Antioxidants and oxidants regulated signal transduction pathways

Abstract

Many drugs and xenobiotics induce signal transduction events leading to gene expression of either pharmacologically beneficial effects, or unwanted side effects such as cytotoxicity which can compromise drug therapy. Using dietary chemopreventive compounds (isothiocyanates and green tea polyphenols), which are effective against various chemically-induced carcinogenesis models in animals studies, we studied the signal transduction events and gene expression profiles. These compounds have typically generated cellular “oxidative stress” and modulated gene expression including phase II detoxifying enzymes GST and QR as well as cellular defensive enzymes, heme oxygenase 1 (HO-1) and GSTvia the antioxidant/electrophile response element (ARE/EpRE). Members of the bZIP transcription factor, Nrf2 which heterodimerizes with Maf G/K, were found to bind to ARE, and transcriptionally activate ARE. Additionally the mitogen-activated protein kinases (MAPK; ERK, JNK and p38) were differentially activated by these compounds, and involved in the transcriptional activation of ARE-mediated reporter gene. Transfection studies with various cDNA encoding for wild-type of MAPK and Nrf2 showed synergistic response during co-transfection and to these agents. However, by increasing the concentrations of these xenobiotics, caspase activities and apoptosis were observed which were preceded by mitochondria damage and cytochrome c mitochondria release. Further, increased concentrations led to rapid cell necrosis. DNA microarray analyses were performed to ascertain the gene expression profiles elicited by these compounds at low concentrations as well as at higher concentrations. Thus, we have proposed a model, that at low concentrations, these compounds activate MAPK pathway leading to activation of Nrf2 and ARE with subsequent induction of phase II and other defensive genes which protect cells against toxic insults thereby enhancing cell survival, a beneficial homeostatic response. At higher concentrations, these agents activate the caspase pathways, leading to apoptosis, a potential cytotoxic effect if it occurred in normal cells. The studies of these signaling pathways may yield important insights into the pharmacodynamic and toxicodynamic effects of drugs and xenobiotics during pharmaceutical drug discovery and development.

Introduction

Components of natural and synthetic compounds are known to be potent in cancer chemopreventive properties, in chemically-induced carcinogenesis models. These cancer chemopreventive agents are very promising in that they offer a non-toxic route through intervention on processes of carcinogenesis. However, understanding the processes that lead to carcinogenesis requires a clear identification of molecular targets of cancer causing agents. This is fundamental in designing effective clinical cancer therapy programs. The lack of understanding of signal transduction events that are mobilized by molecular targets upon activation by the cancer causing agents, is a major impediment in designing cancer therapeutic and chemopreventive agents. In this review, we have characterized signal transduction events that are turned-on by two classes of potential cancer chemopreventive compounds, namely phenolic compounds/antioxidants and isothiocyanates. This review examines the potential utility of mitogen-activated protein kinases (MAPKs), the ICE/Ced-3 family proteases (caspases), and their modulation by these compounds in the decision process for cell life or death. The modulation of cellular survival signaling pathways vs. cell death pathways has significant biological consequences that are important in developing predictions on various pharmacological and toxicological responses.