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107.

HER2/neu positive breast tumors are difficult to treat. About 25 to 30% of invasive breast tumors overexpress the HER2/neu oncogene. These tumors are aggressive and become resistant to chemotherapeutic drugs. 3'3'-diindolylmethane (DIM), the active metabolite of indole-3-carbinol, a naturally occurring compound found in cruciferous vegetables, has been found to have anti-cancer properties in both humans and animals. DIM has been shown to induce cell cycle arrest and apoptosis in animal breast cancer models. Because HER2/neu overexpression confers resistance to paclitaxel, and DIM has anti-tumor effects, we hypothesized that DIM will enhance the cytotoxic effects of paclitaxel, a common taxane drug, on human Her2/neu breast cancer cells by potentiating its effect on cell cycle and stimulating apoptosis. METHODS: The MDA-MB-435eB1 human Her2/neu breast cancer cells were treated with varying concentrations of DIM and paclitaxel. The cells were analyzed at different time points (24, 48, and 72 h). Proliferation was measured by a commercial cell proliferation assay (Promega Procheck Assay). Cell-cycle analysis and apoptosis were determined by flow cytometry. Western blot analysis was performed on to determine the effect of DIM and/or paclitaxel on the proteins involved in apoptosis, and epidermal growth factor-induced activation of HER2/neu and ERK1/2 signaling proteins. RESULTS: Both DIM and paclitaxel exhibited time and concentration dependent inhibition of cell proliferation. TUNEL assay indicated that the combination also increased the number of apoptotic cells more than either agent alone. The presence of cleaved poly (ADP-Ribose) polymerase (PARP) significantly increased in the combination treatment, whereas Bcl-2 is decreased. DIM alone decreased the activation of the Her2/neu receptor; the combination decreased the activation of ERK1/ERK2.

CONCLUSIONS: DIM in combination with paclitaxel synergistically inhibits growth of Her2/neu human breast cancer cells through G2M phase cell-cycle arrest and induction of apoptosis/necrosis. The Her2/neu receptor and its downstream signaling protein ERK1/2 appear to be involved in DIM's affect on cell growth and differentiation, whereas apoptosis appears to be mediated through the mitochondrial pathway (Bcl-2/PARP). It appears DIM, a naturally occurring, nontoxic compound, may be a beneficial addition to a traditional (taxane-based) chemotherapy regimen.

DIM Clinical Applications and Research

DIM is currently used to treat Recurring Respiratory Papillomatosis caused by the Human Papilloma Virus and is in Phase III clinical trials for Cervical Dysplasia at 2mg/kg of body weight. Cervical Dysplasia is a precancerous condition also caused by the Human Papilloma Virus. Until recently, DIM's biological mode of action for these conditions was not clearly understood, until scientists discovered that DIM is a potent modulator of the innate immune response system, which then placed DIM's anti-viral activity against the Human Papilloma Virus in perspective.

As a result of this discovery, DIM is currently sold as an immune enhancing supplement (www.ActivaMune.com) and it is under investigation as a therapeutic for viral and bacterial infections (including HIV, HPV, Hepatitis, Influenza, the Pandemic Flu and antibiotic resistant bacteria), immune deficiency conditions and multiple forms of cancer. DIM's primary immune modulatory mode of action is the stimulation of Interferon-Gamma receptor transcription as well as the production of Interferon-Gamma. DIM has also been shown to synergize with Interferon-Gamma in the potentiation of the MHC-I Complex.

Its multitude of favorable biological activities such as immune modulation, apoptosis and suppression of inflammation (NFkB) are among the reasons why the National Cancer Institute has begun clinical studies of DIM for multiple forms of cancer.

Another significant discovery that has recently been made about DIM that has fueled international interest in this unique phytochemical is its synergy with the number one cancer drug worldwide (Taxol) in the promotion of apoptosis. This discovery has paved the way for the investigation of DIM as an adjuvant therapeutic to Taxol to reduce patient resistance to this important drug. (Taxol is another plant-derived chemical that was discovered in and extracted from the Pacific Yew Tree.)

UC Berkeley faculty members Dr. Leonard Bjeldanes, Professor and former Chairman of the Nutritional Sciences and Toxicology Department, and Dr. Gary Firestone, Director of the NIH Cancer Biology Program and Professor of the Molecular and Cell Biology Department, have focused on DIM research at Berkeley for over two decades and have elucidated many of its principal molecular mechanisms of action.

In addition to elucidating DIM's molecular mechanisms of action, Dr. Bjeldanes and Dr. Firestone conducted a human clinical trial of DIM and demonstrated that it increases the 2-hydroxylation of estrogen metabolites, a study that received a lot of media attention as oncologists believe that this activity helps to reduce the risk of breast and prostate cancer. Abstracts of two papers on this subject are provided below.

Pilot study: effect of 3,3'diindolylmethane supplements on urinary hormone metabolites in postmenopausal women with a history of early-stage breast cancer. Journal of Nutrition and Cancer. 2004;50(2):161-7. Dalessandri KM, Firestone GL, Fitch MD, Bradlow HL, Bjeldanes LF Department of Molecular and Cell Biology, University of California, Berkeley, 94720-3200, USA.

Dietary indoles, present in Brassica plants such as cabbage, broccoli, and Brussels sprouts, have been shown to provide potential protection against hormone-dependent cancers. 3,3'-Diindolylmethane (DIM) is under study as one of the main protective indole metabolites. Postmenopausal women aged 50-70 yr from Marin County, California, with a history of early-stage breast cancer, were screened for interest and eligibility in this pilot study on the effect of DIM supplements on urinary hormone metabolites. The treatment group received daily DIM (108 mg DIM/day) supplements for 30 days, and the control group received a placebo capsule daily for 30 days. Urinary metabolite analysis included 2-hydroxyestrone (2-OHE1), 16-alpha hydroxyestrone (16alpha-OHE1), DIM, estrone (El), estradiol(E2), estriol (E3), 6beta-hydroxycortisol (6beta-OHC), and cortisol in the first morning urine sample before intervention and 31 days after intervention. Nineteen women completed the study,for a total of 10 in the treatment group and 9 in the placebo group. DIM-treated subjects, relative to placebo, showed a significant increase in levels of 2-OHE1 (P=0. 020), DIM (P =0. 045), and cortisol (P = 0.039), and an increase of 47% in the 2-OHE1/16alpha-OHE1 ratio from 1.46 to 2.14 (P=0.059). In this pilot study, DIM increased the 2-hydroxylation of estrogen urinary metabolites.

Estrogen metabolism and risk of breast cancer: a prospective study of the 2:16alpha-hydroxyestrone ratio in premenopausal and postmenopausal women. Epidemiology. 2000 Nov;11(6):635-40. Muti P, Bradlow HL, Micheli A, Krogh V, Freudenheim JL, Schunemann HJ, Stanulla M, Yang J, Sepkovic DW, Trevisan M, Berrino F. Department of Social and Preventive Medicine, University at Buffalo, State University of New York at Buffalo, Buffalo, NY, USA, Epidemiology Division of the National Cancer Intitute (Istituto Nazionale Tumori), Milan, Italy, Department of Pediatric Hematology and Oncology, Medical School of Hannover, Hannover, Germany.

Experimental and clinical evidence suggests that 16alpha-hydroxylated estrogen metabolites, biologically strong estrogens, are associated with breast cancer risk, while 2-hydroxylated metabolites, with lower estrogenic activity, are weakly related to this disease. This study analyzes the association of breast cancer risk with estrogen metabolism, expressed as the ratio of 2-hydroxyestrone to 16alpha-hydroxyestrone, in a prospective nested case-control study. Between 1987 and 1992, 10,786 women (ages 35-69 years) were recruited to a prospective study on breast cancer in Italy, the "Hormones and Diet in the Etiology of Breast Cancer" (ORDET) study. Women with a history of cancer and women on hormone therapy were excluded at baseline. At recruitment, overnight urine was collected from all participants and stored at -80 degrees C. After an average of 5.5 years of follow-up, 144 breast cancer cases and four matched controls for each case were identified among the participants of the cohort. Among premenopausal women, a higher ratio of 2-hydroxyestrone to 16alpha-hydroxyestrone at baseline was associated with a reduced risk of breast cancer: women in the highest quintile of the ratio had an adjusted odds ratio (OR) for breast cancer of 0.58 [95% confidence interval (CI) = 0.25-1.34]. The corresponding adjusted OR in postmenopausal women was 1.29 (95% CI = 0.53-3.10). Results of this prospective study support the hypothesis that the estrogen metabolism pathway favoring 2-hydroxylation over 16alpha-hydroxylation is associated with a reduced risk of invasive breast cancer risk in premenopausal women.

References:

http://www.diindolylmethane.org/

http://www.activamune.com/

Formation of Diindolylmethane from I3C

Indole-3-carbinol is the immediate molecular precursor of Diindolylmethane (DIM). Upon consumption of Brassica vegetables, the enzyme myrosinase is released from the plants, which cleaves glucobrassicin to release I3C.

I3C has been shown to degrade fairly readily in aqueous systems to a reactive indolinium ion intermediate. In the environment of the stomach, the indolinium ion reacts with I3C or other indolinium ions to form oligomers such as DIM and Ctr. In cellular environments, the indolinium ion binds non-specifically with free thiols on proteins and glutathione.

Due to I3C's high degree of reactivity and instability within the body, DIM is more recommended as a dietary supplement than I3C as all of I3C's derivatives and their variety of biological activities have not been fully explored. DIM, on the other hand, is more stable and less reactive as a compound, with extensive human clinical studies on its use as a supplement.

Breakthrough Discovery in Nutritional Immunology

Dear colleagues:

I wanted to bring an important discovery in nutritional immunology to your attention. Scientists at UC Berkeley have identified a compound in broccoli that significantly boosts the immune system and as such has potent anti-cancer and anti-viral properties. The compound is Diindolylmethane (DIM).

Diindolylmethane (DIM) boosts the immune system by increasing the sensitivity of cells in the body to the Interferon-gamma protein. Interferon-gamma is the key cytokine in the body responsible for the entire immune response system. It is responsible for mobilizing the body's ability and agility to respond to infections and cancer. DIM has also been shown to increase T-Cell counts, a rare and very interesting activity from a dietary compound, interestingly enough, the exact opposite mode of action as the activity of the HIV virus.

DIM is currently being used to treat RRP tumors caused by the Human Papilloma Virus and is in Phase III clinical trials for Cervical Dysplasia, a precancerous condition also caused by the Human Papilloma Virus. Until recently it was not clearly understood why DIM was so effective in treating these conditions until this groundbreaking discovery at UC Berkeley revealed its potent immune modulating resulting in potent anti-cancer and anti-viral properties.

As a result of this important discovery, DIM, which is currently available as a supplement, is under investigation as a treatment for most viral infections known to man (including HIV, HPV, Influenza, and Hepatitis) and most forms of cancer (breast, prostate, lung, cervical, colorectal).

More information about this discovery may be found by visiting the ActivaMune website.

These other websites also have information about Diindolylmethane (DIM):

Diindolylmethane (DIM) Information Website

Diindolylmethane (DIM) Information Website

Diindolylmethane (DIM) Information Website

Diindolylmethane (DIM) Information Website

Diindolylmethane (DIM) Information Website

Diindolylmethane (DIM) Information Website

Diindolylmethane (DIM) Information Website

Diindolylmethane (DIM) Information Website

Diindolylmethane (DIM) Information Website

Diindolylmethane (DIM) Information Website