Advertisement

Cellular, Molecular and Biological Insight into Chemopreventive and Therapeutic Potential of 3,3’-Diindolylmethane (DIM)

  • Sanjeev Banerjee
  • Mansi A. Parasramka
  • Fazlul H. SarkarEmail author

Abstract

Emerging evidence suggest that bioactive phytochemical is achievable by consuming moderate amount of cruciferous vegetables, such as broccoli, brussel sprouts, cauliflower and cabbage. Evaluation for chemopreventive effectiveness of these vegetables led to the identification of 3,3’-Diindolylmethane (DIM) which is generated in the acidic environment of the stomach following dimerization of Indole-3-Carbinol (I3C) monomers originating from the aforementioned class of vegetables. This article evaluates the potential targets and biological effects elicited by DIM against tumor cells to ascertain chemopreventive and therapeutic efficacy. We provide mechanistic insight into their pleiotropic action resulting in the induction of cell cycle arrest and apoptosis, and the disruption of intracellular signaling network cascade that are known to regulate angiogenesis, metastasis and invasion. The beneficial effect of DIM has been observed by preclinical in vitro and in vivo studies, suggesting that DIM could be useful as a chemopreventive agent and an adjunct to conventional therapeutics. Moreover, DIM has moved through preclinical development into clinical trials and the outcome of such investigation would likely provide definitive role of DIM in human health and diseases.

Keywords

3,3’-Diindolylmethane Brassica genus Prevention Therapy 

Notes

Acknowledgement

Grant support from National Cancer Institute/NIH grants 5R01CA083695, 5R01CA108535 and 5R01CA101870 is gratefully acknowledged. The authors also express their sincere appreciation to Ms Jacqueline Schaffert for her editorial assistance.

References

  1. Abdelrahim M, Newman K, Vanderlaag K et al (2006) 3,3'-diindolylmethane (DIM) and its derivatives induce apoptosis in pancreatic cancer cells through endoplasmic reticulum stress-dependent upregulation of DR5. Carcinogenesis 27:717–728PubMedCrossRefGoogle Scholar
  2. Ahmad A, Kong D, Sarkar SH et al (2009a) Inactivation of uPA and its receptor uPAR by 3,3'-diindolylmethane (DIM) leads to the inhibition of prostate cancer cell growth and migration. J Cell Biochem 107:516–527PubMedCrossRefGoogle Scholar
  3. Ahmad A, Kong D, Wang Z et al (2009b) Down-regulation of uPA and uPAR by 3,3'-diindolylmethane contributes to the inhibition of cell growth and migration of breast cancer cells. J Cell Biochem 108:916–925PubMedCrossRefGoogle Scholar
  4. Ahmad A, Ali S, Wang Z et al (2011) 3, 3'-diindolylmethane enhances taxotere-induced growth inhibition of breast cancer cells through down-regulation of FoxM1. Int J Cancer 129:1781–1791Google Scholar
  5. Ali S, Banerjee S, Ahmad A et al (2008) 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 7:1708–1719PubMedCrossRefGoogle Scholar
  6. Ali S, Varghese L, Pereira L et al (2009) Sensitization of squamous cell carcinoma to cisplatin induced killing by natural agents. Cancer Lett 278:201–209PubMedCrossRefGoogle Scholar
  7. Ali S, Banerjee S, Schaffert JM et al (2010) Concurrent inhibition of NF-kappaB, cyclooxygenase-2, and epidermal growth factor receptor leads to greater anti-tumor activity in pancreatic cancer. J Cell Biochem 110:171–181Google Scholar
  8. Auborn KJ (2002) Therapy for recurrent respiratory papillomatosis. Antivir Ther 7:1–9PubMedGoogle Scholar
  9. Azmi AS, Ahmad A, Banerjee S et al (2008) Chemoprevention of pancreatic cancer: characterization of Par-4 and its modulation by 3,3' diindolylmethane (DIM). Pharm Res 25:2117–2124PubMedCrossRefGoogle Scholar
  10. Banerjee S, Wang Z, Kong D et al (2009) 3,3'-Diindolylmethane enhances chemosensitivity of multiple chemotherapeutic agents in pancreatic cancer. Cancer Res 69:5592–5600PubMedCrossRefGoogle Scholar
  11. Bartel DP (2009) MicroRNAs: target recognition and regulatory functions. Cell 136:215–233PubMedCrossRefGoogle Scholar
  12. Bhatnagar N, Li X, Chen Y et al (2009) 3,3'-diindolylmethane enhances the efficacy of butyrate in colon cancer prevention through down-regulation of survivin. Cancer Prev Res (Phila Pa) 2:581–589CrossRefGoogle Scholar
  13. Bhuiyan MM, Li Y, Banerjee S et al (2006) Down-regulation of androgen receptor by 3,3'-diindolylmethane contributes to inhibition of cell proliferation and induction of apoptosis in both hormone-sensitive LNCaP and insensitive C4-2B prostate cancer cells. Cancer Res 66:10064–10072PubMedCrossRefGoogle Scholar
  14. Bonnesen C, Eggleston IM, Hayes JD (2001) Dietary indoles and isothiocyanates that are generated from cruciferous vegetables can both stimulate apoptosis and confer protection against DNA damage in human colon cell lines. Cancer Res 61:6120–6130PubMedGoogle Scholar
  15. Cano E, Mahadevan LC (1995) Parallel signal processing among mammalian MAPKs. Trends Biochem Sci 20:117–122PubMedCrossRefGoogle Scholar
  16. Casalini P, Iorio MV (2009) MicroRNAs and future therapeutic applications in cancer. J BUON 14 Suppl 1:S17–S22Google Scholar
  17. Chang X, Tou JC, Hong C et al (2005) 3,3'-Diindolylmethane inhibits angiogenesis and the growth of transplantable human breast carcinoma in athymic mice. Carcinogenesis 26:771–778PubMedCrossRefGoogle Scholar
  18. Chang X, Firestone GL, Bjeldanes LF (2006) Inhibition of growth factor-induced Ras signaling in vascular endothelial cells and angiogenesis by 3,3'-diindolylmethane. Carcinogenesis 27:541–550PubMedCrossRefGoogle Scholar
  19. Chen DZ, Qi M, Auborn KJ et al (2001) Indole-3-carbinol and diindolylmethane induce apoptosis of human cervical cancer cells and in murine HPV16-transgenic preneoplastic cervical epithelium. J Nutr 131:3294–302PubMedGoogle Scholar
  20. Chen Y, Xu J, Jhala N et al (2006) Fas-mediated apoptosis in cholangiocarcinoma cells is enhanced by 3,3'-diindolylmethane through inhibition of AKT signaling and FLICE-like inhibitory protein. Am J Pathol 169:1833–1842PubMedCrossRefGoogle Scholar
  21. Cheng JS, Shu SS, Kuo CC et al (2011) Effect of diindolylmethane on Ca(2+) movement and viability in HA59T human hepatoma cells. Arch Toxicol 85:1257–1266Google Scholar
  22. Chinnakannu K, Chen D, Li Y et al (2009) Cell cycle-dependent effects of 3,3'-diindolylmethane on proliferation and apoptosis of prostate cancer cells. J Cell Physiol 219:94–99PubMedCrossRefGoogle Scholar
  23. Cho HJ, Park SY, Kim EJ et al (2011) 3,3'-Diindolylmethane inhibits prostate cancer development in the transgenic adenocarcinoma mouse prostate model. Mol Carcinog 50:100–112PubMedCrossRefGoogle Scholar
  24. Choi HJ, Lim dY, Park JH (2009) Induction of G1 and G2/M cell cycle arrests by the dietary compound 3,3'-diindolylmethane in HT-29 human colon cancer cells. BMC Gastroenterol 9:39PubMedCrossRefGoogle Scholar
  25. Contractor R, Samudio IJ, Estrov Z et al (2005) A novel ring-substituted diindolylmethane,1,1-bis[3'-(5-methoxyindolyl)]-1-(p-t-butylphenyl) methane, inhibits extracellular signal-regulated kinase activation and induces apoptosis in acute myelogenous leukemia. Cancer Res 65:2890–2898PubMedCrossRefGoogle Scholar
  26. Crowell JA, Page JG, Levine BS et al (2006) Indole-3-carbinol, but not its major digestive product 3,3'-diindolylmethane, induces reversible hepatocyte hypertrophy and cytochromes P450. Toxicol Appl Pharmacol 211:115–123PubMedCrossRefGoogle Scholar
  27. Degner SC, Papoutsis AJ, Selmin O et al (2009) Targeting of aryl hydrocarbon receptor-mediated activation of cyclooxygenase-2 expression by the indole-3-carbinol metabolite 3,3'-diindolylmethane in breast cancer cells. J Nutr 139:26–32PubMedGoogle Scholar
  28. Del PG, Gudipudi DK, Montemarano N et al (2010) Oral diindolylmethane (DIM): pilot evaluation of a nonsurgical treatment for cervical dysplasia. Gynecol Oncol 116:464–467CrossRefGoogle Scholar
  29. Dong L, Xia S, Gao F et al (2010) 3,3'-Diindolylmethane attenuates experimental arthritis and osteoclastogenesis. Biochem Pharmacol 79:715–721PubMedCrossRefGoogle Scholar
  30. Faivre S, Kroemer G, Raymond E (2006) Current development of mTOR inhibitors as anticancer agents. Nat Rev Drug Discov 5:671–688PubMedCrossRefGoogle Scholar
  31. Fan S, Meng Q, Saha T et al (2009) Low concentrations of diindolylmethane, a metabolite of indole-3-carbinol, protect against oxidative stress in a BRCA1-dependent manner. Cancer Res 69:6083–6091PubMedCrossRefGoogle Scholar
  32. Garikapaty VP, Ashok BT, Tadi K et al (2006) 3,3'-Diindolylmethane downregulates pro-survival pathway in hormone independent prostate cancer. Biochem Biophys Res Commun 340:718–725PubMedCrossRefGoogle Scholar
  33. Gartel AL, Serfas MS, Tyner AL (1996) p21 – negative regulator of the cell cycle. Proc Soc Exp Biol Med 213:138–149PubMedGoogle Scholar
  34. Gong Y, Firestone GL, Bjeldanes LF (2006a) 3,3'-diindolylmethane is a novel topoisomerase IIalpha catalytic inhibitor that induces S-phase retardation and mitotic delay in human hepatoma HepG2 cells. Mol Pharmacol 69:1320–1327PubMedCrossRefGoogle Scholar
  35. Gong Y, Sohn H, Xue L et al (2006b) 3,3'-Diindolylmethane is a novel mitochondrial H(+)-ATP synthase inhibitor that can induce p21(Cip1/Waf1) expression by induction of oxidative stress in human breast cancer cells. Cancer Res 66:4880–4887PubMedCrossRefGoogle Scholar
  36. Gudmundsdottir K, Ashworth A (2006) The roles of BRCA1 and BRCA2 and associated proteins in the maintenance of genomic stability. Oncogene 25:5864–5874PubMedCrossRefGoogle Scholar
  37. Hankinson O (1995) The aryl hydrocarbon receptor complex. Annu Rev Pharmacol Toxicol 35:307–340PubMedCrossRefGoogle Scholar
  38. Heath EI, Heilbrun lk, Vaishampayan UN et al (2009) A phase-I dose escalation study of oral BR-DIM (BioResponse 3,3'-Diindolylmethane) in castrate-resistant, non-metastatic, PSA relapse prostate cancer patients. ASCO Meeting Genitourinary Cancer Symposium, Chicago, ILGoogle Scholar
  39. Hong C, Firestone GL, Bjeldanes LF (2002a) Bcl-2 family-mediated apoptotic effects of 3,3'-diindolylmethane (DIM) in human breast cancer cells. Biochem Pharmacol 63:1085–1097PubMedCrossRefGoogle Scholar
  40. Hong C, Kim HA, Firestone GL et al (2002b) 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 23:1297–1305PubMedCrossRefGoogle Scholar
  41. Huang X, Guo B (2006) Adenomatous polyposis coli determines sensitivity to histone deacetylase inhibitor-induced apoptosis in colon cancer cells. Cancer Res 66:9245–9251PubMedCrossRefGoogle Scholar
  42. Ichite N, Chougule MB, Jackson T et al (2009) Enhancement of docetaxel anticancer activity by a novel diindolylmethane compound in human non-small cell lung cancer. Clin Cancer Res 15:543–552PubMedCrossRefGoogle Scholar
  43. Iorio MV, Croce CM (2009) MicroRNAs in cancer: small molecules with a huge impact. J Clin Oncol 27:5848–5856PubMedCrossRefGoogle Scholar
  44. Iorio MV, Ferracin M, Liu CG et al (2005) MicroRNA gene expression deregulation in human breast cancer. Cancer Res 65:7065–7070PubMedCrossRefGoogle Scholar
  45. Jacobs IC, Zeligs MA (1999) Facilitated absorption of a hydrophobic dietary ingredient. Proc Int Symp Control Rel Bioact Mater 26:958–959Google Scholar
  46. Jacobs IC, Zeligs MA (2000) New formulation strategies for bioavailability enhancement of two poorly absorbed phytonutrient supplements: diindolylmethane and yohimbine bark extract. Proc Int Symp Control Rel Bioact Mater 27:1324–1325Google Scholar
  47. Jellinck PH, Forkert PG, Riddick DS et al (1993) Ah receptor binding properties of indole carbinols and induction of hepatic estradiol hydroxylation. Biochem Pharmacol 45:1129–1136PubMedCrossRefGoogle Scholar
  48. Jemal A, Bray F, Center MM et al (2011) Global cancer statistics. CA Cancer J Clin 61:69–90PubMedCrossRefGoogle Scholar
  49. Jin Y, Zou X, Feng X (2010) 3,3'-Diindolylmethane negatively regulates Cdc25A and induces a G2/M arrest by modulation of microRNA 21 in human breast cancer cells. Anticancer Drugs 21:814–822PubMedCrossRefGoogle Scholar
  50. Juge N, Mithen RF, Traka M (2007) Molecular basis for chemoprevention by sulforaphane: a comprehensive review. Cell Mol Life Sci 64:1105–1127PubMedCrossRefGoogle Scholar
  51. Kandala PK, Srivastava SK (2010) Activation of checkpoint kinase 2 by 3,3'-diindolylmethane is required for causing G2/M cell cycle arrest in human ovarian cancer cells. Mol Pharmacol 78:297–309PubMedCrossRefGoogle Scholar
  52. Kim EJ, Shin M, Park H et al (2009) Oral administration of 3,3'-diindolylmethane inhibits lung metastasis of 4T1 murine mammary carcinoma cells in BALB/c mice. J Nutr 139:2373–2379PubMedCrossRefGoogle Scholar
  53. Kong D, Li Y, Wang Z et al (2007) 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 67:3310–3319PubMedCrossRefGoogle Scholar
  54. Kong D, Banerjee S, Huang W et al (2008) Mammalian target of rapamycin repression by 3,3'-diindolylmethane inhibits invasion and angiogenesis in platelet-derived growth factor-D-overexpressing PC3 cells. Cancer Res 68:1927–1934PubMedCrossRefGoogle Scholar
  55. Lee SH, Kim JS, Yamaguchi K et al (2005) Indole-3-carbinol and 3,3'-diindolylmethane induce expression of NAG-1 in a p53-independent manner. Biochem Biophys Res Commun 328:63–69PubMedCrossRefGoogle Scholar
  56. Li Y, Li X, Sarkar FH (2003) Gene expression profiles of I3C- and DIM-treated PC3 human prostate cancer cells determined by cDNA microarray analysis. J Nutr 133:1011–1019PubMedGoogle Scholar
  57. Li Y, Chinni SR, Sarkar FH (2005) Selective growth regulatory and pro-apoptotic effects of DIM is mediated by AKT and NF-kappaB pathways in prostate cancer cells. Front Biosci 10:236–243PubMedCrossRefGoogle Scholar
  58. Li Y, Wang Z, Kong D et al (2007) Regulation of FOXO3a/beta-catenin/GSK-3beta signaling by 3,3'-diindolylmethane contributes to inhibition of cell proliferation and induction of apoptosis in prostate cancer cells. J Biol Chem 282:21542–21550PubMedCrossRefGoogle Scholar
  59. Li Y, VandenBoom TG, Kong D et al (2009) Up-regulation of miR-200 and let-7 by natural agents leads to the reversal of epithelial-to-mesenchymal transition in gemcitabine-resistant pancreatic cancer cells. Cancer Res 69:6704–6712PubMedCrossRefGoogle Scholar
  60. Li Y, Li X, Guo B (2010) Chemopreventive agent 3,3'-diindolylmethane selectively induces proteasomal degradation of class I histone deacetylases. Cancer Res 70:646–654PubMedCrossRefGoogle Scholar
  61. Maciejewska D, Rasztawicka M, Wolska I et al (2009) Novel 3,3'-diindolylmethane derivatives: synthesis and cytotoxicity, structural characterization in solid state. Eur J Med Chem 44:4136–4147PubMedCrossRefGoogle Scholar
  62. McDougal A, Gupta MS, Morrow D et al (2001) Methyl-substituted diindolylmethanes as inhibitors of estrogen-induced growth of T47D cells and mammary tumors in rats. Breast Cancer Res Treat 66:147–157PubMedCrossRefGoogle Scholar
  63. McGuire KP, Ngoubilly N, Neavyn M et al (2006) 3,3'-diindolylmethane and paclitaxel act synergistically to promote apoptosis in HER2/Neu human breast cancer cells. J Surg Res 132:208–213PubMedCrossRefGoogle Scholar
  64. Morse MA, Stoner GD (1993) Cancer chemoprevention: principles and prospects. Carcinogenesis 14:1737–1746PubMedCrossRefGoogle Scholar
  65. Nachshon-Kedmi M, Yannai S, Haj A et al (2003) Indole-3-carbinol and 3,3'-diindolylmethane induce apoptosis in human prostate cancer cells. Food Chem Toxicol 41:745–752PubMedCrossRefGoogle Scholar
  66. Nachshon-Kedmi M, Fares FA, Yannai S (2004a) Therapeutic activity of 3,3'-diindolylmethane on prostate cancer in an in vivo model. Prostate 61:153–160PubMedCrossRefGoogle Scholar
  67. Nachshon-Kedmi M, Yannai S, Fares FA (2004b) Induction of apoptosis in human prostate cancer cell line, PC3, by 3,3'-diindolylmethane through the mitochondrial pathway. Br J Cancer 91:1358–1363PubMedCrossRefGoogle Scholar
  68. Narayanan R, Yepuru M, Szafran AT et al (2010) Discovery and mechanistic characterization of a novel selective nuclear androgen receptor exporter for the treatment of prostate cancer. Cancer Res 70:842–851PubMedCrossRefGoogle Scholar
  69. Parkin DR, Malejka-Giganti D (2004) Differences in the hepatic P450-dependent metabolism of estrogen and tamoxifen in response to treatment of rats with 3,3'-diindolylmethane and its parent compound indole-3-carbinol. Cancer Detect Prev 28:72–79PubMedCrossRefGoogle Scholar
  70. Rahimi M, Huang KL, Tang CK (2010) 3,3'-Diindolylmethane (DIM) inhibits the growth and invasion of drug-resistant human cancer cells expressing EGFR mutants. Cancer Lett 295:59–68PubMedCrossRefGoogle Scholar
  71. Rahman KW, Sarkar FH (2005) Inhibition of nuclear translocation of nuclear factor-{kappa}B contributes to 3,3'-diindolylmethane-induced apoptosis in breast cancer cells. Cancer Res 65:364–371PubMedGoogle Scholar
  72. Rahman KW, Li Y, Wang Z et al (2006) Gene expression profiling revealed survivin as a target of 3,3'-diindolylmethane-induced cell growth inhibition and apoptosis in breast cancer cells. Cancer Res 66:4952–4960PubMedCrossRefGoogle Scholar
  73. Rahman KM, Ali S, Aboukameel A et al (2007) Inactivation of NF-kappaB by 3,3'-diindolylmethane contributes to increased apoptosis induced by chemotherapeutic agent in breast cancer cells. Mol Cancer Ther 6:2757–2765PubMedCrossRefGoogle Scholar
  74. Rahman KM, Banerjee S, Ali S et al (2009) 3,3'-Diindolylmethane enhances taxotere-induced apoptosis in hormone-refractory prostate cancer cells through survivin down-regulation. Cancer Res 69:4468–4475PubMedCrossRefGoogle Scholar
  75. Rajoria S, Suriano R, George A et al (2011) Estrogen induced metastatic modulators MMP-2 and MMP-9 are targets of 3,3'-diindolylmethane in thyroid cancer. PLoS One 6:e15879PubMedCrossRefGoogle Scholar
  76. Reed GA, Arneson DW, Putnam WC et al (2006) Single-dose and multiple-dose administration of indole-3-carbinol to women: pharmacokinetics based on 3,3'-diindolylmethane. Cancer Epidemiol Biomarkers Prev 15:2477–2481PubMedCrossRefGoogle Scholar
  77. Reed GA, Sunega JM, Sullivan DK et al (2008) Single-dose pharmacokinetics and tolerability of absorption-enhanced 3,3'-diindolylmethane in healthy subjects. Cancer Epidemiol Biomarkers Prev 17:2619–2624PubMedCrossRefGoogle Scholar
  78. Riby JE, Firestone GL, Bjeldanes LF (2008) 3,3'-diindolylmethane reduces levels of HIF-1alpha and HIF-1 activity in hypoxic cultured human cancer cells. Biochem Pharmacol 75:1858–1867PubMedCrossRefGoogle Scholar
  79. Roy A, Ganguly A, BoseDasgupta S et al (2008) Mitochondria-dependent reactive oxygen species-mediated programmed cell death induced by 3,3'-diindolylmethane through inhibition of F0F1-ATP synthase in unicellular protozoan parasite Leishmania donovani. Mol Pharmacol 74:1292–1307PubMedCrossRefGoogle Scholar
  80. Savino JA, III, Evans JF, Rabinowitz D et al (2006) Multiple, disparate roles for calcium signaling in apoptosis of human prostate and cervical cancer cells exposed to diindolylmethane. Mol Cancer Ther 5:556–563PubMedCrossRefGoogle Scholar
  81. Sepkovic DW, Bradlow HL, Bell M (2001) Quantitative determination of 3,3'-diindolylmethane in urine of individuals receiving indole-3-carbinol. Nutr Cancer 41:57–63PubMedCrossRefGoogle Scholar
  82. Sepkovic DW, Stein J, Carlisle AD et al (2009) Diindolylmethane inhibits cervical dysplasia, alters estrogen metabolism, and enhances immune response in the K14-HPV16 transgenic mouse model. Cancer Epidemiol Biomarkers Prev 18:2957–2964PubMedCrossRefGoogle Scholar
  83. Sepkovic DW, Stein J, Carlisle AD et al (2011) Results from a dose response study using 3, 3'-diindolylmethane in the K14-HPV16 transgenic mouse model: Cervical histology. Cancer Prev Res (Phila) 4:890–896Google Scholar
  84. Stresser DM, Bjeldanes LF, Bailey GS et al (1995) The anticarcinogen 3,3'-diindolylmethane is an inhibitor of cytochrome P-450. J Biochem Toxicol 10:191–201PubMedCrossRefGoogle Scholar
  85. Sun S, Han J, Ralph WM, Jr et al (2004) Endoplasmic reticulum stress as a correlate of cytotoxicity in human tumor cells exposed to diindolylmethane in vitro. Cell Stress Chaperones 9:76–87PubMedGoogle Scholar
  86. Tadi K, Chang Y, Ashok BT et al (2005) 3,3'-Diindolylmethane, a cruciferous vegetable derived synthetic anti-proliferative compound in thyroid disease. Biochem Biophys Res Commun 337:1019–1025PubMedCrossRefGoogle Scholar
  87. Thimmulappa RK, Mai KH, Srisuma S et al (2002) Identification of Nrf2-regulated genes induced by the chemopreventive agent sulforaphane by oligonucleotide microarray. Cancer Res 62:5196–5203PubMedGoogle Scholar
  88. Vivar OI, Saunier EF, Leitman DC et al (2010) Selective Activation of Estrogen Receptor-{beta} Target Genes by 3,3'-Diindolylmethane. Endocrinology 151:1662–1667Google Scholar
  89. Wang Z, Yu BW, Rahman KM et al (2008) Induction of growth arrest and apoptosis in human breast cancer cells by 3,3-diindolylmethane is associated with induction and nuclear localization of p27kip. Mol Cancer Ther 7:341–349PubMedCrossRefGoogle Scholar
  90. Wattenberg LW (1985) Chemoprevention of cancer. Cancer Res 45:1–8PubMedCrossRefGoogle Scholar
  91. Wortelboer HM, de Kruif CA, van Iersel AA et al (1992) Acid reaction products of indole-3-carbinol and their effects on cytochrome P450 and phase II enzymes in rat and monkey hepatocytes. Biochem Pharmacol 43:1439–1447PubMedCrossRefGoogle Scholar
  92. Xue L, Firestone GL, Bjeldanes LF (2005) DIM stimulates IFNgamma gene expression in human breast cancer cells via the specific activation of JNK and p38 pathways. Oncogene 24: 2343–2353PubMedCrossRefGoogle Scholar
  93. Zhang S, Shen HM, Ong CN (2005) Down-regulation of c-FLIP contributes to the sensitization effect of 3,3'-diindolylmethane on TRAIL-induced apoptosis in cancer cells. Mol Cancer Ther 4:1972–1981PubMedCrossRefGoogle Scholar
  94. Zhang B, Pan X, Cobb GP et al (2007) microRNAs as oncogenes and tumor suppressors. Dev Biol 302:1–12PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2012

Authors and Affiliations

  • Sanjeev Banerjee
    • 1
  • Mansi A. Parasramka
    • 1
  • Fazlul H. Sarkar
    • 2
    Email author
  1. 1.Department of PathologyBarbara Ann Karmanos Cancer Institute, Wayne State University School of MedicineDetroitUSA
  2. 2.Departments of Pathology and OncologyKarmanos Cancer Institute, Wayne State UniversityDetroitUSA

Personalised recommendations