DIM Supplement

Per Sloan-Kettering

Uses

• Cancer prevention
• Estrogen metabolism
• Detoxification

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.

DIM demonstrated anti-inflammatory, antiproliferative  and chemopreventive effects in vitro and in animal models. It was also shown to increase bone mass, 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. But DIM supplementation did not exert any positive effects in women with cervical cell abnormalities  although conflicting evidence indicates that it may help reverse cervical intraepithelial neoplasia . 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. 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).  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.

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. It was also shown to inhibit invasion of normal tissue by cancer cells, and to inhibit angiogenesis in cell culture models. DIM induces apoptosis in pancreatic cancer cells and enhances the effect of erlotinib. In colon cancer and prostate cancer cells, DIM inhibits CDK activities  and induces apoptosis by down regulating survivin . DIM supplementation alters estrogen urinary metabolite profiles in women and has androgen-antagonistic effects. It also inhibits prostate cancer cell proliferation and induces apoptosis through Akt activation, NF-KB DNA binding, and androgen receptor phosphorylation.

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 .
• Rash with eosinophilia and systemic symptoms have been reported following use of DIM. . Drug rash with eosinophilia and systemic symptoms caused by the dietary supplement diindolylmethane.

Herb/Drug Interactions

• Cytochrome P450 substrates: DIM induces CYP3A4 and may affect the serum concentration of drugs metabolized by this enzyme.
• Multidrug Resistance Protein (MDR1) subsrates: DIM was also shown to induce MDR1 and can affect the transport of drugs mediated by this protein.

Lab Interactions

DIM supplementation has been shown to alter estrogen urinary metabolites in women

Studies

Single-dose pharmacokinetics and tolerability of absorption-enhanced 3,3’-diindolylmethane in healthy subjects. 

Antibacterial/Antifungal

The anticancer agent 3,3'-diindolylmethane Inhibits multispecies biofilm formation by acne-causing bacteria and Candida albicans.

Cancer

• Antiproliferative and anti-inflammatory properties of diindolylmethane and lupeol against N-butyl-N-(4-hydroxybutyl) nitrosamine induced **bladder carcinogenesis** in experimental rats.
• Pilot study: effect of 3,3’-diindolylmethane supplements on urinary hormone metabolites in postmenopausal women with a history of early-stage **breast cancer**. 
• A randomized, placebo-controlled trial of diindolylmethane for **breast cancer** biomarker modulation in patients taking tamoxifen
• This review describes current evidence related to the metabolism and mechanisms of DIM involved in the prevention of **breast cancer**
• 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**.
• Induction of G1 and G2/M cell cycle arrests by the dietary compound 3,3’-diindolylmethane in HT-29 human **colon cancer** cells. 
• 3,3’-Diindolylmethane Enhances the Efficacy of Butyrate in **Colon Cancer** Prevention through Down-Regulation of Survivin.
• A synergistic induction of apoptosis and inhibition of cell proliferation was observed in human **colorectal cancer** cells treated with the combination of capsaicin and DIM.
• 3,3’-diindolylmethane potentiates tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis of **gastric cancer** cells. 
• 3,3'-Diindolylmethane induces ferroptosis by BAP1-IP3R axis in BGC-823 **gastric cancer** cells.
• The studies to date offer strong evidence to support the use of DIM as an anticancer and therapeutic agent for **gastrointestinal cancer**.
• Chemoprevention of **lung tumorigenesis** by intranasally administered diindolylmethane in A/J mice.
• 7,8-Dihydroxyflavone suppresses proliferation and induces apoptosis of human **osteosarcoma** cells.
• Multidrug Resistant Cancer Cells: These data provide a rationale for the use of DIM as a promising radio-sensitizer to MDR cancer cells.
• Chemoprevention of **pancreatic cancer**: characterization of Par-4 and its modulation by 3,3’ diindolylmethane (DIM). 
• Apoptosis-inducing effect of erlotinib is potentiated by 3,3’-diindolylmethane in vitro and in vivo using an orthotopic model of **pancreatic cancer**.
• 3,3’-Diindolylmethane enhances taxotere-induced apoptosis in hormone-refractory **prostate cancer** cells through survivin down-regulation.
• Cell cycle-dependent effects of 3,3’-diindolylmethane on proliferation and apoptosis of **prostate cancer** cells. 
• Role of BioResponse 3,3’-Diindolylmethane in the Treatment of Human **Prostate Cancer**: Clinical Experience.
• Indole-3-carbinol as a chemoprotective agent in **breast and prostate cancer**. 
• 3,3'-diindolylmethane (DIM) has multiple anticancer properties making it one of the most hopeful phytochemicals in treating and preventing **prostate cancer and HGPIN**.

Neuroprotective

• The neuroprotective action of 3,3'-diindolylmethane against ischemia involves an inhibition of apoptosis and autophagy.
• Suggesting 7,8-dihydroxyflavone as a promising nutraceutical against CNS disorders.

Osteoporosis

7,8-Dihydroxyflavone modulates bone formation and resorption and ameliorates ovariectomy-induced osteoporosis.

Other Effects

• Bilateral central serous chorioretinopathy associated with estrogen modulator diindolylmethane. 
• Effect of diindolylmethane supplementation on low-grade cervical cytological abnormalities: double-blind, randomised, controlled trial. 
• Diindolylmethane, a naturally occurring compound, induces CYP3A4 and MDR1 gene expression by activating human PXR.