Cellular response to cancer chemopreventive agents: contribution of the antioxidant responsive element to the adaptive response to oxidative and chemical stress

Cancer chemopreventive agents can act by inhibiting either the acquisition of mutations or the neoplastic processes that occur subsequent to mutagenesis. Compounds that reduce the rate at which mutations arise, referred to as blocking agents, exert their effects largely through their ability to induce the expression of antioxidant and detoxification proteins. This is achieved by the transcriptional activation of a small number of genes that are co-regulated through the presence of an antioxidant responsive element (ARE) in their promoters. Blocking agents can cause gene induction by producing oxidative and/or chemical stress within the cell and, as the inducible proteins act to ameliorate the metabolic insult, the process represents a form of adaptive response. The transcription factors which mediate this response through the ARE are members of the basic leucine zipper superfamily. The mechanism whereby cells sense and respond to the chemical signal(s) generated by chemopreventive blocking agents is discussed.