Diindolylmethane

• How It Works

  Diindolylmethane (DIM) has anticancer effects but clinical data are limited.

  Diindolylmethane is a compound found in cruciferous vegetables including broccoli, cabbage, and cauliflower. It showed anti-inflammatory and anticancer effects in laboratory and animal studies. It was also shown to increase bone mass, which may have implications for patients with osteoporosis. Clinical studies show that DIM may benefit patients with castration-resistant prostate cancer and help reverse cervical intraepithelial neoplasia (abnormal changes in cells on the surface of the cervix). More studies are needed.

• Purported Uses
  • Cancer Prevention
    Studies suggest that DIM may benefit patients with castration-resistant prostate cancer and help reverse cervical intraepithelial neoplasia.
  • Estrogen metabolism
    DIM supplementation resulted in changes in estrogen urinary metabolites in post menopausal women with a history of early stage breast cancer.
  • Detoxification
    There is no scientific evidence to back this claim.
• Do Not Take If
  • You are taking drugs that are substrates of Cytochrome P450: DIM may make them less effective.
  • You are taking drugs that are substrates of Multidrug Resistance Protein (MDR1): DIM can reduce their effectiveness.
• Side Effects
  • Central serous chorioretinopathy (CSCR), an idiopathic disease resulting in visual impairment, was reported in a healthy female patient after excessive daily intake of DIM for 2-months. Her symptoms resolved 8 weeks after discontinuing the use of DIM.
  • Rash with eosinophilia (an increase in the number of eosinophils in the blood, occurring in response to some allergens or drugs) has been reported following use of DIM.
• Special Point

  DIM (and I3C) were shown to alter estrogen urinary metabolite profiles in women. However, their effects on breast cancer risk are unknown.

• Scientific Name

  3,3′-diindolylmethane

• Clinical Summary

  Diindolylmethane (DIM) is a metabolite of Indole-3-carbinol (I3C), a compound found in cruciferous vegetables including broccoli, cabbage and cauliflower. It is the most studied of all I3C metabolites and is thought to be superior to IC3 as a chemoprotective compound for breast cancer and prostate cancer ⁽³⁾.

  DIM demonstrated anti-inflammatory ^(16) (17), antiproliferative ⁽¹⁶⁾ and chemopreventive ⁽¹⁸⁾ effects in vitro and in animal models. It was also shown to increase bone mass ⁽¹⁹⁾, which may have implications for patients with osteoporosis.

  Limited clinical data indicate that daily supplementation with DIM may benefit patients with castration-resistant prostate cancer by inhibiting androgen receptor ⁽²⁰⁾. But DIM supplementation did not exert any positive effects in women with cervical cell abnormalities ⁽¹³⁾ although conflicting evidence indicates that it may help reverse cervical intraepithelial neoplasia ⁽²¹⁾. Additional studies are needed.

  A pilot study showed that daily DIM leads to changes in estrogen metabolism in postmenopausal women with a history of early stage breast cancer ⁽⁴⁾. In a RCT of estrogen receptor-positive breast cancer patients taking tamoxifen, daily DIM promoted an increase in the metabolite ratio of 2-hydroxyestrone (2-OHE1) (anti-tumorigenic) to 16α-hydroxyestrone (16α-OHE1) (pro-tumorigenic) ⁽²⁵⁾.  However, this increase was coupled with a reduction in metabolites from tamoxifen. More research is needed to elucidate the pharmacokinetics and clinical efficacy of tamoxifen when taken with DIM.

• Food Sources

  Vegetables including broccoli, Brussels sprouts, cauliflower and cabbage ⁽¹⁾

• Purported Uses
  • Cancer prevention
  • Estrogen metabolism
  • Detoxification
• Mechanism of Action

  Diindolylmethane (DIM), a metabolite of I3C, can induce apoptosis by modulating the expression of the Bax/Bcl-2. It demonstrated antiproliferative effects in animal and cancer cell models ⁽¹⁾. It was also shown to inhibit invasion of normal tissue by cancer cells, and to inhibit angiogenesis in cell culture models ⁽⁵⁾. DIM induces apoptosis in pancreatic cancer cells ⁽⁶⁾ and enhances the effect of erlotinib ⁽⁷⁾. In colon cancer and prostate cancer cells, DIM inhibits CDK activities ^(8) (9) and induces apoptosis by down regulating survivin ^(10) (11). DIM supplementation alters estrogen urinary metabolite profiles in women ⁽⁴⁾ and has androgen-antagonistic effects ⁽¹⁴⁾. It also inhibits prostate cancer cell proliferation and induces apoptosis through Akt activation, NF-KB DNA binding, and androgen receptor phosphorylation ⁽¹⁵⁾.

• Adverse Reactions
  • Central serous chorioretinopathy (CSCR), an idiopathic disease resulting in visual impairment, was reported in a healthy female patient after excessive daily intake of DIM for 2-months. Her symptoms resolved 8 weeks after discontinuing use of DIM ⁽²²⁾.
  • Rash with eosinophilia and systemic symptoms have been reported following use of DIM ⁽²³⁾.
• Herb-Drug Interactions
  • Tamoxifen: DIM modulates Phase I metabolism through several CYP isoenzymes, resulting in favorable estrogen metabolism and sex hormone-binding globulin (SHBG) levels.  However, one clinical study showed a significant decrease in serum endoxifen, without adversely affecting breast density or SHBG ⁽²⁴⁾.

    (Endoxifen is an active metabolite of tamoxifen during Phase I metabolism, and exhibits higher affinity for ER)

• Herb Lab Interactions

  DIM supplementation has been shown to alter estrogen urinary metabolites in women ⁽⁴⁾.

• References

  1. Minich DM, Bland JS. A review of the clinical efficacy and safety of cruciferous vegetable phytochemicals. Nutr Rev 2007;65(6 Pt 1):259-267.

  2. Howells LM, Moiseeva EP, Neal CP et al. Predicting the physiological relevance of in vitro cancer preventive activities of phytochemicals. Acta Pharmacol Sin 2007;28(9):1274-1304.

  3. Bradlow HL. Review. Indole-3-carbinol as a chemoprotective agent in breast and prostate cancer. In Vivo 2008;22(4):441-445.

  4. Dalessandri KM, Firestone GL, Fitch MD, Bradlow HL, Bjeldanes LF.Pilot study: effect of 3,3’-diindolylmethane supplements on urinary hormone metabolites in postmenopausal women with a history of early-stage breast cancer. Nutr Cancer 2004;50(2), 161-167.

  5. Higdon JV, Delage B, Williams DE, Dashwood RH. Cruciferous vegetables and human cancer risk: epidemiologic evidence and mechanistic basis. Pharmacol Res 2007;55(3):224-236.

  6. Azmi AS, Ahmad A, Banerjee S et al. Chemoprevention of pancreatic cancer: characterization of Par-4 and its modulation by 3,3’ diindolylmethane (DIM). Pharm Res 2008;25(9):2117-2124.

  7. Ali S, Banerjee S, Ahmad A 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(6):1708-1719.

  8. Choi HJ, Lim DY, Park JH. 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 2009;9(1):39.

  9. Chinnakannu K, Chen D, Li Y et al. Cell cycle-dependent effects of 3,3’-diindolylmethane on proliferation and apoptosis of prostate cancer cells. J Cell Physiol 2009;219(1):94-99.

  10. 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 (Phila Pa) 2009;2(6):581-589.

  11. Rahman KM, Banerjee S, Ali S et al. 3,3’-Diindolylmethane enhances taxotere-induced apoptosis in hormone-refractory prostate cancer cells through survivin down-regulation. Cancer Res 2009;69(10):4468-4475.

  12. Reed GA, Sunega JM, Sullivan DK et al. Single-dose pharmacokinetics and tolerability of absorption-enhanced 3,3’-diindolylmethane in healthy subjects. Cancer Epidemiol Biomarkers Prev 2008;17(10):2619-2624.

  13. Castañon 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 Jan 3;106(1):45-52.

  14. Le HT, Schaldach CM, Firestone GL, et al. Plant-derived 3,3’-Diindolylmethane is a strong androgen antagonist in human prostate cancer cells. J Biol Chem. 2003 Jun 6;278(23):21136-45.

  15. 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 Oct 15;66(20):10064-72.

  16. Prabhu B, Balakrishnan D, Sundaresan S. Antiproliferative and anti-inflammatory properties of diindolylmethane and lupeol against N-butyl-N-(4-hydroxybutyl) nitrosamine induced bladder carcinogenesis in experimental rats. Hum Exp Toxicol. 2015 Aug 6. pii: 0960327115597985. [Epub ahead of print]

  17. Ye Y, Miao S, Wang Y, Zhou J, Lu R. 3,3’-diindolylmethane potentiates tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis of gastric cancer cells. Oncol Lett. 2015 May;9(5):2393-2397.

  18. Qian X, Song JM, Melkamu T, Upadhyaya P, Kassie F. Chemoprevention of lung tumorigenesis by intranasally administered diindolylmethane in A/J mice. Carcinogenesis. 2013 Apr;34(4):841-9.

  19. Yu TY, Pang WJ, Yang GS. 3,3’-Diindolylmethane increases bone mass by suppressing osteoclastic bone resorption in mice. J Pharmacol Sci. 2015 Jan;127(1):75-82.

  20. Li Y, Sarkar FH. Role of BioResponse 3,3’-Diindolylmethane in the Treatment of Human Prostate Cancer: Clinical Experience. Med Princ Pract. 2015 Oct 27. [Epub ahead of print

  21. 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 Dec 21;6:25.

  22. Bussel II, Lally DR, Waheed NK. Bilateral central serous chorioretinopathy associated with estrogen modulator diindolylmethane. Ophthalmic Surg Lasers Imaging Retina. 2014 Nov-Dec;45(6):589-91.

  23. Le TM, Sanders CJ, van de Corput L, van Erpecum KJ, Röckmann H. Drug rash with eosinophilia and systemic symptoms caused by the dietary supplement diindolylmethane. J Allergy Clin Immunol Pract. 2016 Jan-Feb;4(1):175-6.

  24. Pondugula SR, Flannery PC, Abbott KL, et al. Diindolylmethane, a naturally occurring compound, induces CYP3A4 and MDR1 gene expression by activating human PXR. Toxicol Lett. 2015 Feb 3;232(3):580-9.

  25. 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 Aug;165(1):97-107. Epub 2017 May 30.