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.

Peroxisome proliferator-activated receptor γ in bladder cancer: A promising therapeutic target

“…102,103 Nonetheless, not all effects of C-DIMs are promoted by PPARγ activation, but instead, in other responses, the C-DIMs induce pro-apoptotic and growth inhibitory effects also in a PPARγ-independent manner. 107 Currently, combined therapy has become a breakthrough in treating cancer. In a range of tumor entities, such approach has produced impressive results.…”

The novel indole compound SK228 induces apoptosis and FAK/Paxillin disruption in tumor cell lines and inhibits growth of tumor graft in the nude mouse

“…I3C and its metabolites inhibited proliferation, cell cycle progression and cell survival and induced cell death in several cancer cell lines. 5 Synthetically developed indole compounds, for example, BPR0L075, caused G2/M arrest and apoptosis, 6 JKA97 has been shown to induce a p53-independent and Bax-dependent apoptosis in human colon cancer cells in vitro and in vivo. 7…”

“…I3C and its metabolites inhibited proliferation, cell cycle progression and cell survival and induced cell death in several cancer cell lines. 5 Synthetically developed indole compounds, for example, BPR0L075, caused G2/M arrest and apoptosis, 6 JKA97 has been shown to induce a p53-independent and Bax-dependent apoptosis in human colon cancer cells in vitro and in vivo. 7 We previously developed a novel 2-step synthesized indole compound, 1,1,3-tri(3-indolyl)cyclohexane (3-indole), which exhibits anticancer growth effect in human lung cancer cell lines (A549, H1299 and CL1-1).…”

New Green Synthesis and Antineoplastic Activity of Bis (3-Arylimidazolidinyl-1) Methanes

“…Of these, the most studied compounds are synthetic ring-substituted bis (3'-indolyl) methane (DIM) analogues [11,12]. Other compounds are characterized by the presence of two saturated 1,3-N,X-heterocycles connected by a methylene of general formula A for which antitumor activity has been described.…”