Natural dietary anti-cancer chemopreventive compounds: redox-mediated differential signaling mechanisms in cytoprotection of normal cells versus cytotoxicity in tumor cells

Abstract

Many dietary phytochemicals exhibit health-beneficial effects including prevention of diseases such as cancer, as well as neurological, cardiovascular, inflammatory, and metabolic diseases. Evolutionarily, herbivorous and omnivorous animals have been ingesting plants. This interaction between "animal-plant" ecosystems has resulted in an elaborate system of detoxification and defense mechanisms evolved by animals including humans. Mammalian cells, including human cells, respond to these dietary phytochemicals by "non-classical receptor sensing" mechanisms of electrophilic chemical-stress typified by "thiol-modulated" cellular signaling events primarily leading to the gene expression of pharmacologically beneficial effects, but sometimes unwanted cytotoxicity also. Our laboratory has been studying two groups of dietary phytochemical cancer-chemopreventive compounds (isothiocyanates and polyphenols), which are effective in chemical-induced, as well as genetically-induced, animal carcinogenesis models. These compounds typically generate "cellular stress" and modulate gene expression of phase II detoxifying/antioxidant enzymes. Electrophiles, reactive oxygen species, and reactive nitrogen species are known to act as second messengers in the modulation of many cellular signaling pathways leading to gene expression changes and pharmacological responses. Redox-sensitive transcription factors such as nuclear factor-E2-related factor 2 (Nrf2), AP-1, NF-kappaB, to cite a few examples, sense and transduce changes in the cellular redox status and modulate gene expression responses to oxidative and electrophilic stresses, presumably via sulfhydryl modification of critical cysteine residues found on these proteins and/or other upstream redox-sensitive molecular targets. In the current review, we will explore dietary cancer chemopreventive phytochemicals, discuss the link between oxidative/electrophilic stresses and the redox circuitry, and consider different redox-sensitive transcription factors. We will also discuss the kelch-like erythroid Cap'n'Collar homologue-associated protein 1 (Keap1)-Nrf2 axis in redox signaling of induction of phase II detoxifying/antioxidant defense mechanisms, an important target and preventive strategy for normal cells against carcinogenesis, and the converse inhibition of cell growth/inflammatory signaling pathways that would confer therapeutic intervention in many types of cancers. Finally, we will summarize the Nrf2 paradigm in gene expression, the pharmacotoxicogenomic relevance of redox-sensitive Nrf2, and the redox regulation of cell death mechanisms.