Attenuation of multi-targeted proliferation-linked signaling by 3,3′-diindolylmethane (DIM): From bench to clinic

Abstract

Emerging evidence provide credible support in favor of the potential role of bioactive products derived from ingesting cruciferous vegetables such as broccoli, brussel sprouts, cauliflower and cabbage. Among many compounds, 3,3′-Diindolylmethane (DIM) is generated in the acidic environment of the stomach following dimerization of Indole-3-Carbinol (I3C) monomers present in these classes of vegetables. Both I3C and DIM have been investigated for their use in preventing, inhibiting, and reversing the progression of cancer- as a chemopreventive agent. In this review, we summarize an updated, wide-ranging pleiotropic anti-tumor and biological effects elicited by DIM against tumor cells. It is unfeasible to point one single target as basis of cellular target of action of DIM. We emphasize key cellular and molecular events that are effectively modulated in the direction of inducing apoptosis and suppressing cell proliferation. Collectively, DIM orchestrates signaling through Ah receptor, NF-κB/Wnt/Akt/mTOR pathways impinging on cell cycle arrest, modulation of key cytochrome P450 enzymes, altering angiogenesis, invasion, metastasis and epigenetic behaviors of cancer cells. The ability of DIM to selectively induce tumor cells to undergo apoptosis has been observed in preclinical models, and thus it has been speculated in improving the therapeutic efficacy of other anticancer agents that have diverse molecular targets. Consequently, DIM has moved through preclinical development into phase-I clinical trials, thereby suggesting that DIM could be a promising and novel agent either alone or as an adjunct to conventional therapeutics such as chemo-radio therapy, and targeted therapies. An important development has been the availability of DIM formulation with superior bioavailability for humans. Therefore, DIM appears to be a promising chemopreventive agent or chemo-radio-sensitizer for the prevention of tumor recurrence and/or for the treatment of human malignancies.

Chemopreventive properties of 3,3′-diindolylmethane in breast cancer: evidence from experimental and human studies

“…87 Numerous mechanisms by which dietary exposure to these compounds may modulate breast cancer have been reported, including apoptosis, modulation of response to oxidative stress, estrogen metabolism, and cell cycle modulation, and other antiproliferative activities have been evaluated, largely in cell culture and animal studies. 24,30 The evidence for a protective role of DIM against breast cancer continues to grow, but additional research is needed to further identify and refine the mechanistic targets of this compound, particularly in humans. DIM is available to consumers in a generic crystalline formulation (low bioavailability) and in a microencapsulated form as BR-DIM (higher bioavailability).…”

“…More recently, a wide array of mechanisms of cancer-related bioactivity of DIM have been described, 30 including the specific efficacy of DIM in modulating carcinogenesis at all stages of breast tumor development, including initiation, promotion, and progression ( Figure 2). …”

“…32 Modulation of AhR by DIM treatment has also been shown to stimulate the Nrf2-mediated phase II response, which enhances excretion of genotoxins and induces a significant antioxidant response. 30,33 Through the activation of AhR and Nrf2 signaling pathways, DIM effectively increases detoxification and reduces inflammatory signaling, blocking what could otherwise be cancer-initiating events. Furthermore, modulation of AhR by DIM inhibited the growth of mammary gland cell cancer, an action suggested as a mechanism of crosstalk between estrogen receptor a and AhR.…”

Epigenetic Modifications of Nrf2 by 3,3′-diindolylmethane In Vitro in TRAMP C1 Cell Line and In Vivo TRAMP Prostate Tumors

“…Recently, our laboratory showed that curcumin, a potent anticancer agent against many cancers such as prostate cancer, suppresses DNA methyltransferases (DNMT) expression and modifies the histone deacetylases (HDAC) activity in human prostate LNCaP cells, which might contribute to DNA demethylation in promoter region of Nrf2 gene in TRAMP-C1 cells as well as Neurog1 gene in LNCaP cells (14,15). 3,3′-diindolylmethane (DIM), a compound derived from indole-3-carbinol (I3C), is found abundantly in cruciferous vegetables and its multi-target anticancer and cancer chemopreventive effects have been demonstrated in many in vivo and in vitro cancer models (16)(17)(18)(19). Currently, there are around ten clinical trials being conducted in early stage of prostate, breast, and cervical cancer patients for this compound (www.clinicaltrial.gov).…”

Ovarian cancer: Concept of pathogenesis and principles of therapy

“…К настоящему моменту всесторонне изучена и подробно описана мультитаргетная противоопухолевая активность I3C, DIM и EGCG в отношении опухолей различного происхождения [17][18][19], в том числе и РЯ [20][21][22], а так-же обнаружена способность DIM [23,24] и EGCG [25,26] …”