Research Indole-3-carbinol: A glucosinolate derivative from cruciferous vegetables for prevention and complementary treatment of breast cancer Ben L. Pfeifer1, Theodor Fahrendorf2 Summary spect seem to be secondary plant sub- stances from cruciferous vegetables, Breast cancer is the most common malignancy in women today. Despite such as indole 3-carbinol (I3C). This is a improved therapies, only every second woman with breast cancer can ex- glucosinolate derivative containing sul- pect cure. If cancer is metastatic at diagnosis, or recurs with metastases, phur whose metabolic products are then treatment is limited to palliative measures only, and cure is usually not widely known for their anti-cancer expected. Under these circumstances, quality of life as well as overall surviv- effects [34-36, 44, 46]. Detailed studies al of the patient is significantly reduced. It is therefore advisable for pa- have been carried out regarding their tients, their physicians, and the entire society at large, to search for more preventive and therapeutic effectiveness effective and less toxic treatment methods and develop better prevention in treating breast cancer and other types strategies that can reduce the burden of this cancer on the individual pa- tient and society as a whole. Indole-3-carbinol, a glucosinolate derivative of cancer [7, 12, 18, 30, 62, 79]. Labora- from cruciferous vegetables, seems to be a strong candidate to achieve tory tests on cell cultures and animal ex- these goals. It is abundantly available, well tolerated and non-toxic. Suffi- periments showed that I3C prevents the cient amounts for prevention of breast cancer can be taken up by daily con- development of cancer in various organs sumption of cruciferous vegetables. Higher, therapeutic concentrations can in rodents, slows down the growth of ex- be achieved with certain food supplements or functional foods. Indole-3- isting tumours and reduces metastases carbinol is known to have cancer preventive properties, reduces develop- [13, 14, 45, 66, 74, 82]. Besides, several ment and propagation of metastases, and enhances the therapeutic effects partially synergistic mechanisms of action of various standard chemotherapy as well as other drugs used in conven- have been suggested based on experi- tional treatment regimens. ments of I3C and its derivatives in cancer prevention and therapy. These include: Key words: Breast cancer, prevention, complementary therapy, glucosin- inactivation of carcinogenic substances, protection against DNA damage, antiviral and antibacterial effects, anti- phonate treatment of bone infection as Introduction inflammatory effects, apoptosis induc- well as antibody therapies for human epi- tion, angiogenesis and cell migration inhi- Apart from cardiovascular diseases, can- dermal growth factor receptor 2 (HER2) bition. However, there is less clarity of cer is the second leading cause of death positive tumours. Over the years, these epidemiological studies regarding the re- in the Western world. Based on data improvements can lead to disease and duction of the risk of breast cancer in hu- from Europe and the United States, symptom control depending on the indi- mans by I3C. For example, a meta- breast cancer is the most common malig- vidual case of the patient. However, the analysis of 8 prospective studies from the nant tumour in women. Today the major- median overall survival of patients with United States, Canada, the Netherlands ity of affected patients can be cured by remote metastatic breast cancer is still and Sweden, could not establish any sig- adherence to modern therapy guidelines significantly low. nificant correlation [73]. Nonetheless, a provided the disease is detected in its Against this background, it is easy to un- recent meta-analysis of 13 epidemiologi- early stages. However, our standard ther- derstand only too well why the health cal studies found a significant reduction apies have proven unsuccessful in almost systems need to put more emphasis on in the risk of breast cancer with in- half of the patients and the tumours have effective prevention, and why doctors creased ingestion of cruciferous vegeta- relapsed. The resultant metastasization and patients are looking for effective ad- bles [53]. Different case and cohort stud- of the tumours limits the treatment strat- ditional therapies, with less toxic side ies also showed that women with higher egy to palliative measures. effects that could lead to improved tu- consumption of cruciferous vegetables This notwithstanding, there have been mour control, survival, longevity as well have a significantly lower risk of suffering significant improvements in recent years as good quality of life. from breast cancer [7, 34, 84]. Moreover, in the standard treatment of cytotoxic the study entitled "Women's Healthy Some of the best candidates in this re- and anti-hormonal therapies, bisphos- Pfeifer BL, Fahrendorf T. Indol-3-Carbinol – ein Glucosinolat-Derivat aus Kreuzblütler-Gemüsen Deutsche Zeitschrift für Onkologie 2015; 47: 20–27 Fig. 1: Glucosinolate structure Fig. 1: Glucobrassicin catabolism to I3C and DIM Eating and Living (WHEL)", in which more olates have a typical basic structure, con- the seeds or young sprouts of the plants. than 3,000 breast cancer patients partici- sisting of a glucose unit, a sulphur group, a During the preparation and consumption pated, offered proof of additional reduc- group of aglucon products and a sulphate of cruciferous vegetables, plant cells are tion in the risk of recurrence when tamoxi- group (fig. 1). Over 150 different glucosin- broken up and the glucosinolates metabo- fen therapy was supplemented by the con- olates have hitherto been identified and lised by myrosinase (ß-thioglucosidase) in- comitant intake of cruciferous vegetables described. These differ only in the aglucon to mustard oil, also referred to as isothio- [78]. products, which can have an alkyl, alkenyl, cyanates. In an acidic environment (e.g. aryl or indolyl structure and are ultimately gastric juice) I3C dimerizes to 3, 3'- It may appear premature, based on this crucial for the physiological effects of the diindolylmethan (DIM), which is the most data, to give credence to I3C in comple- substances in the group. important condensation product and phar- mentary therapy of breast cancer and pre- macologically active substance of I3Cs (fig. vention. This notwithstanding, it is appar- The development of I3C occurs in succes- 2). ent that an increasing number of anxious sive stages. After splitting glucose and concerned patients and their doctors (glycolysis) from the glucosinolate struc- For more than 25 years, I3C/DIM and oth- trust this substance in achieving their goal ture, in the initial stage, an unstable inter- er glucosinolate derivatives have been the of effective prevention, improved tumour mediate form is developed from which sul- focal point of medical research due to control, longer survival and a good quality phur cyanate is separated in the second their varied positive influence on the oc- of life. It is therefore the objective of this stage and thus the indole-ring of I3C is cre- currence of cancer. Indeed, I3C and DIM article to point out and discuss the new ated. This differs from the aliphatic or aro- serve as blueprints for the development of scientific findings regarding I3C. matic isothiocyanates (such as sul- novel cancer therapeutics. They offer the foraphane from broccoli or PEITC from link between orthodox medicine and evi- Chemistry and Biology of I3C cress), due to the discarded cyanate. dence-based naturopathy where mustard plasters or cabbage poultices have been The source of I3C for humans is mainly I3C is produced by the metabolism of glu- applied for generations for inflammatory through the consumption of cabbage cosinolates (glucobrassicin), which occur processes, and also for cancer treatment. plants such as broccoli, Brussels sprouts or mainly in cruciferous plants. All glucosin- kale. Highest levels of I3C can be found in Pfeifer BL, Fahrendorf T. Indol-3-Carbinol – ein Glucosinolat-Derivat aus Kreuzblütler-Gemüsen Deutsche Zeitschrift für Onkologie 2015; 47: 20–27 Principles of I3C action Mode of action Molecular level Synergisms Epigenetic protection Deactivation of oncogenes, activation of tumour HDAC, DNMT COX-2 ▼ suppressors by acetalization Protection from free radicals, Breakdown in conversion of procarcinogenes to GST, BRCA1 ▲ Detoxification, carcinogenes, detoxification systems are activated, DNA repair mechanisms DNA damages are compensated Hormone intake in the cell and transport into the cell ERb ▲ Tamoxifen Inhibition of hormone-dependent nucleus is suppressed, no activation of ERa, AhR ▼ Herceptin tumour growth hormone-dependent genes Inhibition of protein kinase, induction of inhibitors of P21, P38 ▲ Paclitaxel Inhibition of cell division kinases, stopping of regular organisation of tubulin, CDKs ▼ Vinblastin (cell cycle arrest) stopping of cell division Reduced organization of epithelial cells and formation Catenine ▲ Erlotinib Inhibition of Neoangiongenesis, of capillaries, inactivation of growth factors VEGF ▼ Bevacizumab Reducing metastasis Mitochondrial membrane depolarisation, Survivin, Cyclin D1, NF KappaB ▼ Induction of apoptosis cytochome C release, invalidation of cellular Caspase 9 ▼ mechanisms and protection P38, Bax, P21 ▲ Taxotere, Taxol Increase of chemosensitivity Overcoming resistance to therapeutics NF KappaB ▼ Gemcitabin HDAC Histone deacetylases ▲ activated, induced or highly regulated DNMT DNA methyltransferase