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 γ (PPARγ), and p-methoxyphenyl and p-phenyl compounds activate nerve growth factor-induced-Bα (NGFI-Bα, Nur77) orphan nuclear receptor. The effects of C-DIMs on PPARγ 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.

Introduction

The development of cancer is a complex process that is initiated by some form of DNA damage which ultimately can lead to tumor formation. The conversion of a damaged cell into a tumor requires a series of steps associated with tumor promotion and progression and, for many cancers, the initiation–promotion–progression pathways are accompanied by activating specific protooncogenes and inactivating mutations of tumor suppressor genes [1], [2]. Not surprisingly, many of these critical genes are involved in DNA repair and maintenance of DNA integrity, regulation of cell proliferation, and maintenance of cell survival and cell death pathways. Inherited genetic factors play an important role and can explain enhanced cancer susceptibility in only 5–15% of most cancers, whereas “environmental/lifestyle” or dietary factors are major determinants in cancer formation. With few exceptions, the precise contributions of environmental, lifestyle, dietary or other risk factors for cancer are not well-defined, although, it is generally considered that diets high in vegetables, fruit and fish products and low in red meats are generally protective. Nevertheless, the precise contributions of various food products as protective against or as risk factors for development of specific cancers is not well-defined.