Signal transduction events elicited by natural products that function as cancer chemopreventive agents

Abstract

Cancer chemoprevention is a rapidly emerging paradigm for slowing, stopping or reversing the carcinogenic process. A multiplicity of biological mechanisms, functioning as complex interactions of gene products and regulatory pathways, are stimulated or inhibited by cancer chemopreventive agents. Several natural products and dietary components have been shown to function as chemopreventive agents. Screening chemical libraries of natural products for properties associated with cancer chemoprevention provides important insight into structural motifs driving rational design of more effective agents. In this review, the signal transduction pathways that are modulated by chemopreventive natural products are summarized. The activation of several signal transduction pathways triggered by polyphenolic antioxidants, flavonoids, retinoids, phytoestrogens and isothiocyanates are illustrated. These natural products may disrupt many signaling pathways, including transduction of cell surface (epidermal growth factor) or nuclear (estrogen) receptors via inhibition of their associated tyrosine kinase activities that regulate mitogenic signaling cascades (e.g., c-Raf-1). Alternatively, cytoprotective signal transduction pathways may be activated in a concentration- and time-dependent manner. The consequences of the modulation of signal transduction pathways by administration of these cancer chemopreventive compounds, singly or in combination, are the inhibition of cell cycle activating cascades and induction of cell survival/protection genes. Understanding the activation of signal transduction events elicited by various drugs and chemicals may yield insights into the regulation of the expression of genes coordinating cell proliferation, death, as well as, drug metabolizing and other cytoprotective enzymes. Monitoring the activation or inhibition of these pathways may serve as endpoints for rapid screening of effective cancer chemopreventive agents.