Anti-Cancer and Other Biological Effects of a Dietary Compound 3,3′-Diindolylmethane Supplementation: A Systematic Review of Human Clinical Trials

References

• Johnson IT. Glucosinolates: bioavailability and importance to health. Int J Vitam Nutr Res. 2002;72(1):26–31. doi:10.1024/0300-9831.72.1.26
   PubMed Web of Science ®Google Scholar
• Anderton MJ, Manson MM, Verschoyle RD, et al. Pharmacokinetics and tissue disposition of indole-3-carbinol and its acid condensation products after oral administration to mice. Clin Cancer Res. 2004;10(15):5233–5241. doi:10.1158/1078-0432.CCR-04-0163
   PubMed Web of Science ®Google Scholar
• Bjeldanes LF, Kim JY, Grose KR, et al. Aromatic hydrocarbon responsiveness-receptor agonists generated from indole-3-carbinol in vitro and in vivo: comparisons with 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin. Proc Natl Acad Sci U S A. 1991;88(21):9543–9547. doi:10.1073/pnas.88.21.9543
   PubMed Web of Science ®Google Scholar
• Chang Y-C, Riby J, Chang GH-F, et al. Cytostatic and antiestrogenic effects of 2-(indol-3-ylmethyl)-3, 3′-diindolylmethane, a major in vivo product of dietary indole-3-carbinol. Biochem Pharmacol. 1999;58(5):825–834. doi:10.1016/S0006-2952(99)00165-3
   Web of Science ®Google Scholar
• Chen I, McDougal A, Wang F, et al. Aryl hydrocarbon receptor-mediated antiestrogenic and antitumorigenic activity of diindolylmethane. Carcinogenesis. 1998;19(9):1631–1639. doi:10.1093/carcin/19.9.1631
   Web of Science ®Google Scholar
• Bradfield CA, Bjeldanes LF. High-performance liquid chromatographic analysis of anticarcinogenic indoles in Brassica oleracea. J Agric Food Chem. 1987;35(1):46–49. doi:10.1021/jf00073a010
   Web of Science ®Google Scholar
• Weng J-R, Tsai C-H, Kulp SK, et al. Indole-3-carbinol as a chemopreventive and anti-cancer agent. Cancer Lett. 2008;262(2):153–163. doi:10.1016/j.canlet.2008.01.033
   PubMed Web of Science ®Google Scholar
• Ashok B, Chen YG, Liu X, et al. Multiple molecular targets of indole-3-carbinol, a chemopreventive anti-estrogen in breast cancer. Eur J Cancer Prev. 2002;11:S86–S93.
   Web of Science ®Google Scholar
• Auborn KJ, Fan S, Rosen EM, et al. Indole-3-carbinol is a negative regulator of estrogen. J Nutr. 2003;133(7):2470S–2475S. doi:10.1093/jn/133.7.2470S
   Web of Science ®Google Scholar
• Bradlow HL. Indole-3-carbinol as a chemoprotective agent in breast and prostate cancer. In Vivo. 2008;22(4):441–445.
   Web of Science ®Google Scholar
• Garikapaty VP, Ashok BT, Tadi K, et al. 3,3ʹ-Diindolylmethane downregulates pro-survival pathway in hormone independent prostate cancer. Biochem Biophys Res Commun. 2006;340(2):718–725. doi:10.1016/j.bbrc.2005.12.059
   Web of Science ®Google Scholar
• Li Y, Li X, Sarkar FH. Gene expression profiles of I3C- and DIM-treated PC3 human prostate cancer cells determined by cDNA microarray analysis. Case Rep Med. 2003;133(4):1011–1019.
   Google Scholar
• Sarkar FH, Li Y. Indole-3-carbinol and prostate cancer. J Nutr. 2004;134(12 Suppl):3493s–3498s. doi:10.1093/jn/134.12.3493S
   Web of Science ®Google Scholar
• Wortelboer HM, De Kruif CA, Van Iersel AAJ, 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(7):1439–1447. doi:10.1016/0006-2952(92)90200-3
   Web of Science ®Google Scholar
• Nho CW, Jeffery E. The synergistic upregulation of phase II detoxification enzymes by glucosinolate breakdown products in cruciferous vegetables. Toxicol Appl Pharmacol. 2001;174(2):146–152. doi:10.1006/taap.2001.9207
   PubMed Web of Science ®Google Scholar
• Abdelrahim M, Newman K, Vanderlaag K, et al. 3, 3′-diindolylmethane (DIM) and its derivatives induce apoptosis in pancreatic cancer cells through endoplasmic reticulum stress-dependent upregulation of DR5. Carcinogenesis. 2005;27(4):717–728. doi:10.1093/carcin/bgi270
   Web of Science ®Google Scholar
• Ge X, Yannai S, Rennert G, et al. 3, 3′-Diindolylmethane induces apoptosis in human cancer cells. Biochem Biophys Res Commun. 1996;228(1):153–158. doi:10.1006/bbrc.1996.1631
   PubMed Web of Science ®Google Scholar
• Nachshon-Kedmi M, Yannai S, Haj A, et al. Indole-3-carbinol and 3, 3′-diindolylmethane induce apoptosis in human prostate cancer cells. Food Chem Toxicol. 2003;41(6):745–752. doi:10.1016/S0278-6915(03)00004-8
   Web of Science ®Google Scholar
• Rodan GA, Martin TJ. Therapeutic approaches to bone diseases. Science. 2000;289(5484):1508–1514. doi:10.1126/science.289.5484.1508
   PubMed Web of Science ®Google Scholar
• Yu T-Y, Pang W-J, Yang G-S. 3, 3′-Diindolylmethane increases bone mass by suppressing osteoclastic bone resorption in mice. J Pharmacol Sci. 2015;127(1):75–82. doi:10.1016/j.jphs.2014.11.006
   PubMed Web of Science ®Google Scholar
• Dong L, Xia S, Gao F, et al. 3, 3′-Diindolylmethane attenuates experimental arthritis and osteoclastogenesis. Biochem Pharmacol. 2010;79(5):715–721. doi:10.1016/j.bcp.2009.10.010
   Web of Science ®Google Scholar
• Katsuta T, Miyaji Y, Offit PA, et al. Treatment with quadrivalent human papillomavirus vaccine for juvenile-onset recurrent respiratory papillomatosis: case report and review of the literature. J Pediatric Infect Dis Soc. 2017;6(4):380–385. doi:10.1093/jpids/pix063
   Web of Science ®Google Scholar
• Zeligs MA. Diindolylmethane for the treatment of HPV infection. Google Patents. 2012
   Google Scholar
• Wattenberg LW, Weng J-R, Tsai C-H, Kulp SK, Chen C-S. Effects of dietary constituents on the metabolism of chemical carcinogens. Cancer Res. 1975;35(11 Part 2):3326–3331.
   Web of Science ®Google Scholar
• Loub WD, Wattenberg LW, Davis DW. Aryl hydrocarbon hydroxylase induction in rat tissues by naturally occurring indoles of cruciferous plants. J Natl Cancer Inst. 1975;54(4):985–988.
   PubMedGoogle Scholar
• Aggarwal BB, Ichikawa H. Molecular targets and anticancer potential of indole-3-carbinol and its derivatives. Cell Cycle. 2005;4(9):1201–1215. doi:10.4161/cc.4.9.1993
   PubMed Web of Science ®Google Scholar
• Stresser DM, Bailey GS, Williams DE, et al. The anticarcinogen 3,3ʹ-diindolylmethane is an inhibitor of cytochrome P-450. J Biochem Toxicol. 1995;10(4):191–201. doi:10.1002/jbt.2570100403
   PubMedGoogle Scholar
• Dalessandri KM, Firestone GL, Fitch MD, et al. Pilot study: effect of 3,3ʹ-diindolylmethane supplements on urinary hormone metabolites in postmenopausal women with a history of early-stage breast cancer. Nutr Cancer. 2004;50(2):161–167. doi:10.1207/s15327914nc5002_5
   PubMed Web of Science ®Google Scholar
• Le HT, Schaldach CM, Firestone GL, et al. Plant-derived 3,3ʹ-Diindolylmethane is a strong androgen antagonist in human prostate cancer cells. J Biol Chem. 2003;278(23):21136–21145. doi:10.1074/jbc.M300588200
   PubMed Web of Science ®Google Scholar
• 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(5):1134–1138. doi:10.1093/jn/134.5.1134
   PubMed Web of Science ®Google Scholar
• Higdon JV, Delage B, Williams DE, et al. Cruciferous vegetables and human cancer risk: epidemiologic evidence and mechanistic basis. Pharmacol Res. 2007;55(3):224–236. doi:10.1016/j.phrs.2007.01.009
   PubMed Web of Science ®Google Scholar
• Nachshon‐Kedmi M, Fares FA, Yannai S. Therapeutic activity of 3, 3′‐diindolylmethane on prostate cancer in an in vivo model. Prostate. 2004;61(2):153–160. doi:10.1002/pros.20092
   Web of Science ®Google Scholar
• Rahman KM, Banerjee S, Ali S, et al. 3,3ʹ-Diindolylmethane enhances taxotere-induced apoptosis in hormone-refractory prostate cancer cells through survivin down-regulation. Cancer Res. 2009;69(10):4468–4475. doi:10.1158/0008-5472.CAN-08-4423
   Web of Science ®Google Scholar
• Cho HJ, Park SY, Kim EJ, et al. 3, 3′‐diindolylmethane inhibits prostate cancer development in the transgenic adenocarcinoma mouse prostate model. Mol Carcinog. 2011;50(2):100–112. doi:10.1002/mc.20698
   Web of Science ®Google Scholar
• Wu T-Y, Jain MG, Hislop GT, et al. Epigenetic modifications of Nrf2 by 3, 3′-diindolylmethane in vitro in TRAMP C1 cell line and in vivo TRAMP prostate tumors. AAPS J. 2013;15(3):864–874. doi:10.1208/s12248-013-9493-3
   Web of Science ®Google Scholar
• Fares F, Azzam N, Appel B, et al. The potential efficacy of 3, 3′-diindolylmethane in prevention of prostate cancer development. Eur J Cancer Prev. 2010;19(3):199–203. doi:10.1097/CEJ.0b013e328333fbce
   Web of Science ®Google Scholar
• Bhuiyan MM, Li Y, Banerjee S, et al. 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. 2006;66(20):10064–10072. doi:10.1158/0008-5472.CAN-06-2011
   PubMed Web of Science ®Google Scholar
• Rahman KM, Ali S, Aboukameel A, et al. Inactivation of NF-kappaB by 3,3ʹ-diindolylmethane contributes to increased apoptosis induced by chemotherapeutic agent in breast cancer cells. Mol Cancer Ther. 2007;6(10):2757–2765. doi:10.1158/1535-7163.MCT-07-0336
   Web of Science ®Google Scholar
• Ahmad A, Ali S, Wang Z, et al. 3, 3′‐diindolylmethane enhances taxotere‐induced growth inhibition of breast cancer cells through downregulation of FoxM1. Int J Cancer. 2011;129(7):1781–1791. doi:10.1002/ijc.25839
   PubMed Web of Science ®Google Scholar
• Ali S, Banerjee S, Ahmad A, et al. Apoptosis-inducing effect of erlotinib is potentiated by 3,3ʹ-diindolylmethane in vitro and in vivo using an orthotopic model of pancreatic cancer. Mol Cancer Ther. 2008;7(6):1708–1719. doi:10.1158/1535-7163.MCT-08-0354
   PubMed Web of Science ®Google Scholar
• Banerjee S, Wang Z, Kong D, et al. 3, 3′-Diindolylmethane enhances chemosensitivity of multiple chemotherapeutic agents in pancreatic cancer. Cancer Res. 2009;69(13):5592–5600. doi:10.1158/0008-5472.CAN-09-0838
   Web of Science ®Google Scholar
• Kim YH, Kwon HS, Kim DH, et al. 3, 3′-diindolylmethane attenuates colonic inflammation and tumorigenesis in mice. Inflamm Bowel Dis. 2009;15(8):1164–1173. doi:10.1002/ibd.20917
   PubMed Web of Science ®Google Scholar
• Choi HJ, Park JHY. Induction of G1 and G2/M cell cycle arrests by the dietary compound 3, 3ʹ-diindolylmethane in HT-29 human colon cancer cells. BMC Gastroenterol. 2009;9(1):39. doi:10.1186/1471-230X-9-39
   PubMedGoogle Scholar
• Bhatnagar N, Li X, Chen Y, et al. 3, 3′-diindolylmethane enhances the efficacy of butyrate in colon cancer prevention through down-regulation of survivin. Cancer Prev Res. 2009;2(6):581–589. doi:10.1158/1940-6207.CAPR-08-0142
   Web of Science ®Google Scholar
• Femia AP, Garikapaty VPS, Ashok BT, et al. Sulindac, 3, 3ʹ-diindolylmethane and curcumin reduce carcinogenesis in the Pirc rat, an Apc-driven model of colon carcinogenesis. BMC Cancer. 2015;15(1):611. doi:10.1186/s12885-015-1627-9
   Google Scholar
• Kim EJ, Park SY, Shin HK, et al. Activation of caspase-8 contributes to 3, 3′-diindolylmethane-induced apoptosis in colon cancer cells. J Nutr. 2007;137(1):31–36. doi:10.1093/jn/137.1.31
   Web of Science ®Google Scholar
• Kim EJ, Shin M, Park H, et al. Oral administration of 3, 3′-diindolylmethane inhibits lung metastasis of 4T1 murine mammary carcinoma cells in BALB/c mice. J Nutr. 2009;139(12):2373–2379. doi:10.3945/jn.109.111864
   PubMed Web of Science ®Google Scholar
• Ichite N, Chougule MB, Jackson T, et al. Enhancement of docetaxel anticancer activity by a novel diindolylmethane compound in human non–small cell lung cancer. Clin Cancer Res. 2009;15(2):543–552. doi:10.1158/1078-0432.CCR-08-1558
   PubMed Web of Science ®Google Scholar
• Wu T, Chen C, Li F, et al. 3, 3ʹ‑Diindolylmethane inhibits the invasion and metastasis of nasopharyngeal carcinoma cells in vitro and in vivo by regulation of epithelial mesenchymal transition. Exp Ther Med. 2014;7(6):1635–1638. doi:10.3892/etm.2014.1649
   PubMed Web of Science ®Google Scholar
• Xu Y, Zhang J, Shi W, et al. Anticancer effects of 3, 3ʹ-diindolylmethane are associated with G1 arrest and mitochondria-dependent apoptosis in human nasopharyngeal carcinoma cells. Oncol Lett. 2013;5(2):655–662. doi:10.3892/ol.2012.1063
   Web of Science ®Google Scholar
• Xue L, Pestka J, Li M, et al. 3, 3′-Diindolylmethane stimulates murine immune function in vitro and in vivo. J Nutr Biochem. 2008;19(5):336–344. doi:10.1016/j.jnutbio.2007.05.004
   PubMed Web of Science ®Google Scholar
• Cho HJ, Seon MR, Lee YM, et al. 3, 3′-Diindolylmethane suppresses the inflammatory response to lipopolysaccharide in murine macrophages. J Nutr. 2008;138(1):17–23. doi:10.1093/jn/138.1.17
   Web of Science ®Google Scholar
• Bradlow HL, Michnovicz JJ, Telang NT, et al. Effects of dietary indole-3-carbinol on estradiol metabolism and spontaneous mammary tumors in mice. Carcinogenesis. 1991;12(9):1571–1574. doi:10.1093/carcin/12.9.1571
   Web of Science ®Google Scholar
• Roy A, Ganguly A, BoseDasgupta S, et al. 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. 2008;74(5):1292–1307. doi:10.1124/mol.108.050161
   Web of Science ®Google Scholar
• Bharate SB, Bharate JB, Khan SI, et al. Discovery of 3, 3′-diindolylmethanes as potent antileishmanial agents. Eur J Med Chem. 2013;63:435–443.
   PubMed Web of Science ®Google Scholar
• Roy A, Das BB, Ganguly, A, et al. An insight into the mechanism of inhibition of unusual bi-subunit topoisomerase I from Leishmania donovani by 3, 3′-di-indolylmethane, a novel DNA topoisomerase I poison with a strong binding affinity to the enzyme. Biochem J. 2007;409(2):611–622.
   Google Scholar
• Rieck GC, Fiander AN. Human papillomavirus, cervical carcinogenesis and chemoprevention with Indole derivates–a review of pathomechanisms. Mol Nutr Food Res. 2008;52(1):105–113.
   Web of Science ®Google Scholar
• Sepkovic DW, Stein J, Carlisle AD, et al. Results from a dose–response study using 3, 3′-diindolylmethane in the K14-HPV16 transgenic mouse model: cervical histology. Cancer Prev Res. 2011;4(6):890–896.
   Web of Science ®Google Scholar
• Auborn KJ, Carter TH. Treatment of human papillomavirus gynecologic infections. Clin Lab Med. 2000;20(2):407–422.
   Web of Science ®Google Scholar
• Ashrafian L, Sukhikh G, Kiselev V, et al. Double-blind randomized placebo-controlled multicenter clinical trial (phase IIa) on diindolylmethane’s efficacy and safety in the treatment of CIN: implications for cervical cancer prevention. EPMA J. 2015;6(1):25.
   Google Scholar
• Luo Y, Wang TT, Teng Z et al. Encapsulation of indole-3-carbinol and 3, 3′-diindolylmethane in zein/carboxymethyl chitosan nanoparticles with controlled release property and improved stability. Food Chem. 2013;139(1–4):224–230.
   PubMed Web of Science ®Google Scholar
• McAlindon T, Gulin J, Chen T, et al. Indole-3-carbinol in women with SLE: effect on estrogen metabolism and disease activity. Lupus. 2001;10(11):779–783.
   Web of Science ®Google Scholar
• Wong GY, Bradlow L, Sepkovic D, et al. Dose‐ranging study of Indole‐3‐Carbinol for breast cancer prevention. J Cell Biochem. 1997;67(S28‒29):111–116.
   Google Scholar
• Rosen CA, Woodson GE, Thomson JW, et al. Preliminary results of the use of indole-3-carbinol for recurrent respiratory papillomatosis. Otolaryngol Head Neck Surg. 1998;118(6):810–815.
   PubMed Web of Science ®Google Scholar
• 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(11):2257–2264.
   Web of Science ®Google Scholar
• Kim DJ, Han BS, Ahn B, et al. Enhancement by indole-3-carbinol of liver and thyroid gland neoplastic development in a rat medium-term multiorgan carcinogenesis model. Carcinogenesis. 1997;18(2):377–381.
   Web of Science ®Google Scholar
• Pence BC, Buddingh F, Yang SP. Multiple dietary factors in the enhancement of dimethylhydrazine carcinogenesis: main effect of indole-3-carbinol. J Natl Cancer Inst. 1986;77(1):269–276.
   Google Scholar
• Anderton MJ, Manson MM, Verschoyle R, et al. Physiological modeling of formulated and crystalline 3,3ʹ-diindolylmethane pharmacokinetics following oral administration in mice. Drug Metab Dispos. 2004;32(6):632–638. doi:10.1124/dmd.32.6.632
   Web of Science ®Google Scholar
• Sepkovic DW, Bradlow HL, Bell M. Quantitative determination of 3,3ʹ-diindolylmethane in urine of individuals receiving indole-3-carbinol. Nutr Cancer. 2001;41(1–2):57–63.
   Web of Science ®Google Scholar
• Bradlow HL, Zeligs MA. Diindolylmethane (DIM) spontaneously forms from indole-3-carbinol (I3C) during cell culture experiments. In Vivo (Brooklyn). 2010;24(4):387–391.
   PubMed Web of Science ®Google Scholar
• Zeligs MA, Jacobs IC. Compositions and methods of adjusting steroid hormone metabolism through phytochemicals. Google Patents. 2000
   Google Scholar
• Reed GA, Arneson DW, Putnam WC, et al. Single-dose and multiple-dose administration of indole-3-carbinol to women: pharmacokinetics based on 3,3ʹ-diindolylmethane. Cancer Epidemiol Biomarkers Prev. 2006;15(12):2477–2481.
   PubMed Web of Science ®Google Scholar
• Kravchenko LV, Avren'eva LI, Guseva GV, et al. Effect of nutritional indoles on activity of xenobiotic metabolism enzymes and T-2 toxicity in rats. Bull Exp Biol Med. 2001;131(6):544–547.
   Web of Science ®Google Scholar
• Fujioka N, Ainslie-Waldman CE, Upadhyaya P, et al. Urinary 3,3ʹ-diindolylmethane: a biomarker of glucobrassicin exposure and indole-3-carbinol uptake in humans. Cancer Epidemiol Biomarkers Prev. 2014;23(2):282–287.
   Web of Science ®Google Scholar
• Fujioka N, Ransom BW, Carmella SG, et al. Harnessing the power of cruciferous vegetables: developing a biomarker for brassica vegetable consumption using urinary 3,3ʹ-diindolylmethane. Cancer Prev Res. 2016;9(10):788–793.
   Web of Science ®Google Scholar
• Gee JR, Saltzstein DR, Messing E, et al. Phase Ib placebo-controlled, tissue biomarker trial of diindolylmethane (BR-DIMNG) in patients with prostate cancer who are undergoing prostatectomy. Eur J Cancer Prev. 2016;25(4):312–320.
   Web of Science ®Google Scholar
• Rajoria S, Suriano R, Parmar PS, et al. 3,3ʹ-diindolylmethane modulates estrogen metabolism in patients with thyroid proliferative disease: a pilot study. Thyroid. 2011;21(3):299–304.
   Web of Science ®Google Scholar
• Heath EI, Heilbrun LK, Li J, et al. A Phase I dose-escalation study of oral BR-DIM (BioResponse 3,3ʹ- Diindolylmethane) in castrate-resistant, non-metastatic prostate cancer. Am J Transl Res. 2010;2(4):402–411.
   Web of Science ®Google Scholar
• Hwang C, Sethi S, Heilbrun LK, et al. Anti-androgenic activity of absorption-enhanced 3, 3ʹ-diindolylmethane in prostatectomy patients. Am J Transl Res. 2016;8(1):166.
   PubMed Web of Science ®Google Scholar
• Hong C, Kim H-A, Firestone GL, et al. 3, 3′-Diindolylmethane (DIM) induces a G1 cell cycle arrest in human breast cancer cells that is accompanied by Sp1-mediated activation of p21WAF1/CIP1 expression. Carcinogenesis. 2002;23(8):1297–1305.
   Web of Science ®Google Scholar
• Smith S, Sepkovic D, Bradlow HL, et al. 3, 3′-Diindolylmethane and genistein decrease the adverse effects of estrogen in LNCaP and PC-3 prostate cancer cells. J Nutr. 2008;138(12):2379–2385.
   Web of Science ®Google Scholar
• Bovee TF, Schoonen WG, Hamers AR, et al. Screening of synthetic and plant-derived compounds for (anti) estrogenic and (anti) androgenic activities. Anal Bioanal Chem. 2008;390(4):1111–1119.
   PubMed Web of Science ®Google Scholar
• Bryant HU, Dere WH. Selective estrogen receptor modulators: an alternative to hormone replacement therapy. Proc Soc Exp Biol Med. 1998;217(1):45–52.
   PubMed Web of Science ®Google Scholar
• Jordan VC. Antiestrogens and selective estrogen receptor modulators as multifunctional medicines. 2. Clinical considerations and new agents. J Med Chem. 2003;46(7):1081–1111.
   PubMed Web of Science ®Google Scholar
• Nuttall ME, Bradbeer JN, Stroup GB, et al. Idoxifene: a novel selective estrogen receptor modulator prevents bone loss and lowers cholesterol levels in ovariectomized rats and decreases uterine weight in intact rats. Endocrinology. 1998;139(12):5224–5234.
   Web of Science ®Google Scholar
• Oseni T, Patel R, Pyle J, et al. Selective estrogen receptor modulators and phytoestrogens. Planta Med. 2008;74(13):1656–1665.
   PubMed Web of Science ®Google Scholar
• Tsuchiya Y, Nakajima M, Yokoi T. Cytochrome P450-mediated metabolism of estrogens and its regulation in human. Cancer Lett. 2005;227(2):115–124.
   PubMed Web of Science ®Google Scholar
• Martucci CP, Fishman J. P450 enzymes of estrogen metabolism. Pharmacol Ther. 1993;57(2–3):237–257.
   PubMed Web of Science ®Google Scholar
• Bradlow H, Telang N, Sepkovic D, et al. 2-hydroxyestrone: the ‘good’ estrogen. J Endocrinol. 1996;150(3_Suppl):S259–S265.
   Google Scholar
• Telang NT, Suto A, Wong GY, et al. Induction by estrogen metabolite 16α;-hydroxyestrone of genotoxic damage and aberrant proliferation in mouse mammary epithelial cells. J Natl Cancer Inst. 1992;84(8):634–638. doi:10.1093/jnci/84.8.634
   Google Scholar
• Yuan F, Chen DZ, Liu K, et al. Anti-estrogenic activities of indole-3-carbinol in cervical cells: implication for prevention of cervical cancer. Anticancer Res. 1999;19(3A):1673–1680.
   Web of Science ®Google Scholar
• Muti P, Bradlow HL, Micheli A, et al. Estrogen metabolism and risk of breast cancer: a prospective study of the 2: 16α-hydroxyestrone ratio in premenopausal and postmenopausal women. Epidemiology. 2000;11(6):635–640.
   Web of Science ®Google Scholar
• Im A, Vogel VG, Ahrendt G, et al. Urinary estrogen metabolites in women at high risk for breast cancer. Carcinogenesis. 2009;30(9):1532–1535. doi:10.1093/carcin/bgp139
   Web of Science ®Google Scholar
• Ursin G, London S, Stanczyk FZ, et al. Urinary 2-hydroxyestrone/16α-hydroxyestrone ratio and risk of breast cancer in postmenopausal women. J Natl Cancer Inst. 1999;91(12):1067–1072.
   PubMedGoogle Scholar
• Cauley JA, Zmuda JM, Danielson ME, et al. Estrogen metabolites and the risk of breast cancer in older women. Epidemiology. 2003;14(6):740–744. doi:10.1097/01.ede.0000091607.77374.74
   Web of Science ®Google Scholar
• Rajoria S, Suriano R, Wilson YL, et al. 3,3ʹ-diindolylmethane inhibits migration and invasion of human cancer cells through combined suppression of ERK and AKT pathways. Oncol Rep. 2011;25(2):491–497. doi:10.3892/or.2010.1076
   Web of Science ®Google Scholar
• Thomson CA, Chow HHS, Wertheim BC, et al. A randomized, placebo-controlled trial of diindolylmethane for breast cancer biomarker modulation in patients taking tamoxifen. Breast Cancer Res Treat. 2017;165(1):97–107. doi:10.1007/s10549-017-4292-7
   PubMed Web of Science ®Google Scholar
• Nikitina D, Llacuachaqui M, Sepkovic D, et al. The effect of oral 3,3ʹ-diindolylmethane supplementation on the 2:16alpha-OHE ratio in BRCA1 mutation carriers. Fam Cancer. 2015;14(2):281–286. doi:10.1007/s10689-015-9783-2
   Web of Science ®Google Scholar
• Kotsopoulos J, Zhang S, Akbari M, et al. BRCA1 mRNA levels following a 4-6-week intervention with oral 3,3ʹ-diindolylmethane. Br J Cancer. 2014;111(7):1269–1274. doi:10.1038/bjc.2014.391
   Web of Science ®Google Scholar
• Turner N, Reis-Filho JS, Russell AM, et al. BRCA1 dysfunction in sporadic basal-like breast cancer. Oncogene. 2007;26(14):2126. doi:10.1038/sj.onc.1210014
   PubMed Web of Science ®Google Scholar
• Thompson ME, Jensen RA, Obermiller PS, et al. Decreased expression of BRCA1 accelerates growth and is often present during sporadic breast cancer progression. Nat Genet. 1995;9(4):444. doi:10.1038/ng0495-444
   PubMed Web of Science ®Google Scholar
• Dobrovic A, Simpfendorfer D. Methylation of the BRCA1 gene in sporadic breast cancer. Cancer Res. 1997;57(16):3347–3350.
   PubMed Web of Science ®Google Scholar
• Van’t Veer LJ, Dai H, van de Vijver MJ, et al. Gene expression profiling predicts clinical outcome of breast cancer. Nature. 2002;415(6871):530. doi:10.1038/415530a
   PubMed Web of Science ®Google Scholar
• Abdelbaqi K,Lack N, Guns ET, et al. Antiandrogenic and growth inhibitory effects of ring‐substituted analogs of 3, 3′‐diindolylmethane (Ring‐DIMs) in hormone‐responsive LNCaP human prostate cancer cells. Prostate. 2011;71(13):1401–1412.
   Web of Science ®Google Scholar
• Vasaitis T, Belosay A, Schayowitz A, et al. Androgen receptor inactivation contributes to antitumor efficacy of 17α-hydroxylase/17, 20-lyase inhibitor 3β-hydroxy-17-(1H-benzimidazole-1-yl) androsta-5, 16-diene in prostate cancer. Mol Cancer Ther. 2008;7(8):2348–2357.
   PubMed Web of Science ®Google Scholar
• Vivar OI, Lin C-L, Firestone GL, et al. 3, 3′-Diindolylmethane induces a G1 arrest in human prostate cancer cells irrespective of androgen receptor and p53 status. Biochem Pharmacol. 2009;78(5):469–476.
   PubMed Web of Science ®Google Scholar
• Cohen JH, Kristal AR, Stanford JL. Fruit and vegetable intakes and prostate cancer risk. J Natl Cancer Inst. 2000;92(1):61–68. doi:10.1093/jnci/92.1.61
   PubMedGoogle Scholar
• Jain MG, Hislop GT, Howe GR, et al. Plant foods, antioxidants, and prostate cancer risk: findings from case-control studies in Canada. Nutr Cancer. 1999;34(2):173–184. doi:10.1207/S15327914NC3402_8
   PubMed Web of Science ®Google Scholar
• Joseph MA, Moysich KB, Freudenheim JL, et al. Cruciferous vegetables, genetic polymorphisms in glutathione S-transferases M1 and T1, and prostate cancer risk. Nutr Cancer. 2004;50(2):206–213. doi:10.1207/s15327914nc5002_11
   PubMed Web of Science ®Google Scholar
• Kolonel LN, Hankin JH, Whittemore AS, et al. Vegetables, fruits, legumes and prostate cancer: a multiethnic case-control study. Cancer Epidemiol Prev Biomarkers. 2000;9(8):795–804.
   PubMed Web of Science ®Google Scholar
• Giovannucci E, Rimm EB, Liu Y, et al. A prospective study of cruciferous vegetables and prostate cancer. Cancer Epidemiol Prev Biomarkers. 2003;12(12):1403–1409.
   PubMed Web of Science ®Google Scholar
• Hsing AW, McLaughlin JK, Schuman LM, et al. Diet, tobacco use, and fatal prostate cancer: results from the Lutheran Brotherhood Cohort Study. Cancer Res. 1990;50(21):6836–6840.
   PubMed Web of Science ®Google Scholar
• Key TJ, Allen N, Appleby P, et al. Fruits and vegetables and prostate cancer: no association among 1104 cases in a prospective study of 130,544 men in the European Prospective Investigation into Cancer and Nutrition (EPIC). Int J Cancer. 2004;109(1):119–124. doi:10.1002/ijc.11671
   Web of Science ®Google Scholar
• Schuurman AG, Goldbohm RA, Dorant E, et al. Vegetable and fruit consumption and prostate cancer risk: a cohort study in The Netherlands. Cancer Epidemiol Prev Biomarkers. 1998;7(8):673–680.
   Web of Science ®Google Scholar
• Kong D, Heath E, Chen W, et al. Loss of let-7 up-regulates EZH2 in prostate cancer consistent with the acquisition of cancer stem cell signatures that are attenuated by BR-DIM. PLoS One. 2012;7(3):e33729. doi:10.1371/journal.pone.0033729
   PubMed Web of Science ®Google Scholar
• Li Y, VandenBoom TG, Kong D, et al. 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. 2009;69(16):6704–6712. doi:10.1158/0008-5472.CAN-09-1298
   PubMed Web of Science ®Google Scholar
• Lilja H, Ulmert D, Vickers AJ. Prostate-specific antigen and prostate cancer: prediction, detection and monitoring. Nat Rev Cancer. 2008;8(4):268. doi:10.1038/nrc2351
   PubMed Web of Science ®Google Scholar
• Oesterling JE. Prostate-specific antigen and prostate cancer. Curr Opin Urol. 1992;2(5):348–355. doi:10.1097/00042307-199210000-00006
   Google Scholar
• Partin AW, Kattan MW, Subong EN, et al. Combination of prostate-specific antigen, clinical stage, and Gleason score to predict pathological stage of localized prostate cancer: a multi-institutional update. JAMA. 1997;277(18):1445–1451. doi:10.1001/jama.1997.03540420041027
   PubMed Web of Science ®Google Scholar
• Ahmad A, Kong D, Sarkar SH, et al. 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. 2009;107(3):516–527. doi:10.1002/jcb.22152
   PubMed Web of Science ®Google Scholar
• Li Y, Wang Z, Kong D, et al. Regulation of FOXO3a/β-catenin/GSK-3β signaling by 3, 3′-diindolylmethane contributes to inhibition of cell proliferation and induction of apoptosis in prostate cancer cells. J Biol Chem. 2007;282(29):21542–21550. doi:10.1074/jbc.M701978200
   Web of Science ®Google Scholar
• Kjær SK, van den Brule AJC, Bock JE, et al. Human papillomavirus—the most significant risk determinant of cervical intraepithelial neoplasia. Int J Cancer. 1996;65(5):601–606. doi:10.1002/(SICI)1097-0215(19960301)65:5<601::AID-IJC8>3.0.CO;2-6
   Web of Science ®Google Scholar
• Koutsky L. Epidemiology of genital human papillomavirus infection. Am J Med. 1997;102(5):3–8. doi:10.1016/S0002-9343(97)00177-0
   PubMedGoogle Scholar
• Ho GY, Burk RD, Klein S, et al. Persistent genital human papillomavirus infection as a risk factor for persistent cervical dysplasia. J Natl Cancer Inst. 1995;87(18):1365–1371. doi:10.1093/jnci/87.18.1365
   PubMed Web of Science ®Google Scholar
• Schiffman M, Castle PE. Human papillomavirus: epidemiology and public health. Arch Pathol Lab Med. 2003;127(8):930–934.
   PubMed Web of Science ®Google Scholar
• Zur Hausen H. Papillomaviruses and cancer: from basic studies to clinical application. Nat Rev Cancer. 2002;2(5):342. doi:10.1038/nrc798
   PubMed Web of Science ®Google Scholar
• Del Priore G, Gudipudi DK, Montemarano N, et al. Oral diindolylmethane (DIM): pilot evaluation of a nonsurgical treatment for cervical dysplasia. Gynecol Oncol. 2010;116(3):464–467. doi:10.1016/j.ygyno.2009.10.060
   Web of Science ®Google Scholar
• Paltsev M, Kiselev V, Muyzhnek E, et al. Safety and tolerability of DIM-based therapy designed as personalized approach to reverse prostatic intraepithelial neoplasia (PIN). EPMA J. 2014;5(1):18. doi:10.1186/1878-5085-5-18
   Google Scholar
• Paltsev M, Kiselev V, Drukh V, et al. First results of the double-blind randomized placebo-controlled multicenter clinical trial of DIM-based therapy designed as personalized approach to reverse prostatic intraepithelial neoplasia (PIN). EPMA J. 2016;7(1):5. doi:10.1186/s13167-016-0057-3
   Google Scholar
• Castanon A, Tristram A, Mesher D, et al. Effect of diindolylmethane supplementation on low-grade cervical cytological abnormalities: double-blind, randomised, controlled trial. Br J Cancer. 2012;106(1):45–52. doi:10.1038/bjc.2011.496
   Web of Science ®Google Scholar
• Reed GA, Sunega JM, Sullivan DK, et al. Single-dose pharmacokinetics and tolerability of absorption-enhanced 3,3ʹ-diindolylmethane in healthy subjects. Cancer Epidemiol Biomarkers Prev. 2008;17(10):2619–2624. doi:10.1158/1055-9965.EPI-08-0520
   Web of Science ®Google Scholar
• Lorincz AT, Brentnall AR, Vasiljević N, et al. HPV16 L1 and L2 DNA methylation predicts high-grade cervical intraepithelial neoplasia in women with mildly abnormal cervical cytology. Int J Cancer. 2013;133(3):637–644. doi:10.1002/ijc.28050
   Web of Science ®Google Scholar
• Morales-Prieto DM, Herrmann J, Osterwald H, et al. Comparison of dienogest effects upon 3,3ʹ-diindolylmethane supplementation in models of endometriosis and clinical cases. Reprod Biol. 2018;18(3):252–258. doi:10.1016/j.repbio.2018.07.002
   Web of Science ®Google Scholar