Cancer chemotherapy with indole-3-carbinol, bis(3'-indolyl)methane and synthetic analogs

Abstract

Indole-3-carbinol (I3C) conjugates are phytochemicals expressed in brassica vegetables and have been associated with the anticancer activities of vegetable consumption. I3C and its metabolite bis(3'-indolyl)methane (DIM) induce overlapping and unique responses in multiple cancer cell lines and tumors, and these include growth inhibition, apoptosis and antiangiogenic activities. The mechanisms of these responses are complex and dependent on cell context. I3C and/or DIM activate or inactivate multiple nuclear receptors, induce endoplasmic reticulum stress, decrease mitochondrial membrane potential, and modulate multiple signaling pathways including kinases. DIM has been used as a template to synthesize a series of 1,1-bis(3'indolyl)-1-(substituted aromatic)methanes (i.e. C-DIMs) which are also cytotoxic to cancer cells and tumors. Some of the effects of C-DIMs resemble those reported for DIM analogs; however, structure-activity studies with the aromatic ring has resulted in generation of highly unique receptor agonists. For example, p-trifluoromethylphenyl, p-t-butylphenyl and p-biphenyl analogs activate peroxisome proliferator-activated receptor gamma (PPARgamma), and p-methoxyphenyl and p-phenyl compounds activate nerve growth factor-induced-Balpha (NGFI-Balpha, Nur77) orphan nuclear receptor. The effects of C-DIMs on PPARgamma and Nur77 coupled with their receptor-independent activities has resulted in the development of a novel group of multi-targeted anticancer drugs with excellent potential for clinical treatment of cancer.

Fig. 1

I3C undergoes acid-catalyzed rearrangement into multiple condensation products including DIM.

Fig. 2

I3C and DIM modulate multiple responses and genes in cancer cell lines through several pathways.

Fig. 3

Comparative effects of DIM and ring-substituted DIMs as inhibitors of carcinogen-induced rat mammary tumor growth in female Sprague–Dawley rats. Animals were treated with 1.0 mg/kg/d DIM or ring-substituted DIMs, and corn oil (100%) served as a vehicle control [77,107,108]. 5,5′-Dimethyl- DIM (5,5′-Me₂), 2,2′-dimethylDIM (2,2′-Me₂), 1,1′-dimethylDIM (1,1′-Me₂), 4,4-dichloroDIM (4,4′-Cl₂) and 5,5′-dibromoDIM (5,5′-Br₂) all significantly (p < 0.05) decreased tumor weights and volumes (*).

Fig. 4

PPARγ-active C-DIMs and their effects on cancer cells and tumors [–118].

Fig. 5

Nur77-active D-DIMs and their effects on cancer cells and tumors [119,120].