Deutsche Zeitschrift für Onkologie 2015; 47(01): 20-27
DOI: 10.1055/s-0034-1395861
Forschung
© Karl F. Haug Verlag in MVS Medizinverlage Stuttgart GmbH & Co. KG

Indol-3-Carbinol – ein Glucosinolat-Derivat aus Kreuzblütler-Gemüsen zur Vorbeugung und komplementär-onkologischen Behandlung von Brustkrebs

Ben L Pfeifer
,
Theodor Fahrendorf
Weitere Informationen

Publikationsverlauf

Publikationsdatum:
09. April 2015 (online)

Zusammenfassung

Brustkrebs ist der häufigste maligne Tumor der Frau. Trotz verbesserter Therapien kann heute nur etwa die Hälfte der Betroffenen mit Heilung rechnen. Wenn der Tumor mit Metastasen zurückkommt, bleiben nur noch palliative Maßnahmen. Lebensqualität und Überlebenszeit der Patientinnen sind dann in der Regel stark reduziert. Vor diesem Hintergrund lohnt es sich für Betroffene und Ärzte sowie die Gesellschaft als Ganzes, nach besseren und weniger toxischen Behandlungswegen zu suchen sowie eine effektive Strategie zur Vorbeugung der Brustkrebserkrankung aufzubauen. Ein guter Kandidat für ein solches Vorhaben scheint Indol-3-Carbinol, ein Glucosinolat-Derivat der Kreuzblütler-Gemüse, zu sein. Es steht durch sein üppiges Vorkommen in den beliebten Gemüsesorten der breiten Masse recht einfach zur Verfügung, es ist gut verträglich und auch in höheren Dosen unschädlich. Es kann in therapeutisch ausreichender Menge durch täglichen Gemüseverzehr oder in angereicherter Form als „Functional Food“ oder als „Food Supplement“ zugeführt werden. Es hat eine krebsverhütende Wirkung, vermindert die Metastasenbildung und verstärkt die Wirksamkeit verschiedener chemotherapeutischer Standardtherapien.

Summary

Breast cancer is the most common malignancy in women today. Despite improved therapies, only every second woman with breast cancer can expect cure. If cancer is metastatic at diagnosis, or returns with metastases, then only palliative treatment remains, and cure is usually not expected any longer. Under these circumstances, quality of life as well as overall survival of those patients is significantly reduced. With this in mind, it seems advisable for patients, their physicians, and the entire society alike, to search for more effective and less toxic treatment methods and develop a better prevention strategy that can reduce the burden of this cancer on the individual patient and society as a whole. Indol-3-carbinol, a glucosinolate derivative from cruciferous vegetables, seems to be a strong candidate to achieve these goals. It is abundantly available, well tolerated and not toxic. Sufficient amounts for prevention of breast cancer can be taken up by daily consumption of cruciferous vegetables. Higher, therapeutic concentrations can be achieved with certain food supplements or functional foods. Indole-3-carbinol is known to have cancer preventive properties, it reduces development and propagation of metastases, and it enhances the therapeutic effects of various standard chemotherapy- and other drugs used in conventional treatment regimens.

 
  • Literatur

  • 1 Aggarwal BB, Ichikawa H. Molecular targets and antic- cancer potential of indole-3-carbinol and its derivatives. Cell Cycle 2005; 4: 1201-15
  • 2 Ahmad A, Sakr WA, Rahman KM. Anticancer properties of indole compounds: Mechanism of apoptosis induction and role in chemotherapy. Curr Drug Targets 2010; 11: 652-66
  • 3 Ahmad A, Ali S, Ahmed A et al. 3,3‛-diindolylmethane Enhances the Effectiveness of Herceptin against HER-2/Neu-Expressing Breast Cancer Cells. PLoS ONE 2013; 8: e54657.
  • 4 Ahmad A, Ali S, Wang Z et al. 3,3’-diindolylmethane enhances taxotere-induced growth inhibition of breast cancer cells through down-regulation of FoxM1. Int J Cancer 2011; 129: 1781-91
  • 5 Albini AD, Noonan M, Ferrari N. Molecular pathways for cancer angioprevention. Clin Cancer Res 2007; 13(15): 4320-5
  • 6 Ali S, Banerjee S, Ahmad A, El-Rayes BF et al. Apoptosis-inducing effect of erlotinib is potentiated by 3,3’-diindolylmethane in vitro and in vivo using an orthotopic model of pancreatic cancer. Mol Cancer Ther 2008; 7: 1708-19
  • 7 Ambrosone CB, McCann SE, Freudenheim JL et al. Breast cancer risk in premenopausal women is inversely associated with consumption of broccoli, a source of isothiocyanates, but is not modified by GST genotype. J Nutr 2004; 134: 1134-8
  • 8 Anderton MJ, Manson MM, Verschoyle R et al. Physiological modeling of formulated and crystalline 3,3‛-diindolylmethane pharmacokinetics following oral administration in mice. Drug Metab Dispos 2004; 32: 632-8
  • 9 Asakage M, Tsuno NH, Kitayama J et al. Sulforaphane induces inhibition of human umbilical vein endothelial cells proliferation by apoptosis. Angiogenesis 2006; 9: 83-91
  • 10 Bailey GS, Hendricks JD, Shelton DW et al. Enhancement of carcinogenesis by the natural anticarcinogen indole-3-carbinol. J Natl Cancer Inst 1987; 78: 931-4
  • 11 Banerjee S, Wang Z, Kong D et al. 3, 3’-Diindolylmethane enhances chemosensitivity of multiple chemotherapeutic agents in pancreatic cancer. Cancer Res 2009; 69: 5592-5600
  • 12 Bell MC, Crowley-Nowick P, Bradlow HL et al. Placebo-controlled trial of indole-3-carbinol in the treatment of CIN. Gynecol Oncol 2000; 78: 123-9
  • 13 Bradlow H, Michnovicz JJ, Telang N et al. Effect of dietary indole-3-carbinol on estradiol metabolism and spontaneous mammary tumors in mice. Carcinogenesis 1991; 12: 1571-4
  • 14 Chang X Tou, JC, Hong, et al. 3,3’-Diindolylmethane inhibits angiogenesis and the growth of transplantable human breast carcinoma in athymic mice. Carcinogenesis 2005; 26: 771-8
  • 15 Chinni SR, Li Y, Upadhyay S et al. Indole- 3-carbinol (I3C) induced cell growth inhibition, G1 cell cycle arrest and apoptosis in prostate cancer cells. Oncogene 2001; 20: 2927-36
  • 16 Cho HJ, Seon MR, Lee YM et al. 3,3’-Diindolylmethane suppresses the inflammatory response to lipopolysaccharide in murine macrophages. J Nutr 2008; 138: 17-23
  • 17 Christensen JG, LeBlanc GA. Reversal of multidrug resistance in vivo by dietary administration of the phytochemical indole-3-carbinol. Cancer Res 1996; 56: 574-81
  • 18 Cohen JH, Kristal AR, Stanford JL. Fruit and vegetable intakes and prostate cancer risk. J Natl Cancer Inst 2000; 92: 61-8
  • 19 Cover CM, Hsieh SJ, Tran SH et al. Indole-3-carbinol inhibits the expression of cyclin-dependent kinase-6 and induces a G1 cell cycle arrest of human breast cancer cells independent of estrogen receptor signaling. J Biol Chem 1998; 273: 3838-47
  • 20 Cover CM, Hsieh SJ, Cram EJ et al. Indole-3-carbinol and tamoxifen cooperate to arrest the cell cycle of MCF-7 human breast cancer cells. Cancer Res 1999; 59: 1244-51
  • 21 Cover CM, Hsieh SJ, Tran SH et al. Indole-3-carbinol inhibits the expression of cyclin-dependent kinase-6 and induces a G1 cell cycle arrest of human breast cancer cells independent of estrogen receptor signaling. J Biol Chem 1998; 273: 3838-47
  • 22 Davis R, Singh KP, Kurzrock R et al. Sulforaphane inhibits angiogenesis through activation of FOXO transcription factors. Oncol Rep 2009; 22: 1473-8
  • 23 Fan S, Meng Q, Saha T et al. Low concentrations of diindolylmethane, a metabolite of indole-3-carbinol, protect against oxidative stress in a BRCA1-dependent manner. Cancer Res 2009; 69: 6083-91
  • 24 Firestone GL, Bjeldanes LF. Indole-3-carbinol and 3–3’diindolylmethane antiproliferative signaling pathways control cell-cycle gene transcription in human breast cancer cells by regulating promoter-Sp1 transcription factor interactions. J Nutr 2003; 133: 2448-55
  • 25 Folkman J. Tumor angiogenesis: therapeu- tic implications. N Engl J Med 1971; 285: 1182-6
  • 26 Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med 1995; 1: 27-31
  • 27 Fowke JH, Longcope C, Hebert JR. Brassica vegetable consumption shifts estrogen metabolism in healthy postmenopausal women. Cancer Epidemiol Biomarkers Prev 2000; 9: 773-9
  • 28 Gao X, Petroff BK, Oluola O et al. Endocrine disruption by indole-3-carbinol and tamoxifen: blockage of ovulation. Toxicol Appl Pharmacol 2002; 183: 179-88
  • 29 Garcia HH, Brar GA, Nguyen DHH et al. Indole-3-carbinol (I3C) inhibits cyclin-dependent kinase-2 function in human breast cancer cells by regulating the size distribution, associated cyclin E forms, and subcellular localization of the CDK2 protein complex. J Biol Chem 2005; 280: 8756-64
  • 30 Giovannucci E, Rimm EB, Liu Y et al. A prospective study of cruciferous vegetables and prostate cancer. Cancer Epidemiol Biomarkers Prev 2003; 12: 1403-9
  • 31 Gong Y, Sohn H, Xue L et al. 3,3’diindolylmethane is a novel mitochondrial H(+)-ATP synthase inhibitor that can induce p21 (Cip/Waf1) expression by induction of oxidative stress in human breast cancer cells. Cancer Res 2006; 66: 4880-7
  • 32 Gross-Steinmeyer K, Stapleton PL, Tracy JH et al. Modulation of aflatoxin B1-mediated genotoxicity in primary cultures of human hepatocytes by diindolylmethane, curcumin, and xanthohumols. Toxicol Sci 2009; 112: 303-10
  • 33 Haefner B. NF-kappa B: Arresting a major culprit in cancer. Drug Discov Today 2002; 7: 653-63
  • 34 Hayes JD, Kelleher MO, Eggleston IM. The cancer chemopreventive actions of phytochemicals derived from glucosinolates. Eur J Nutr 2008; 47 Suppl 2: 73-88
  • 35 Hecht SS. Inhibition of carcinogenesis by isothiocyanates. Drug Metab Rev 2000; 32: 395-411
  • 36 Higdon JV, Delage B, Williams DE et al. Cruciferous vegetables and human cancer risk: epidemiologic evidence and mechanistic basis. Pharmacol Res 2007; 55: 224-36
  • 37 Hong C, Firestone GL, Bjeldanes LF. Bcl-2 family-mediated apoptotic effects of 3,3’-diindolylmethane (DIM) in human breast cancer cells. Biochem Pharmacol 2002; 63: 1085-97
  • 38 Hong C, Kim HA, Firestone GL et al. 3,3’-Diindolylmethane (DIM) induces a G(1) cell cycle arrest in human breast cancer cells that is accompanied by Sp1-mediated activation of p21(WAF1/CIP1) expression. Carcinogenesis 2002; 23: 1297-305
  • 39 Kang JS, Kim DJ, Ahn B et al. Post-initiation treatment of Indole-3-carbinol did not suppress N-methyl-N-nitrosourea induced mammary carcinogenesis in rats. Cancer Lett 2001; 169: 147-54
  • 40 Karin M, Greten FR. NF-kappaB: Linking inflammation and immunity to cancer development and progression. Nat Rev Immunol 2005; 5: 749-59
  • 41 Karin M. Nuclear factor-kappaB in cancer development and progression. Nature 2006; 441: 431-6
  • 42 Kim SJ, Lee JS, Kim SM. 3,3‛-Diindolylmethane suppresses growth of human esophageal squamous cancer cells by G1 cell cycle arrest. Oncol Rep 2012; 27: 1669-73
  • 43 Kim HW, Kim J, Kim J et.al. 3,3’-Diindolylmethane inhibits lipopolysaccharide-induced microglial hyperactivation and attenuates brain inflammation. Toxicol Sci 2014; 137: 158-67
  • 44 Kirsh VA, Peters U, Mayne ST et al. Prospective study of fruit and vegetable intake and risk of prostate cancer. J Natl Cancer Inst 2007; 99: 1200-9
  • 45 Kojima T, Tanaka T, Mori H. Chemoprevention of spontaneous endometrial cancer in female Donryku rats by dietary indole-3-carbinol. Cancer Res 1994; 5: 1446-9
  • 46 Kolonel LN, Hankin JH, Whittemore AS et al. Vegetables, fruits, legumes and prostate cancer: a multiethnic case-control study. Cancer Epidemiol Biomarkers Prev 2000; 9: 795-804
  • 47 Kong D, Li Y, Wang Z et al. Inhibition of angiogenesis and invasion by 3,3’-diindolylmethane is mediated by the nuclear factor-kappaB downstream target genes MMP-9 and uPA that regulated bioavailability of vascular endothelial growth factor in prostate cancer. Cancer Res 2007; 67: 3310-9
  • 48 Kong D, Banerjee S, Huang W et al. Mammalian target of rapamycin repression by 3,3’-diindolylmethane inhibits invasion and angiogenesis in platelet-derived growth factor-D-overexpressing PC3 cells. Cancer Res 2008; 68: 1927-34
  • 49 Kunimasa KT, Kobayashi S, Sugiyama K et al. Indole-3-carbinol suppresses tumor-induced angiogenesis by inhibiting tube formation and inducing apoptosis. Biosci Biotechnol Biochem 2008; 72: 2243-6
  • 50 Li WW, Li WV, Hutnik M et al. Tumor angiogenesis as a target for dietary cancer prevention. J Oncol 2012 2012; 1155-1178 DOI: 10.1155/2012/879623.
  • 51 Li Y, Li X, Guo B. Chemopreventive agent 3,3’-diindolylmethane selectively induces proteasomal degradation of class I histone deacetylases. Cancer Res 2010; 70: 646-54
  • 52 Li Y, Kong D, Ahmad A et al. Antioxidant function of isoflavone and 3,3’-diindolylmethane: are they important for cancer prevention and therapy?. Antioxid Redox Signal 2013; 19: 139-50
  • 53 Liu X, Lv K. Cruciferous vegetables intake is inversely associated with risk of breast cancer: a meta-analysis. Breast 2013; 22: 309-13
  • 54 Malejka-Giganti D, Parkin DR, Bennett KK et al. Suppression of mammary gland carcinogenesis by post-initiation treatment of rats with tamoxifen or indole-3-carbinol or their combination. Eur J Cancer Prev 2007; 16: 130-41
  • 55 Mao CG, Tao ZZ, Chen Z et al. Indole-3-carbinol inhibits nasopharyngeal carcinoma cell growth in vivo and in vitro through inhibition of the PI3K/Akt pathway. Exp Ther Med 2014; 8: 207-12
  • 56 McGuire KP, Ngoubilly N, Neavyn M et al. 3,3’-diindolylmethane and paclitaxel act synergistically to promote apoptosis in HER2/Neu human breast cancer cells. J Surg Res 2006; 132: 208-13
  • 57 Meng Q, Qi M, Chen DZ et al. Suppression of breast cancer invasion and migration by indole-3-carbinol: Associated with up-regulation of BRCA1 and E-cadherin/catenin complexes. J Mol Med 2000; 78: 155-65
  • 58 Meng Q, Yuan F, Goldberg ID et al. Indole-3-carbinol is a negative regulator of estrogen receptor-alpha signaling in human tumor cells. J Nutr 2000; 130: 2927-31
  • 59 Minich DM, Bland JS. A review of the clinical efficacy and safety of cruciferous vegetable phytochemicals. Nutr Rev 2007; 65: 259-67
  • 60 Michnovicz JJ, Bradlow HL. Altered estrogen metabolism and excretion in humans following consumption of indole-3-carbinol. Nutr Cancer 1991; 16: 59-66
  • 61 Moiseeva EP, Almeida GM, Jones GD et al. Extended treatment with physiologic concentrations of dietary phytochemicals results in altered gene expression, reduced growth, and apoptosis of cancer cells. Mol Cancer Ther 2007; 6: 3071-9
  • 62 Murillo G, Mehta RG. Cruciferous vegetables and cancer prevention. Nutr Cancer 2001; 41: 17-28
  • 63 Oganesian A, Hendricks JD, Pereira CB et al. Potency of dietary indole-3-carbinol as a promoter of aflatoxin B1-initiated hepatocarcinogenesis: Results from a 9000 animal tumor study. Carcinogenesis 1999; 20: 453-8
  • 64 Pfeifer BL, DeFilippo J, Chen S. Eine neue komplexe Heilkräuterkombination in der komplementären Krebsbehandlung. Erfahrungsheilkunde 2000; 4: 205-14
  • 65 Rahman KM, Aranha O, Glazyrin A et al. Translocation of Bax to mitochondria induces apoptotic cell death in indole-3-carbinol (I3C) treated breast cancer cells. Oncogene 2000; 19: 5764-71
  • 66 Rahman KM, Aranha O, Sarkar FH. Indole-3-carbinol (I3C) induces apoptosis in tumorigenic but not in nontumorigenic breast epithelial cells. Nutr Cancer 2003; 45: 101-12
  • 67 Rahman KW, Sarkar FH. Inhibition of nuclear translocation of nuclear factor-{kappa}B contributes to 3,3’-diindolylmethane-induced apoptosis in breast cancer cells. Cancer Res 2005; 65: 364-71
  • 68 Rahman KM, Ali S, Aboukameel A et al. Inactivation of NF-kappaB by 3,3’-diindolylmethane contributes to increased apoptosis induced by chemotherapeutic agent in breast cancer cells. Mol Cancer Ther 2007; 6: 2757-65
  • 69 Reed GA, Arneson DW, Putman WC et al. Single-dose and multiple-dose administration of indole-3-carbinol to women: pharmacokinetics based on 3,3‛-diindolylmethane. Cancer Epidemiol Biomarkers Prev 2006; 15: 2477-81
  • 70 Safe S, Papineni S, Chintharlapalli S. Cancer chemotherapy with indole-3-carbinol, bis(3’-indolyl)methane and synthetic analogs. Cancer Lett 2008; 269: 326-38
  • 71 Sarkar FH, Li Y, Wang Z, Kong D. Cellular signaling perturbation by natural products. Cell Signal 2009; 21: 1541-7
  • 72 Saw CL, Cintrón M, Wu TY et al. Pharmacodynamics of dietary phytochemical indoles I3C and DIM: Induction of Nrf2-mediated phase II drug metabolizing and antioxidant genes and synergism with isothiocyanates. Biopharm Drug Dispos 2011; 32: 289-300
  • 73 Smith-Warner SA, Spiegelman D, Yaun SS et al. Intake of fruits and vegetables and risk of breast cancer: a pooled analysis of cohort studies. JAMA 2001; 285: 769-76
  • 74 Souli E, Machluf M, Morgenstern A et al. Indole-3-carbinol (I3C) exhibits inhibitory and preventive effects on prostate tumors in mice. Food Chem Toxicol 2008; 46: 815-28
  • 75 Stewart ZA, Westfall MD, Pietenpol JA. Cell-cycle dysregulation and anticancer therapy. Trends Pharmacol Sci 2003; 24: 139-45
  • 76 Taylor-Harding B, Agadjanian H, Nassanian H et al. Indole-3-carbinol synergistically sensitises ovarian cancer cells to bortezomib treatment. Br J Cancer 2012; 106: 333-43
  • 77 Thomson CA, Rock CL, Thompson PA et al. Vegetable intake is associated with reduced breast cancer recurrence in tamoxifen users: a secondary analysis from the Women’s Healthy Eating and Living Study. Breast Cancer Res Treat 2011; 125: 519-27
  • 78 Vivar O, Lin CL, Firestone GL et al. 3,39-Diindolylmethane induces a G(1) arrest in human prostate cancer cells irrespective of androgen receptor and p53 status. Biochem Pharmacol 2009; 78: 469-76
  • 79 Voorrips LE, Goldbohm RA, Verhoeven DT et al. Vegetable and fruit consumption and lung cancer risk in the Netherlands Cohort Study on diet and cancer. Cancer Causes Control 2000; 11: 101-15
  • 80 Wang H, Word BR, Lyn-Cook BD. Enhanced efficacy of gemcitabine by indole-3-carbinol in pancreatic cell lines: the role of human equilibrative nucleoside transporter 1. Anticancer Res 2011; 31: 3171-80
  • 81 Wang Z, Banerjee S, Li Y et al. Down-regulation of notch-1 inhibits invasion by inactivation of nuclear factor-kappaB, vascular endothelial growth factor, and matrix metalloproteinase-9 in pancreatic cancer cells. Cancer Res 2006; 66: 2778-84
  • 82 Wattenberg LW, Loub WD. Inhibition of polycyclic aromatic hydrocarbon-induced neoplasia by naturally occurring indoles. Cancer Res 1978; 38: 1410-3
  • 83 Wong GY, Bradlow L, Sepkovic D et al. Dose-ranging study of indole-3-carbinol for breast cancer prevention. J Cell Biochem Suppl 1997; 28-29: 111-6
  • 84 Wortelboer HM, de Kruif CA, van Iersel AA et al. Acid reaction products of indole-3-carbinol and their effects on cytochrome P450 and phase II enzymes in rat and monkey hepatocytes. Biochem Pharmacol 1992; 43: 1439-47
  • 85 Yoshida M, Katashima S, Ando J et al. Dietary indole-3-carbinol promotes endometrial adenocarcinoma development in rats initiated with N-ethyl-N’-nitro-N-nitrosoguanidine, with induction of cytochrome P450s in the liver and consequent modulation of estrogen metabolism. Carcinogenesis 2004; 25: 2257-64